Dendrimer formulations and uses thereof

Abstract

Provided herein are compositions comprising dendrimer conjugates and N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt solvate, or hydrate thereof. Also provided herein are compositions comprising dendrimer conjugates and caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further provided herein are compositions comprising dendrimer conjugates and capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Kits comprising the compositions, as well as methods and uses utilizing the compositions are also disclosed.

Description

DENDRIMER FORMULATIONSAND USES THEREOFRELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 637,545, filed April 23, 2024, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Advancements in the field of nanotechnology have resulted in the creation of many new materials and devices with a vast range of applications. Nanotechnology manifests in a wide range of materials and particles, such as fullerenes and dendrimers. However, in vivo application of these compounds can be challenged by their bioavailability and physical properties at physiological conditions and in plasma. Alternative strategies in dendrimer formulations could allow for more effective utilization of dendrimers in the context of therapeutic, diagnostic, and research applications.SUMMARY

[0003] Provided herein, in some aspects, are compositions comprising N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof (e.g., salcaprozate sodium, “SNAC”) and dendrimer conjugates with improved bioavailability. Provided herein, in some aspects, are compositions comprising caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof (e.g., sodium caprylate) and dendrimer conjugates with improved bioavailability. Provided herein, in some aspects, are compositions comprising capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof (e.g., sodium caprate) and dendrimer conjugates with improved bioavailability. The utility of the compositions in methods and kits are also disclosed herein.

[0004] In one aspect, provided herein are compositions comprising: a dendrimer conjugate, or a pharmaceutically acceptable salt thereof, where the dendrimer conjugate comprises a dendrimer conjugated to a therapeutic agent; and N-(8-[2-hydroxybenzoyl]amino)capiy'lic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0005] In one aspect, provided herein are compositions comprising: a dendrimer conjugate, or a pharmaceutically acceptable salt thereof, where the dendrimer conjugate comprises a dendrimer conjugated to a therapeutic agent; and caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0006] In one aspect, provided herein are compositions comprising: a dendrimer conjugate, or a pharmaceutically acceptable salt thereof, where the dendrimer conjugate comprises a dendrimer conjugated to a therapeutic agent; and capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0007] In another aspect, provided herein are kits comprising: a composition as disclosed herein, and instructions for using the composition.

[0008] In a further aspect, provided herein are m ethods of modulating a receptor tyrosine kinase in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition provided herein.

[0009] In one aspect, provided herein are methods of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition provided herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1 shows a statistical analysis of day 7 fluorescein angiography lesion area; ns = not significant, * --- p < 0.05,p <0.01.

[0011] FIG. 2 shows a statistical analysis of day 14 fluorescein angiography lesion area; ns = not significant, * = p< 0.05, **=p<Q .01.

[0012] FIG. 3 shows a statistical analysis of fluorescein angiography lesion area; ns = not significant, * = p< 0.05, ** = p <0.01.

[0013] FIG. 4 shows representative images from day 7 fluorescein angiography.

[0014] FIG. 5 shows representative images from day 14 fluorescein angiography.

[0015] FIG. 6 show's a statistical analysis of day 14 isolectin IB4 lesion area; ns:= not significant, ** =p<0.01, *** =p<0.001, **** =p<0.0001.

[0016] FIG. 7 shows a statistical analysis of day 14 isolectin IB4 lesion area; ns = not significant, ** = / ><0.01, *** = / ><0.001, **** =p<0.0001.

[0017] FIG. 8 show's a statistical analysis of day 14 isolectin IB4 lesion area; ** =p<0.01, ***» =p<Q.QQQ] ,

[0018] FIG. 9 shows a plasma exposure graph showing the plasma exposure levels of different oral formulations of D-4517.2 from rat plasma at different timepoints (0.5, 2, 4, 8 and 24-hours post injection).

[0019] FIGs. 10A-10D show7first generation CSF1 RTKi small molecule linkers and HDTs (D4 = generation 4 PAMAM hydroxyl dendrimers; D6 = generation 6 PAM AM hydroxyl dendrimers).

[0020] FIGs. 11A-11D show dasatinib linker and HDT compounds (D4 = generation 4 PAMAM hydroxyl dendrimers; D6 = generation 6 PAM AM hydroxyl dendrimers).

[0021] FIGs. 12A-12F show pexidartinib (or pexidartinib2) linker and HDT compounds (D4 = generation 4 PAMAM hydroxyl dendrimers; D6 = generation 6 PAMAM hydroxyl dendrimers).

[0022] FIGs. 13A-13C show third generation HDTs with CSF 1 RTKi (D4 = generation 4 PAMAM hydroxyl dendrimers; D6 = generation 6 PAMAM hydroxyl dendrimers).

[0023] FIGs. 14A-14I show7weight during mEAE development. The daily treatment with the test items was initiated on day 11. A significant difference in weight was observed in the Fingolimod and Dasatinib groups in comparison to the vehicle. There is a tendency of the higher weight of the H74DS3M8 - 4.4% Trehalose-Histidine 60 mg / kg i.p. group compared to the vehicle, however not statistically significant. Data is presented as SEM. * represents a p-value<0.05, ** represents a p-value<0.005. FIG. 14A shows weight graphs for Fingolimod 3 mg / kg p.o. compared to vehicle. FIG. 14B shows weight graphs for Dasatinib 30 mg / mL, p.o. compared to vehicle. FIG. 14C show's weight graphs for H74 / SNAC 20 mg / kg, p.o. compared to vehicle. FIG. 14D shows weight graphs for H74 / SNAC 60 mg / kg, p.o. compared to vehicle. FIG. 14E shows weight graphs for H74 / SNAC 200 mg / kg, p.o. compared to vehicle. FIG. 14F shows weight graphs for H74 / SNAC 400 mg / kg, p.o. compared to vehicle. FIG. 14G shows weight graphs for H74 / SNAC 580 mg / kg, p.o. compared to vehicle. FIG. 14H shows weight graphs for 74 / Trehalose Histidine 60 mg / kg, s.c. compared to vehicle. FIG. 141 shows weight graphs for H74 / Trehalose Histidine 60 mg / kg, i.p. compared to vehicle.

[0024] FIG. 15 shows EAE development in mice immunized with MOG35-55 in CFA receiving vehicle, H74DS3M8-SNAC (20, 60, 200, 400 and 580 mg / kg) p.o. twice a week from day 11. Fingolimod (3 mg / kg) and Dasatinib-Trehalose-Histidine (30mg / kg) daily p.o. treatment from day 11 . H74DS3M8-Trethalose-Histidine (60mg / kg) daily i.p. or twice a week s.c. from day 11. The termination was split in three sets, therefore the scores of all groups are presented until day 25. Asymptomatic animals were removed from the graph. The individual graphs of the score for each treatment are showm in FIGs. 16A-16I. Data is presented as SEM. Mixed-effects analysis with uncorrected Fisher’s LSD was used to compare disease severity scores between treatments versus vehicle. ** represents a p-value<0.01, *** represents a p-value<0.001, **** represents a p-value<0.0001.

[0025] FIGs. 16A-16I show EAE development in mice comparing individual treatment versus vehicle. The termination was split in three sets, therefore not all the groups wereterminated beyond 25 days. Data is presented as SEM. Statistical comparison with mixed- effect analysis with uncorrected Fisher’s LSD was performed for each day with significance or p-value annotated below each score. Statistical comparison was also performed for overall disease scores between treatments versus vehicle with mixed-effect analysis with uncorrected Fisher’s LSD. * represents a p-va!ue<0.05, ** represents a p-value<0.01, *** represents a p- value<0.001, ****represents a p-value<0.0001. FIG. 16A shows the results for Fingo p.o. 3 mg / kg QD versus vehicle. FIG. 16B shows the results for Dasat p.o. 30mg / kg QD versus vehicle. FIG. 16C shows the results for H74 p.o. 20mg / kg BIW versus vehicle. FIG. 16D shows the results for H74 p.o. 60mg / kg BIW versus vehicle. FIG. 16E shows the results for H74 p.o. 200mg / kg BIW versus vehicle. FIG. I6F shows the results for H74 p.o. 400mg / kg BIW versus vehicle. FIG. 16G shows the results for H74 p.o. 580mg / kg BIW versus vehicle. FIG. 16H shows the results for H74 s.c. 60mg / kg QD versus vehicle. FIG. 161 shows the results for H74 i.p. 60mg / kg QD versus vehicle.

[0026] FIGs. 17A-17B show the efficacy of oral H74DS3M8 in the EAE model. Eight-week- old female C57B1 / 6 mice were injected subcutaneously (s.c.) with MOG35-55 peptide emulsified in the Complete Freund’s Adjuvant (CFA) containing 6 mg / mL H37R (Mycobacterium tuberculosis) on day 0 at Redoxis, Sweden. Booster injections of pertussis toxin (PTX) were administered on day 0 (2hr post-MOG immunization) and again on day 2. On day I I, treatment was initiated with vehicle (daily p.o.), 3 mg / kg fmgolimod (daily p.o.) or 20 mg / kg H74DS3M8 SNAC (twice per week p.o.) and continued throughout the study. FIG. 17A shows disease severity scores were evaluated from day 5 until the end of the study. Treatment started on Day 11. FIG. 17B shows area under the curve (ALIC) of disease scores from study day 12 to day 25. Data are presented as mean + / - SEM and analyzed using a mixed-effects model (A) and one-way ANO VA (B). *p<0.05, **p<0.01, ****<0.0001.

[0027] FIGs. 18A-18B show serum level of H74DS3M8 at 4 hours post-dose on the final day of the study. H74DS3M8 concentrations were quantified with LC-MS (Alturas). Each group consisted of N=12-14 animals. An outlier value was removed from 20mg / kg p.o. group due to potential cross contamination. FIG. 18A shows serum concentration of H74DS3M8 following p.o., i.p. and s.c. administration. FIG. 18B shows the percentage of animals with detectable serum levels of H74DS3M8.

[0028] FIG. 19 shows a plasma exposure graph. Each formulation was dosed at 25 mg / kg to rats (4 animal s / group), orally in 9el size capsule. Plasma exposure levels of different oral formulations of D-4517.2 were analyzed from rat plasma at various timepoints (0.5-, 2-, 5-, 8- and 24-hours post injection).

[0029] FIG. 20 shows mean D-4517.2 concentrations over time for different formulations of a single oral dose of D-4517.2 in non-naive, fasted Beagle dogs.DEFINITIONS

[0030] Definitions of specific terms are described in more detail below. These and other exemplary terms are described in more detail in the Detailed Description, Examples, and Claims.

[0031] The term “about X,” where X is a number or percentage, refers to a number or percentage that is between 99.5% and 100.5%, between 99% and 101%, between 98% and 102%, between 97% and 103%, between 96% and 104%, between 95% and 105%, between 92% and 108%, or between 90% and 110%, inclusive, of X.

[0032] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example, “Ci-6 alkyl” encompasses, Ci, C2, C3, C4, C5, Ce, Ci-6, C1-5, Ci 4, C1 3, Ci 2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4.6, C4-5, and C5 6 alkyl.

[0033] The term “carbocyclyl” or “carbocyclic” refers to a radi cal of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”).Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C?,), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Ci), cyclooctenyl (CC),bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C$>), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 / 7-indenyl (C$>), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary' C3-8 carbocyclyl groups include the aforementioned Cri-io carbocyclyl groups as well as cycloundecyl (Cn), spiro[5.5]undecanyl (Cn), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C H ).. and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and, in some embodiments, are saturated or contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0034] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Unless otheiwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certainembodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C:::C double bonds in the carbocyclic ring system, as valency permits.

[0035] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits. In some embodiments, a heterocyclyl group is monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and, in some embodiments, is saturated or contains one or more carbon-carbon double or triple bonds. In some embodiments, heterocyclyl polycyclic ring systems include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7- membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0036] In some embodiments, a heterocyclyl group is a 5—10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom isindependently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0037] Exemplar}' 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5- dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6- membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary' 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing I heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary' bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, l,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6- dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H- thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3- b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2- c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0038] The term “aryl” refers to a radical of a monocyclic or polycyclic (e g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 n electrons shared in a cyclicarray) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“Cio and”; e.g., naphthyl such as 1 -naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“Cu aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the and ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “un substituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted Cv 14 aryl. In certain embodiments, the aryl group is a substituted Ce-i4 aryl.

[0039] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 % electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, in some embodiments the point of attachment is a carbon or nitrogen atom, as valency permits. In some embodiments, heteroaryl polycyclic ring systems include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more and groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment is on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6- membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl issubstituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. “Heterobiaryl” refers to an instance of two aryl rings being fused together, wherein at least one of the aryl rings is heteroaryl.

[0040] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5- 6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “un substituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0041] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5- membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary' 7- membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0042] The term “unsaturated bond” refers to a double or triple bond.

[0043] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0044] The term “saturated” or “fully saturated” refers to a moiety that does not contain a double or triple bond, e.g., the moiety only contains single bonds.

[0045] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0046] The term “dendrimer” refers to a compound having a molecular architecture with an interior core and layers (or “generations”) of repeating units which are attached to and extend from this interior core, each layer having one or more branching points, and the outermost generation having terminal functional groups. In some embodiments, terminal functional groups of a dendrimer include one or more hydroxyl groups, one or more amine groups, and / or one or more carboxyl groups. In some embodiments, the terminal functional groups of a dendrimer provide attachment sites through which the at least one agent is conjugated to form the dendrimer conjugate. In some embodiments, the at least one agent is conjugated to the dendrimer through an ether bond, an amide bond, or an ester bond formed by conjugation to a terminal functional group of the dendrimer. In some embodiments, the at least one agent is conjugated to the dendrimer through an ether bond or an amide bond. In some embodiments, the at least one agent is conjugated to the dendrimer through an ether bond.

[0047] The term “dendrimer conjugate” refers to a compound, specifically, a dendrimer that comprises at least one agent, such as an active agent, imaging agent, or therapeutic agent described herein. In some embodiments, the dendrimer is conjugated to the at least one agent through a covalent or non-covalent linkage.

[0048] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3--phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0049] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are w7ell known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, andperchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2 -hydroxy -ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(CI-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0050] The terms “CSFIR” and “colony stimulating factor 1 receptor” are used herein to refer to a cell-surface protein encoded by the human CSFIR gene. CSFI R is a tyrosine kinase transmembrane receptor and member of the CSF1 / PDGF receptor family of tyrosine-protein kinases. CSFIR is a receptor that can be activated by two ligands: colony stimulating factor 1 (CSF-1) and interleukin-34 (IL-34). CSFIR signaling is involved in the survival, proliferation, and differentiation of many myeloid cells. CSFIR signaling is involved in many diseases and is targeted in therapies for cancer, neurodegeneration, and inflammatory bone diseases.

[0051] The term “modulate,” “modulating,” “modulation,” or “modulator” refers to the ability of a compound to reduce / increase, slow / speed up, halt / initiate, inhibit / stimulate, or prevent / cause activity of a particular biological target (e.g., receptor tyrosine kinase (e.g., CSFIR)) in a cell relative to vehicle.

[0052] The term “inhibition,” “inhibiting,” “inhibit,” or “inhibitor” refer to the ability of a compound to reduce, slow, halt or prevent activity of a particular biological target (e.g., receptor tyrosine kinase (e g., CSFIR)) in a cell relative to vehicle. As used herein the term “inhibit” or “inhibition” in the context of, for example, a receptor tyrosine kinase (e g., CSFIR), refers to a reduction in the activity of a receptor tyrosine kinase (e.g., CSFIR). Insome embodiments, the term refers to a reduction of the level of activity, e.g., a receptor tyrosine kinase (e.g., CSF1R) activity, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of activity. In some embodiments, the term refers to a reduction of the level of activity, e.g., a receptor tyrosine kinase (e.g., CSF1R) activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of activity.

[0053] The terms “composition” and “formulation” are used interchangeably.

[0054] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non -human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease.

[0055] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.

[0056] The term “tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels, which is the object to which a compound, particle, and / or composition of the present disclosure is delivered. A target tissue may be an abnormal or unhealthy tissue, which may need to betreated. A target tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented. In certain embodiments, the target tissue is the liver. In certain embodiments, the target tissue is the lung. A“non-target tissue” is any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels, which is not a target tissue.

[0057] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.

[0058] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0059] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharm acokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0060] In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a receptor tyrosine kinase (e.g., CSF 1R) by at least about 10%, at least about 20%,at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a receptor tyrosine kinase (e.g., CSF1R) by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a receptor tyrosine kinase (e.g., CSF1R) by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0061] In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[0062] In certain embodiments, the compounds of the present disclosure are administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0063] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0064] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition . A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances thetherapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting a receptor tyrosine kinase (e.g., CSF1 R). In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease or disorder (e g., a neurological disorder, an inflammatory disease, an autoimmune disorder, a cancer, a central nervous system disease, a painful condition, a bone disease, or a tumor). In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting a receptor tyrosine kinase (e.g., CSF1R) and treating a disease or disorder (e.g., a neurological disorder, an inflammatory disease, an autoimmune disorder, a cancer, a central nervous system disease, a painful condition, a bone disease, or a tumor).

[0065] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0066] The terms “neurological disease” and “neurological disorder” are used interchangeably herein and refer to any disease of the nervous system, including diseases that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Neurodegenerative diseases refer to a type of neurological disease marked by the loss of nerve cells, including, but not limited to, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington’s disease.

[0067] Examples of neurological diseases and disorders include, but are not limited to, headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of peripheral nerves, muscle and neuromuscular junctions. Addiction and mental illness, include, but are not limited to, bipolar disorder and schizophrenia, are also included in the definition of neurological diseases. Further examples of neurological diseases include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers’ disease; alternating hemiplegia; Alzheimer’s disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet’s disease; Bell’s palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger’s disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury7; brain abscess; brain injury7; brain tumors (including glioblastoma multiforme); spinal tumor;Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie- Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorders; Cushing’s syndrome; cytomegalic inclusion body disease (CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsi er’s syndrome; Dejerine- Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb’s palsy; essential tremor; Fabry’s disease; Fahr’s syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich’s ataxia; frontotemporal dementia and other “tauopathies”; Gaucher’s disease; Gerstmann’s syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain -Barre syndrome; HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (see also neurological manifestations of AIDS); holoprosencephaly; Huntington’s disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile; phytanic acid storage disease; Infantile Refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsboume syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg- Welander disease; kuru; Lafora disease; Lambert- Eaton myasthenic syndrome; Landau-Kleffher syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh’s disease; Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lew body dementia; lissencephaly; locked-in syndrome; Lou Gehrig’s disease (aka motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; lyme disease-neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome;mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neurone disease; moyamoya disease; mucopolysaccharidoses; multi -infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O’Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson’s disease; paramyotonia congenita; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus- Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick’s disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type I and Type II); Rasmussen’s Encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye’s syndrome; Saint Vitus Dance; Sandhoff' disease; Schilder’s disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren’s syndrome; sleep apnea; Soto’s syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; stiff-person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy; sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; tic douloureux; Todd’s paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury'; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg’s syndrome; Werdnig-Hoffmandisease; West syndrome; whiplash; Williams syndrome; Wilson’s disease; and Zellweger syndrome.

[0068] Exemplary central nervous system (CNS) diseases and disorders include, but are not limited to, neurotoxicity and / or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, amyotrophic lateral sclerosis, Alzheimer’s disease, drug addiction, transient ischemic attack (TIA), subarachnoid hemorrhage, subdural hemorrhage and hematoma, extradural hemorrhage, meningitis, encephalitis, polio, epidural abscess, brain injury, Bell’s palsy, cervical spondylosis, carpal tunnel syndrome, brain tumor, spinal cord tumor, peripheral neuropathy, Charcot-Marie-Tooth disease type 1, Guillain-Barre syndrome, dizziness, neuralgia, Parkinson disease, multiple sclerosis, Huntington chorea. In certain embodiments, the CNS disorder is neurotoxicity and / or neurotrauma, e.g., for example, as a result of acute neuronal injury (e.g., traumatic brain injury (TBI), stroke, epilepsy) or a chronic neurodegenerative disorder (e.g., multiple sclerosis, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Alzheimer’s disease). In certain embodiments, the CNS disorder is a movement disorder, e.g., basal ganglia disorders, such as, for example, Parkinson’s disease, levodopa-induced dyskinesia, Huntington’s disease, Gilles de la Tourette’s syndrome, tardive dyskinesia, or dystonia.

[0069] The terms “inflammatory disease” and “inflammatory condition” are used interchangeably herein and refer to a disease or condition caused by, resulting from, or resulting in inflammation. Inflammatory diseases and conditions include those diseases, disorders or conditions that are characterized by signs of pain (dolor, from the generation of noxious substances and the stimulation of nerves), heat (calor, from vasodilatation), redness (rubor, from vasodilatation and increased blood flow), swelling (tumor, from excessive inflow or restricted outflow of fluid), and / or loss of function (functio laesa, which can be partial or complete, temporary or permanent. Inflammation takes on many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and / or ulcerative inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and / or T-lymphocytes leading to abnormal tissue damage and / or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes.Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus- graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation.

[0070] Additional exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu’s arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter’s arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions,atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus, Type II diabetes mellitus), a skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), endometriosis, Guillain-Barre syndrome, infection, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine headaches, tension headaches), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet’s syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g., Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, scleroderma, sarcoidosis, spondyloarthopathies, Sjogren’s syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scarring, burns, physical injury), vasculitis, vitiligo and Wegener’s granulomatosis. In certain embodiments, the inflammatory disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis and prostatitis. In certain embodiments, the inflammatory condition is an acute inflammatory condition (e.g., for example, inflammation resulting from infection). In certain embodiments, the inflammatory condition is a chronic inflammatory7condition (e.g., conditions resulting from asthma, arthritis and inflammatory bowel disease). The compounds may also be useful in treating inflammation associated with trauma and non-inflammatory myalgia. The compounds disclosed herein may also be useful in treating inflammation associated with cancer.

[0071] The terms “autoimmune disease” and “autoimmune disorder” are used interchangeably herein and refer to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In otherwords, the immune system mistakes some part of the body as a pathogen and attacks its owm cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g.. Goodpasture’s disease which may affect the basement membrane in both the lung and kidney). The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, , psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis, microscopic poly angiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, and cardiomyopathy.

[0072] The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See e.g., Stedmans’ Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma: colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemiasuch as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and nonHodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary7adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary7mucinous neoplasm (IPMN), Islet cell tumors); penilecancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC )); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary7thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e g., Paget’s disease of the vulva).

[0073] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary7benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destraction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary' or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. For example, a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.

[0074] A “painful condition” includes, but is not limited to, neuropathic pain (e.g., peripheral neuropathic pain), central pain, deafferentiation pain, chronic pain (e.g., chronic nociceptive pain, and other forms of chronic pain such as post - operative pain, e.g., pain arising after hip, knee, or other replacement surgery), pre-operative pain, stimulus of nociceptive receptors (nociceptive pain), acute pain (e.g., phantom and transient acute pain), noninflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, postoperative pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome, pain associated with premenstaial dysphoric disorder and / or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with pre-term labor, pain associated with withdrawal symptoms from drug addictionjoint pain, arthritic pain (e.g., pain associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis or Reiter’s arthritis), lumbosacral pain, musculo-skeletal pain, headache, migraine, muscle ache, lo-wer back pain, neck pain, toothache, dental / maxillofacial pain, visceral pain and the like. One or more of the painful conditions contemplated herein can comprise mixtures of various types of pain provided above and herein (e.g. nociceptive pain, inflammatory pain, neuropathic pain, etc}. In some embodiments, a particular pain can dominate. In other embodiments, the painful condition comprises two or more types of pains without one dominating. A skilled clinician can determine the dosage to achieve a therapeutically effective amount for a particular subject based on the painful condition.

[0075] In certain embodiments, the painful condition is neuropathic pain. The term "neuropathic pain" refers to pain resulting from injury to a nerve. Neuropathic pain is distinguished from nociceptive pain, which is the pain caused by acute tissue injury'- involving small cutaneous nerves or small nerves in muscle or connective tissue. Neuropathic pain typically is long-lasting or chronic and often develops days or months following an initial acute tissue injury. Neuropathic pain can involve persistent, spontaneous pain as well as allodynia, which is a painful response to a stimulus that normally is not painful. Neuropathic pain also can be characterized by hyperalgesia, in which there is an accentuated response to a painful stimulus that usually is trivial, such as a pin prick. Neuropathic pain conditions can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury- may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain conditions include, but are not limited to, diabetic neuropathy (e.g., peripheral diabetic neuropathy); sciatica; non-specific lower back pain; multiple sclerosis pain; carpal tunnel syndrome, fibromyalgia;HIV-related neuropathy; neuralgia (e.g., post-herpetic neuralgia, trigeminal neuralgia); pain resulting from physical trauma (e.g., amputation; surgery, invasive medical procedures, toxins, burns, infection), pain resulting from cancer or chemotherapy (e.g., chemotherapy- induced pain such as chemotherapy- induced peripheral neuropathy), and pain resulting from an inflammatory condition (e.g., a chronic inflammatory condition). Neuropathic pain can result from a peripheral nerve disorder such as neuroma; nerve compression; nerve crash, nerve stretch or incomplete nerve transection; mononeuropathy or polyneuropathy. Neuropathic pain can also result from a disorder such as dorsal root ganglion compression; inflammation of the spinal cord; contusion, tumor or hemisection of the spinal cord; tumors of the brainstem, thalamus or cortex; or trauma to the brainstem, thalamus or cortex.

[0076] The symptoms of neuropathic pain are heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain. In addition, there is pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia). In certain embodiments, the painful condition is non-inflammatory pain. The types of non-inflammatory pain include, without limitation, peripheral neuropathic pain (e.g., pain caused by a lesion or dysfunction in the peripheral nervous system), central pain (e.g., pain caused by a lesion or dysfunction of the central nervous system), deafferentation pain (e.g., pain due to loss of sensory input to the central nervous system), chronic nociceptive pain (e.g., certain types of cancer pain), noxious stimulus of nociceptive receptors (e.g., pain felt in response to tissue damage or impending tissue damage), phantom pain (e.g., pain felt in a part of the body that no longer exists, such as a limb that has been amputated), pain felt by psychiatric subjects (e.g., pain where no physical cause may exist), and wandering pain (e.g., wherein the pain repeatedly changes location in the body).

[0077] In certain embodiments, the painful condition is inflammatory pain. In certain embodiments, the painful condition (e.g., inflammatory pain) is associated with an inflammatory condition and / or an immune disorder.

[0078] The term “bone disease” refers to an injury, pain, or condition in the subject’s bones. Examples include, without limitation, achondroplasia, acromegaly, bone callus, bone demineralization, bone fracture, bone marrow disease, bone marrow neoplasm, dyskeratosiscongenita, leukemia (e.g., hairy cell leukemia, lymphocytic leukemia, myeloid leukemia, Philadelphia chromosome-positive leukemia, plasma cell leukemia, stem cell leukemia), systemic mastocytosis, myelodysplastic syndromes, paroxysmal nocturnal hemoglobinuria, myeloid sarcoma, myeloproliferative disorders, multiple myeloma, polycythemia vera, pearson marrow-pancreas syndrome, bone neoplasm, bone marrow neoplasm, Ewing sarcoma, osteochondroma, osteoclastoma, osteosarcoma, brachydactyly, Camurati- Engelmann syndrome, Craniosynostosis, Crouzon craniofacial dysostosis, dwarfism, achondroplasia, bloom syndrome, Cockayne syndrome, Ellis-van Creveld syndrome, Seckel syndrome, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, Werner syndrome, hyperostosis, osteophyte, Klippel-Trenaunay-Weber syndrome, Marfan syndrome, McCune-Albright syndrome, osteitis, osteoarthritis, osteochondritis, osteochondrodysplasia, Kashin-Beck disease, Leri -Weill dyschondrosteosis, osteochondrosis, osteodystrophy, osteogenesis imperfecta, osteolysis, Gorham-Stout syndrome, osteomalacia, osteomyelitis, osteonecrosis, osteopenia, osteopetrosis, osteoporosis, osteosclerosis, otospondylomegaepiphyseal dysplasia, pachydermoperiostosis, Paget disease of bone, Polydactyly, Meckel syndrome, rickets, Rothmund-Thomson syndrome, Sotos syndrome, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, syndactyly, Apert syndrome, syndactyly type II, and Werner syndrome.

[0079] In some aspects, the compositions provided herein comprise N-(8-[2- hydroxybenzoyl]amino)caprylic acid. N-(8-[2~hydroxybenzoyl]amino)caprylic acid has the following structure:. N-(8-[2- hydroxybenzoyl]amino)caprylic acid is also known as 8-[(2-hydroxybenzoyl)amino]octanoic acid, 8-(2-Hydroxybenzamido) octanoic acid, 8-(2-Hydroxybenzoylamino)octanoic acid, 8- [(2-hydroxy phenyl)formamido]octanoic acid, 8-(2-Hydroxybenzamido)octanoic acid, 8-(2- hydroxybenzoyl)aminooctanoic acid, and salcaprozic acid. In some embodiments, N-(8-[2- hydroxybenzoyl]amino)caprylic acid is in the form of a salt. In some embodiments, N-(8-[2- hydroxybenzoyl]amino)caprylic acid is a monosodium salt. In some embodiments, N-(8-[2- hydroxybenzoyl]amino)caprylic acid is in the form of SNAC, which is also known as salcaprozate sodium, sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, and sodium N-(8-[2-hydroxybenzoyl]amino)caprylate, and has the following structure:

[0080] In some aspects, the compositions provided herein comprise caprylic acid. Caprylic acid has the following structure:Caprylic acid is also known as caprylate, octanoic acid, and octanoate. In some embodiments, caprylic acid is in the form of a salt. In some embodiments, caprylic acid is a monosodium salt. In some embodiments, caprylic acid is in the form of sodium caprylate, which is also known as sodium octanoate, and has the following structure:.

[0081] In some aspects, the compositions provided herein comprise capric acid. Capric acidO has the following structure:Capric acid is also known as caprate, decanoic acid, and decanoate. In some embodiments, capric acid is in the form of a salt. In some embodiments, capric acid is a monosodium salt. In some embodiments, capric acid is in the form of sodium caprate, which is also known as sodium decanoate, and has the following structure:.DETAILED DESCRIPTION

[0082] The present disclosure provides compositions comprising dendrimer conjugates and N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and kit comprising and methods of using the compositions.Compositions

[0083] Among other aspects, provided herein are compositions comprising: a dendrimer conjugate, or a pharmaceutically acceptable salt thereof, where the dendrimer conjugate comprises a dendrimer conjugated to a therapeutic agent; and one or more excipients (e.g., N- (8-[2-hydroxybenzoyl]amino)capry'lic acid, caprylic acid, and / or capric acid). As described herein, the concentration of one or more components of a composition may be expressed in terms of a weight percentage. In some embodiments, the concentration of a component in acomposition is described by a percentage of weight by weight (w / w), which refers to the weight of the component expressed as a percentage of the total weight of the composition . By way of example, supposing 100 grams of a composition is made up of 20 grams of Component A and 80 grams of Component B, the concentrations could be expressed as 20% w / w and 80% w / w, respectively. In some embodiments, the concentration of a component in a composition is described by a percentage of weight by volume (w / v), which refers to the number of grains of the component per 100 milliliters of the composition. For example, supposing 100 mL of a composition is made up of 20 grams of Component A, the concentration could be expressed as 20% w / v (or, alternatively, 200 mg / niL).

[0084] In one aspect, provided herein are compositions comprising: a dendrimer conjugate, or a pharmaceutically acceptable salt thereof, where the dendrimer conjugate comprises a dendrimer conjugated to a therapeutic agent; and N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0085] In some embodiments, N-(8-[2-hydroxybenzoyl]amino)caprylic acid is a salt of N-(8- [2-hydroxybenzoyl]amino)caprylic acid. In certain embodiments, N-(8-[2- hydroxybenzoyl]amino)caprylic acid is a sodium salt or a potassium salt of N-(8-[2- hydroxybenzoyl]amino)caprylic acid. In some embodiments, N-(8-[2- hydroxybenzoyl]amino)caprylic acid is a sodium salt of N-(8-[2- hydroxybenzoyl]amino)caprylic acid. In certain embodiments, N-(8-[2- hydroxybenzoyl]amino)caprylic acid is a monosodium salt of N-(8-[2- hydroxybenzoyl]amino)caprylic acid (salcaprozate sodium, “SN AC”).

[0086] In some embodiments, the composition comprises a dendrimer conjugate, or a pharmaceutically acceptable salt thereof, in an amount from about 0. 1% to about 80% weight by weight (w / w). In some embodiments, the composition comprises from about 5% to about 25% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 10% to about 20% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 13% to about 17% w7w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 20% to about 40% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 25% to about 35% w / w of the dendri m er conjugate, or a pharm aceutically acceptable salt thereof. In some embodiments, the composition comprises from about 25% to about 60% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments,the composition comprises from about 30% to about 55% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 35% to about 45% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 10% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the composition comprises N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in an amount from about 1% to about 60% w / w. In some embodiments, the composition comprises from about 5% to about 25% w / w of N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 10% to about 20% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 13% to about 17% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 15% to about 45% w / w of N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 20% to about 40% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 25% to about 35% wz / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 28% to about 32% w / w of N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 30% to about 60% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 40% to about 50% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 42% to about 46% w / w of N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0088] In some embodiments, the composition is in the form of a solid or liquid.

[0089] In certain embodiments, the composition is formulated as a solid. In some embodiments, the composition is in the form of a capsule, tablet, pill, powder, or granule. In certain embodiments, the composition is in the form of a tablet or a capsule. In some embodiments, the capsule is a liquid capsule.

[0090] In some embodiments, the composition comprises: from about 5% to about 25%, from about 10% to about 20%, from about 13% to about 17%, from about 20% to about 40%, from about 25% to about 35%, from about 25% to about 60%, from about 30% to about 55%, from about 35% to about 45%, or from about 10% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 5% to about 25%, from about 10% to about 20%, from about 13% to about 17%, from about 15% to about 45%, from about 20% to about 40%, from about 25% to about 35%, from about 28% to about 32%, from about 30% to about 60%, from about 40% to about 50%, or from about 42% to about 46% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0091] In certain embodiments, the composition comprises: from about 25% to about 60%, from about 30% to about 55%, or from about 35% to about 45% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 5% to about 25%, from about 10% to about 20%, or from about 13% to about 17% w / w of N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0092] In some embodiments, the composition comprises: from about 10% to about 50%, from about 20% to about 40%, or from about 25% to about 35% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 15% to about 45%, from about 20% to about 40%, from about 25% to about 35%, or from about 28% to about 32% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0093] In some embodiments, the composition comprises: from about 5% to about 25%, from about 10% to about 20%, or from about 13% to about 17% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 30% to about 60%, from about 40% to about 50%, or from about 42% to about 46% w / w of N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0094] In some embodiments, the composition comprises: from about 2% to about 20% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about20% to about 40% w / w of N-(8-[2-hydroxybenzoyl]amino)capiylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 5% to about 20% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 25% to about 35% w / w of N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 2% to about 6% w / w of the dendrim er conjugate, or a pharmaceutical ly acceptabl e salt thereof; and from about 28% to about 32% w / w of N-(8-[2-hydroxybenzoyl]amino)capiylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0095] In some embodiments, the composition further comprises an adsorbent. In certain embodiments, the composition comprises from about 25% to about 55%, from about 30% to about 50%, or from about 35% to about 45% w / w of the adsorbent. In certain embodiments, the composition comprises from about 25% to about 55% w / w of the adsorbent. In certain embodiments, the composition comprises from about 30% to about 50% w / w of the adsorbent. In certain embodiments, the composition comprises from about 35% to about 45% w / w of the adsorbent. In certain embodiments, the adsorbent is PROSOLV® 730, ABISORB- DC™, microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), silicon dioxide, or a combination thereof. In some embodiments, the absorbent is a mixture of microcrystalline cellulose, silicon dioxide, and copovidone.

[0096] In some embodiments, the composition comprises: from about 10% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 10% to about 50% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 20% to about 60% w / w of an adsorbent.

[0097] In some embodiments, the composition comprises: from about 1% to about 20% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 20% to about 40% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent. In some embodiments, the composition comprises: from about 2% to about 10% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 25% to about 35% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent. In some embodiments, the composition comprises: from about 2% to about 8% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof;from about 27% to about 32% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent.

[0098] In some embodiments, the composition comprises: from about 40% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 10% to about 20% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent. In some embodiments, the composition comprises: from about 42% to about 46% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 12% to about 16% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent.

[0099] In some embodiments, the composition comprises: from about 25% to about 35% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 25% to about 35% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent. In some embodiments, the composition comprises: from about 27% to about 32% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 27% to about 32% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent.

[0100] In some embodiments, the composition comprises: from about 10% to about 20% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 40% to about 50% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent. In some embodiments, the composition comprises: from about 12% to about 16% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 42% to about 46% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent.

[0101] In some embodiments, the composition does not comprise an adsorbent. For example, in some embodiments, the composition comprises: from about 0.1% to about 10% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and at least 90% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptablesalt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 0.5% to about 8% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and at least 92% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 1% to about 5% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and at least 95% w / w of N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0102] In certain embodiments, the composition comprises: from about 10% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 10% to about 50% w / w of SNAC; and from about 20% to about 60% w / w of a mixture of microcry stall ine cellulose, silicon dioxide, and copovidone.

[0103] In some embodiments, the composition comprises: from about 40% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 10% to about 20% w / w of SNAC; and from about 35% to about 45% w / w of a mixture of microcrystalline cellulose, silicon dioxide, and copovidone.

[0104] In certain embodiments, the composition comprises: from about 25% to about 35% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 25% to about 35 w / w of SNAC; and from about 35% to about 45% w / w of a mixture of microcrystalline cellulose, silicon dioxide, and copovidone.

[0105] In some embodiments, the composition comprises: from about 10% to about 20% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 35% to about 45% w / w of SNAC; and from about 35% to about 45% w / w of a mixture of microcrystalline cellulose, silicon dioxide, and copovidone.

[0106] In some embodiments, the composition is formulated as a liquid. In some embodiments, the composition is in the form of an emulsion, microemulsion, solution, or suspension. In certain embodiments, the composition is in the form of a solution or a suspension.

[0107] In some embodiments, the composition comprises from about 0.001% to about 0.5%, from about 0.01% to about 0.09%, from about 0.01% to about 1%, from about 0.01% to about 5%, from about 0.02% to about 0.06%, from about 0.05% to about 0.7%, from about 0.1% to about 0.3%, from about 0. 1% to about 4%, or from about 1% to about 3% weight by volume (w / v) of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.001% to about 0.5% w / v of thedendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.01% to about 0.09% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.01% to about 1% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.01% to about 5% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.02% to about 0.06% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.05% to about 0.7% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.1% to about 0.3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.1% to about 4% w7v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 1% to about 3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof.

[0108] In certain embodiments, the composition comprises from about 1% to about 10%, from about 2% to about 8%, from about 3% to about 9%, from about 5% to about 7%, or from about 3% to about 7% w / v of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises from about 1% to about 10% w / v of N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises from about 2% to about 8% w / v of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises from about 3% to about 9% w / v of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises from about 5% to about 7% w / v of N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises from about 3% to about 7% w / v of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0109] In some embodiments, the composition comprises: from about 0.001% to about 0.5%, from about 0.01% to about 0.09%, from about 0.01% to about 1%, from about 0.01% toabout 5%, from about 0.02% to about 0.06%, from about 0.05% to about 0.7%, from about 0.1% to about 0.3%, from about 0.1% to about 4%, or from about 1% to about 3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 10%, from about 2% to about 8%, from about 3% to about 9%, from about 5% to about 7%, or from about 3% to about 7% w / v of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0110] In certain embodiments, the composition comprises: from about 0.001% to about 0.5%, from about 0.01% to about 0.09%, or from about 0.02% to about 0.06% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 10%, from about 3% to about 9%, or from about 5% to about 7% w / v of N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0111] In some embodiments, the composition comprises: from about 0.01% to about 1%, from about 0.05% to about 0.7%, or from about 0. 1% to about 0.3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 10%, from about 3% to about 9%, or from about 5% to about 7% w / v of N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0112] In certain embodiments, the composition comprises: from about 0.01% to about 5%, from about 0.1% to about 4%, or from about 1% to about 3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 10%, from about 2% to about 8%, or from about 3% to about 7% w / v of N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0113] In some embodiments, the composition comprises: from about 0.01% to about 1% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 30% w / v of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 0.02% to about 0.8% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 15% w / v of N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 0.02% to about 0.8% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof;and from about 15% to about 30% w / v of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0114] In some embodiments, the composition comprises: from about 0.1% to about 10% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 0.1% to about 10% w / v of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 0. 1% to about 8% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 0.1% to about 6% w / v of N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 1% to about 8% w / V of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 0.1% to about 5% w / v of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0115] In certain embodiments, the composition comprises: from about 0.1% to about 3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 2% to about 10% w / v of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises: from about 0.2% to about 2.5% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 2.5% to about 7.5% w / v of N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises: from about 2% to about 6% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 0.1% to about 5% w / v of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0116] In some embodiments, the composition comprises: from about 0.01% to about 5% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 1% to about 10% w / v of N-(8-[2-hydroxybenzoyl]amino)capiydic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 85% to about 99% w / v of water.

[0117] In certain embodiments, the composition comprises: from about 0.01% to about 2% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 1% to about 10% w / v of SNAC; and from about 89% to about 99% w / v of water.

[0118] In one aspect, provided herein are compositions comprising: a dendrimer conjugate, or a pharmaceutically acceptable salt thereof, where the dendrimer conjugate comprises adendrimer conjugated to a therapeutic agent; and caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0119] In some embodiments, caprylic acid is a salt of caprylic acid. In certain embodiments, caprylic acid is a sodium salt or a potassium salt of caprylic acid. In some embodiments, caprylic acid is a sodium salt of caprylic acid. In certain embodiments, caprylic acid is a monosodium salt of caprylic acid (sodium caprylate).

[0120] In some embodiments, the composition comprises a dendrimer conjugate, or a pharmaceutically acceptable salt thereof, in an amount from about 0.1% to about 80% weight by weight (w / w). In some embodiments, the composition comprises from about 5% to about 25% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 10% to about 20% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 13% to about 17% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 20% to about 40% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 25% to about 35% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 25% to about 60% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 30% to about 55% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 35% to about 45% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition compri ses from about 10% to about 50% wAv of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the composition comprises caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in an amount from about 1% to about 60% w / w. In some embodiments, the composition comprises from about 5% to about 25% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 10% to about 20% w / w7of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 13% to about 17% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 15% to about 45% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, thecomposition comprises from about 20% to about 40% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 25% to about 35% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 28% to about 32% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 30% to about 60% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 40% to about 50% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 42% to about 46% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0122] In some embodiments, the composition is in the form of a solid or liquid.

[0123] In certain embodiments, the composition is formulated as a solid. In some embodiments, the composition is in the form of a capsule, tablet, pill, powder, or granule. In certain embodiments, the composition is in the form of a tablet or a capsule. In some embodiments, the capsule is a liquid capsule.

[0124] In some embodiments, the composition comprises: from about 5% to about 25%, from about 10% to about 20%, from about 13% to about 17%, from about 20% to about 40%, from about 25% to about 35%, from about 25% to about 60%, from about 30% to about 55%, from about 35% to about 45%, or from about 10% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 5% to about 25%, from about 10% to about 20%, from about 13% to about 17%, from about 15% to about 45%, from about 20% to about 40%, from about 25% to about 35%, from about 28% to about 32%, from about 30% to about 60%, from about 40% to about 50%, or from about 42% to about 46% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0125] In certain embodiments, the composition comprises: from about 25% to about 60%, from about 30% to about 55%, or from about 35% to about 45% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 5% to about 25%, from about 10% to about 20%, or from about 13% to about 17% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0126] In some embodiments, the composition comprises: from about 10% to about 50%, from about 20% to about 40%, or from about 25% to about 35% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 15% to about 45%,from about 20% to about 40%, from about 25% to about 35%, or from about 28% to about 32% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0127] In some embodiments, the composition comprises: from about 5% to about 25%, from about 10% to about 20%, or from about 13% to about 17% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 30% to about 60%, from about 40% to about 50%, or from about 42% to about 46% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0128] In some embodiments, the composition comprises: from about 2% to about 20% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 20% to about 40% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 5% to about 20% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 25% to about 35% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 2% to about 6% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 28% to about 32% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0129] In some embodiments, the composition further comprises an adsorbent. In certain embodiments, the composition comprises from about 25% to about 55%, from about 30% to about 50%, or from about 35% to about 45% w / w of the adsorbent. In certain embodiments, the composition comprises from about 25% to about 55% w / w of the adsorbent. In certain embodiments, the composition comprises from about 30% to about 50% w / w of the adsorbent. In certain embodiments, the composition comprises from about 35% to about 45% w / w of the adsorbent. In certain embodiments, the adsorbent is PROSOLV® 730, ABISORB- DC™, microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), silicon dioxide, or a combination thereof. In some embodiments, the absorbent is a mixture of microcrystalline cellulose, silicon dioxide, and copovidone.

[0130] In some embodiments, the composition comprises: from about 10% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 10% to about 50% wz / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 20% to about 60% w / w of an adsorbent.

[0131] In some embodiments, the composition comprises: from about 1% to about 20% w7w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 20% to about 40% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydratethereof; and from about 35% to about 45% w / w of an adsorbent. In some embodiments, the composition comprises: from about 2% to about 10% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 25% to about 35% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent. In some embodiments, the composition comprises: from about 2% to about 8% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 27% to about 32% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent.

[0132] In some embodiments, the composition comprises: from about 40% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 10% to about 20% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent. In some embodiments, the composition comprises: from about 42% to about 46% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 12% to about 16% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent.

[0133] In some embodiments, the composition comprises: from about 25% to about 35% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 25% to about 35% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent. In some embodiments, the composition comprises: from about 27% to about 32% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 27% to about 32% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent.

[0134] In some embodiments, the composition comprises: from about 10% to about 20% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 40% to about 50% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent. In some embodiments, the composition comprises: from about 12% to about 16% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 42% to about 46% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent.

[0135] In some embodiments, the composition does not comprise an adsorbent. For example, in some embodiments, the composition comprises: from about 0.1% to about 10%w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and at least 90% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 0.5% to about 8% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and at least 92% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 1% to about 5% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and at least 95% w / w of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0136] In certain embodiments, the composition comprises: from about 10% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 10% to about 50% w / w of sodium caprylate; and from about 20% to about 60% w / w of a mixture of microcrystalline cellulose, silicon dioxide, and copovidone.

[0137] In some embodiments, the composition comprises: from about 40% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 10% to about 20% w / w of sodium caprylate; and from about 35% to about 45% w / w of a mixture of microcrystalline cellulose, silicon dioxide, and copovidone.

[0138] In certain embodiments, the composition comprises: from about 25% to about 35% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 25% to about 35 w / w of sodium caprylate; and from about 35% to about 45% w / w of a mixture of microcrystalline cellulose, silicon dioxide, and copovidone.

[0139] In some embodiments, the composition comprises: from about 10% to about 20% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 35% to about 45% w / w of sodium caprylate; and from about 35% to about 45% w / w of a mixture of microcrystalline cellulose, silicon dioxide, and copovidone.

[0140] In some embodiments, the composition is formulated as a liquid. In some embodiments, the composition is in the form of an emulsion, microemulsion, solution, or suspension. In certain embodiments, the composition is in the form of a solution or a suspension.

[0141] In some embodiments, the composition comprises from about 0.001% to about 0.5%, from about 0.01% to about 0.09%, from about 0.01% to about 1%, from about 0.01% to about 5%, from about 0.02% to about 0.06%, from about 0.05% to about 0.7%, from about 0.1% to about 0.3%, from about 0. 1% to about 4%, or from about 1% to about 3% weight by volume (w / v) of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.001% to about 0.5% w / v of thedendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.01% to about 0.09% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.01% to about 1% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.01% to about 5% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.02% to about 0.06% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.05% to about 0.7% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.1% to about 0.3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.1% to about 4% w7v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 1% to about 3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof.

[0142] In certain embodiments, the composition comprises from about 1% to about 10%, from about 2% to about 8%, from about 3% to about 9%, from about 5% to about 7%, or from about 3% to about 7% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises from about 1% to about 10% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises from about 2% to about 8% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises from about 3% to about 9% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises from about 5% to about 7% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises from about 3% to about 7% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0143] In some embodiments, the composition comprises: from about 0.001% to about 0.5%, from about 0.01% to about 0.09%, from about 0.01% to about 1%, from about 0.01% to about 5%, from about 0.02% to about 0.06%, from about 0.05% to about 0.7%, from about 0.1% to about 0.3%, from about 0.1% to about 4%, or from about 1% to about 3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% toabout 10%, from about 2% to about 8%, from about 3% to about 9%, from about 5% to about 7%, or from about 3% to about 7% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof

[0144] In certain embodiments, the composition comprises: from about 0.001% to about 0.5%, from about 0.01% to about 0.09%, or from about 0.02% to about 0.06% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 10%, from about 3% to about 9%, or from about 5% to about 7% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0145] In some embodiments, the composition comprises: from about 0.01% to about 1%, from about 0.05% to about 0.7%, or from about 0.1% to about 0.3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 10%, from about 3% to about 9%, or from about 5% to about 7% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0146] In certain embodiments, the composition comprises: from about 0.01% to about 5%, from about 0.1% to about 4%, or from about 1% to about 3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 10%, from about 2% to about 8%, or from about 3% to about 7% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof

[0147] In some embodiments, the composition comprises: from about 0.01% to about 1% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 30% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 0.02% to about 0.8% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 15% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 0.02% to about 0.8% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 15% to about 30% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0148] In some embodiments, the composition comprises: from about 0.1% to about 10% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 0.1% to about 10% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof In some embodiments, the composition comprises: from about 0. 1% to about 8% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 0.1% to about 6% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate,or hydrate thereof. In some embodiments, the composition comprises: from about 1% to about 8% w / v of the dendrimer conjugate, or a pharm aceutically acceptabl e salt thereof; and from about 0.1% to about 5% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0149] In certain embodiments, the composition comprises: from about 0.1% to about 3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 2% to about 10% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises: from about 0.2% to about 2.5% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 2.5% to about 7.5% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises: from about 2% to about 6% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 0.1% to about 5% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof

[0150] In some embodiments, the composition comprises: from about 0.01% to about 5% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 1% to about 10% w / v of caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 85% to about 99% w / v of water.

[0151] In certain embodiments, the composition comprises: from about 0.01% to about 2% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 1% to about 10% w / v of sodium caprylate; and from about 89% to about 99% w / v of water.

[0152] In one aspect, provided herein are compositions comprising: a dendrimer conjugate, or a pharmaceutically acceptable salt thereof, where the dendrimer conjugate comprises a dendrimer conjugated to a therapeutic agent; and capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0153] In some embodiments, capric acid is a salt of capric acid. In certain embodiments, capric acid is a sodium salt or a potassium salt of capric acid. In some embodiments, capric acid is a sodium salt of capric acid. In certain embodiments, capric acid is a monosodium salt of capric acid (sodium caprate).

[0154] In some embodiments, the composition comprises a dendrimer conjugate, or a pharmaceutically acceptable salt thereof, in an amount from about 0.1% to about 80% weight by weight (w / w). In some embodiments, the composition comprises from about 5% to about 25% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 10% to about 20% w / w of thedendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 13% to about 17% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 20% to about 40% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 25% to about 35% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 25% to about 60% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 30% to about 55% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 35% to about 45% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 10% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, the composition comprises capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in an amount from about 1% to about 60% w / w7. In some embodiments, the composition comprises from about 5% to about 25% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 10% to about 20% wAv of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 13% to about 17% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 15% to about 45% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 20% to about 40% w / w7of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 25% to about 35% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 28% to about 32% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 30% to about 60% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises from about 40% to about 50% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, thecomposition comprises from about 42% to about 46% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0156] In some embodiments, the composition is in the form of a solid or liquid.

[0157] In certain embodiments, the composition is formulated as a solid. In some embodiments, the composition is in the form of a capsule, tablet, pill, powder, or granule. In certain embodiments, the composition is in the form of a tablet or a capsule. In some embodiments, the capsule is a liquid capsule.

[0158] In some embodiments, the composition comprises: from about 5% to about 25%, from about 10% to about 20%, from about 13% to about 17%, from about 20% to about 40%, from about 25% to about 35%, from about 25% to about 60%, from about 30% to about 55%, from about 35% to about 45%, or from about 10% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 5% to about 25%, from about 10% to about 20%, from about 13% to about 17%, from about 15% to about 45%, from about 20% to about 40%, from about 25% to about 35%, from about 28% to about 32%, from about 30% to about 60%, from about 40% to about 50%, or from about 42% to about 46% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0159] In certain embodiments, the composition comprises: from about 25% to about 60%, from about 30% to about 55%, or from about 35% to about 45% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 5% to about 25%, from about 10% to about 20%, or from about 13% to about 17% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0160] In some embodiments, the composition comprises: from about 10% to about 50%, from about 20% to about 40%, or from about 25% to about 35% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 15% to about 45%, from about 20% to about 40%, from about 25% to about 35%, or from about 28% to about 32% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0161] In some embodiments, the composition comprises: from about 5% to about 25%, from about 10% to about 20%, or from about 13% to about 17% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 30% to about 60%, from about 40% to about 50%, or from about 42% to about 46% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0162] In some embodiments, the composition comprises: from about 2% to about 20% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 20% to about 40% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, orhydrate thereof. In some embodiments, the composition comprises: from about 5% to about 20% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 25% to about 35% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 2% to about 6% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 28% to about 32% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0163] In some embodiments, the composition further comprises an adsorbent. In certain embodiments, the composition comprises from about 25% to about 55%, from about 30% to about 50%, or from about 35% to about 45% w / w of the adsorbent. In certain embodiments, the composition comprises from about 25% to about 55% w / w of the adsorbent. In certain embodiments, the composition comprises from about 30% to about 50% w / w of the adsorbent. In certain embodiments, the composition comprises from about 35% to about 45% w / w of the adsorbent. In certain embodiments, the adsorbent is PROSOLV® 730, ABISORB- DC™, microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), silicon dioxide, or a combination thereof. In some embodiments, the absorbent is a mixture of microcrystalline cellulose, silicon dioxide, and copovidone.

[0164] In some embodiments, the composition comprises: from about 10% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 10% to about 50% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 20% to about 60% w / w of an adsorbent.

[0165] In some embodiments, the composition comprises: from about 1% to about 20% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 20% to about 40% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent. In some embodiments, the composition comprises: from about 2% to about 10% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 25% to about 35% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent. In some embodiments, the composition comprises: from about 2% to about 8% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 27% to about 32% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent.

[0166] In some embodiments, the composition comprises: from about 40% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about10% to about 20% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent. In some embodiments, the composition comprises: from about 42% to about 46% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 12% to about 16% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent.

[0167] In some embodiments, the composition comprises: from about 25% to about 35% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 25% to about 35% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent. In some embodiments, the composition comprises: from about 27% to about 32% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 27% to about 32% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent.

[0168] In some embodiments, the composition comprises: from about 10% to about 20% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 40% to about 50% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent. In some embodiments, the composition comprises: from about 12% to about 16% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 42% to about 46% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 35% to about 45% w / w of an adsorbent.

[0169] In some embodiments, the composition does not comprise an adsorbent. For example, in some embodiments, the composition comprises: from about 0.1% to about 10% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and at least 90% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 0.5% to about 8% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and at least 92% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 1% to about 5% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and at least 95% w / w of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0170] In certain embodiments, the composition comprises: from about 10% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about10% to about 50% w / w of sodium caprate; and from about 20% to about 60% w / w of a mixture of microcrystalline cellulose, silicon dioxide, and copovidone.

[0171] In some embodiments, the composition comprises: from about 40% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 10% to about 20% w / w of sodium caprate; and from about 35% to about 45% w / w of a mixture of microcrystalline cellulose, silicon dioxide, and copovidone.

[0172] In certain embodiments, the composition comprises: from about 25% to about 35% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 25% to about 35 w / w of sodium caprate; and from about 35% to about 45% w / w of a mixture of microcrystalline cellulose, silicon dioxide, and copovidone.

[0173] In some embodiments, the composition comprises: from about 10% to about 20% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 35% to about 45% w / w of sodium caprate; and from about 35% to about 45% w / w of a mixture of microcrystalline cellulose, silicon dioxide, and copovidone.

[0174] In some embodiments, the composition is formulated as a liquid. In some embodiments, the composition is in the form of an emulsion, microemulsion, solution, or suspension. In certain embodiments, the composition is in the form of a solution or a suspension.

[0175] In some embodiments, the composition comprises from about 0.001% to about 0.5%, from about 0.01% to about 0.09%, from about 0.01% to about 1%, from about 0.01% to about 5%, from about 0.02% to about 0.06%, from about 0.05% to about 0.7%, from about 0.1% to about 0.3%, from about 0.1% to about 4%, or from about 1% to about 3% weight by volume (w / v) of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.001% to about 0.5% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.01% to about 0.09% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.01% to about 1% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.01% to about 5% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.02% to about 0.06% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.05% to about 0.7% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In someembodiments, the composition comprises from about 0.1% to about 0.3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 0.1% to about 4% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 1% to about 3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof.

[0176] In certain embodiments, the composition compri ses from about 1% to about 10%, from about 2% to about 8%, from about 3% to about 9%, from about 5% to about 7%, or from about 3% to about 7% w / v of capric acid, or a pharmaceutically acceptable salt, sol vate, or hydrate thereof. In certain embodiments, the composition comprises from about 1% to about 10% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises from about 2% to about 8% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises from about 3% to about 9% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises from about 5% to about 7% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises from about 3% to about 7% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0177] In some embodiments, the composition comprises: from about 0.001% to about 0.5%, from about 0.01% to about 0.09%, from about 0.01% to about 1%, from about 0.01% to about 5%, from about 0.02% to about 0.06%, from about 0.05% to about 0.7%, from about 0.1% to about 0.3%, from about 0. 1% to about 4%, or from about 1% to about 3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 10%, from about 2% to about 8%, from about 3% to about 9%, from about 5% to about 7%, or from about 3% to about 7% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0178] In certain embodiments, the composition comprises: from about 0.001% to about 0.5%, from about 0.01% to about 0.09%, or from about 0.02% to about 0.06% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 10%, from about 3% to about 9%, or from about 5% to about 7% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0179] In some embodiments, the composition comprises: from about 0.01% to about 1%, from about 0.05% to about 0.7%, or from about 0.1% to about 0.3% w / v of the dendrimerconjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 10%, from about 3% to about 9%, or from about 5% to about 7% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0180] In certain embodiments, the composition comprises: from about 0.01% to about 5%, from about 0.1% to about 4%, or from about 1% to about 3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 10%, from about 2% to about 8%, or from about 3% to about 7% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0181] In some embodiments, the composition comprises: from about 0.01% to about 1% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 30% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 0.02% to about 0.8% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 15% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 0.02% to about 0.8% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 15% to about 30% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0182] In some embodiments, the composition comprises: from about 0.1% to about 10% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 0.1% to about 10% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 0.1% to about 8% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 0.1% to about 6% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the composition comprises: from about 1% to about 8% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 0.1% to about 5% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0183] In certain embodiments, the composition comprises: from about 0.1% to about 3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 2% to about 10% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the composition comprises: from about 0.2% to about 2.5% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 2.5% to about 7.5% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, orhydrate thereof. In certain embodiments, the composition comprises: from about 2% to about 6% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 0.1% to about 5% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0184] In some embodiments, the composition comprises: from about 0.01% to about 5% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 1% to about 10% w / v of capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 85% to about 99% w / v of water.

[0185] In certain embodiments, the composition comprises: from about 0.01% to about 2% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 1% to about 10% w / v of sodium caprate; and from about 89% to about 99% w / v of water.Dendrimer Conjugates

[0186] In some aspects, the compositions provided herein comprise a dendrimer conjugate, or a pharmaceutically acceptable salt thereof, where the dendrimer conjugate comprises a dendrimer conjugated to a therapeutic agent.

[0187] In some embodiments, the dendrimer comprises a plurality of terminal hydroxyl groups, where one or more hydroxyl groups are optionally substituted. In some embodiments, the substituent (i.e., the group on the one or more optionally substituted hydroxyl groups) comprises the therapeutic agent. In certain embodiments, the substituent is attached to the dendrimer via an ether bond. In some embodiments, the therapeutic agent is attached to dendrimer via a linker between the at least one terminal hydroxyl group and the therapeutic agent. In certain embodiments, the therapeutic agent is attached to the linker via an amide bond. In some embodiments, the linker comprises polyethylene glycol.

[0188] In some embodiments, the dendrimer is a poly(amidoamine) (PAMAM) dendrimer. In some embodiments, the dendrimer is a generation 4, generation 5, or generation 6 dendrimer. In certain embodiments, the dendrimer is a generation 4, generation 5, or generation 6 poly(amidoamine) (PAMAM) dendrimer.

[0189] In some embodiments, the dendrimer conjugate is of Formula (0):or a pharmaceutically acceptable salt thereof, wherein:D is a dendrimer;A is a first click-chemistry handle;L1and L2are independently a linker or a bond;X is a moiety resulting from a click-chemistry reaction between the first clickchemistry handle and a second click-chemistry handle;R is a therapeutic agent; m is an integer from 16-4095, inclusive; n is an integer from 1-20, inclusive; and p is an integer from 0-20, inclusive.

[0190] As provided herein, A is a first click-chemistry handle. In some embodiments, A is - N3. In certain embodiments, A is -C=CH. In some embodiments, A reacts with a second clickchemistry handle (z.e., A2) to form X.

[0191] As provided herein, L1and L2are independently a linker or a bond. In some embodiments, L1and L2are each independently a bond, optionally substituted C1-20 alkylene, optionally substituted C2-20 alkenylene, optionally substituted C2-20 alkynylene, optionally substituted Ci-20 heteroalkylene, optionally substituted C2-20 heteroalkenylene, or optionally substituted C2-20 heteroalkynylene, wherein: optionally one or more backbone carbon atoms of the optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenyl ene, and optionally substituted heteroalkynylene are independently replacedoptionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; and optionally one or more backbone heteroatoms of the optionally substituted heteroalkylene, optionally substituted heteroalkenyl ene, and optionally substituted heteroalkynylene are independently replaced with -O-, -S-, -NRA- -C(=O)-, -C(=O)NRA-, -NRAC(=O)-, -C(=O)O-, -OC(=O)-, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene.

[0192] As provided herein, X is a moiety resulting from a click-chemistry reaction between the first click-chemistry handle (A) and a second click-chemistry handle (A2). In someembodiments, X is a triazolyl. In some embodiments,reactsform X in Formula (0).

[0193] In some embodiments, A2is -N3. In certain embodiments. A2is -C=CH.

[0194] In some embodiments, the dendrimer conjugate is of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:D is a dendrimer; q is an integer from 0-50, inclusive;f is an integer from 1-20, inclusive; g is an integer from 0-20, inclusive; each instance of Rzis independently, hydrogen, -CH3, -OH, or -OCH3;R is a therapeutic agent; m is an integer from 16-4095, inclusive; n is an integer from 1-20, inclusive; and p is an integer from 0-20, inclusive.

[0195] In some embodiments, the dendrimer conjugate is of formula:or a pharmaceutically acceptable salt thereof, wherein:D is a dendrimer; q is an integer from 0-50, inclusive; p is an integer from 0-20, inclusive;m is an integer from 16-4095, inclusive;f is an integer from 1-20, inclusive; g is an integer from 0-20, inclusive; each instance of Rz' is independently, hydrogen, -CH3, -OH, or -OCH3;R1is a colony stimulating factor- 1 receptor (CSF1R) inhibitor; and n is an integer from 1 -20, inclusive.

[0196] In certain embodiments, the dendrimer conjugate is of Formula (II):or a pharmaceutically acceptable salt thereof, wherein:D is a dendrimer;R is a therapeutic agent; m is an integer from 16-4095, inclusive; q is an integer from 0-50, inclusive;f is an integer from 1-3, inclusive; g is an integer from 0-10, inclusive; n is an integer from 1 -20, inclusive; and p is an integer from 0-20, inclusive.

[0197] In certain embodiments, the dendrimer conjugate is of formula:or a pharmaceutically acceptable salt thereof, wherein:D is a dendrimer; q is an integer from 0-50, inclusive;p is an integer from 0-20, inclusive; m is an integer from 16-4095, inclusive;f is an integer from 1-3, inclusive; g is an integer from 0-10, inclusive;R1is a colony stimulating factor- 1 receptor (CSF1R) inhibitor; and n is an integer from 1-20, inclusive.

[0198] In certain embodiments, the dendrimer conjugate is of formula:or a pharmaceutically acceptable salt thereof, wherein:D is a dendrimer; q is 1; m is an integer from 16-4095, inclusive;f is an integer from 1-3, inclusive; g is an integer from 0-10, inclusive;R1is a colony stimulating factor- 1 receptor (CSF1R) inhibitor; and p is 0 and n is 8, or p is 1 and n is 7.

[0199] In certain embodiments, the dendrimer conjugate is of formula:or a pharmaceutically acceptable salt thereof, wherein:D is a dendrimer; q is 1; m is an integer from 16-4095, inclusive;f is an integer from 1-3, inclusive; g is an integer from 0-10, inclusive;R1is a colony stimulating factor- 1 receptor (CSF1R) inhibitor; and n is 8.

[0200] In certain embodiments, the dendrimer conjugate is of Formula (III):or a pharmaceutically acceptable salt thereof, wherein:D is a dendrimer;R is a therapeutic agent; m is an integer from 16-4095, inclusive; p is an integer from 3-7, inclusive; n is an integer from 1-20, inclusive;f is an integ Oer from 1-20, 7 inclusive; 7 and g is an integer from 0-20, inclusive.

[0201] In certain embodiments, the dendrimer conjugate is of formula:or a pharmaceutically acceptable salt thereof, wherein:D is a dendrimer; q is an integer from 0-50, inclusive; p is an integer from 3-7, inclusive; m is an inte Oger from 16-4095, 7 inclusive; 7f is an integer from 1-20, inclusive; g is an integer from 0-20, inclusive;R1is a colony stimulating factor- 1 receptor (CSF1R) inhibitor; and n is an integer from 1-5, inclusive.

[0202] In certain embodiments, the dendrimer conjugate is of formula:or a pharmaceutically acceptable salt thereof, wherein:D is a dendrimer; q is an integer from 0-50, inclusive; p is 3; m is an integer from 16-4095, inclusive;f is an integer from 1 -3, inclusive; g is an integer from 0-10, inclusive;R1is a colony stimulating factor-1 receptor (CSF1R) inhibitor; and n is 5.

[0203] In some embodiments, R is a colony stimulating factor-1 receptor (CSF1R) inhibitor. In some embodiments, R is pexidartinib, imatinib, dasatinib, PLX5622, ARRY-382, sotuletinib. edicotinib, Ki20227. or GW 2580, or a derivative or analog thereof. In some embodiments, R is pexidartinib, dasatinib, or PLX5622, or a derivative or analog thereof. In some embodiments, R is pexidartinib, dasatinib, or PLX5622. In some embodiments, R is pexidartinib. In some embodiments, R is imatinib. In some embodiments, R is dasatinib. In some embodiments, R is PLX5622. In some embodiments, R is ARRY-382. In some embodiments, R is sotuletinib. In some embodiments, R is edicotinib. In some embodiments, R is K120227. In some embodiments, R is GW 2580.

[0204] In certain embodiments, R is a derivative of: pexidartinib, imatinib, dasatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580. In certainembodiments, R is a derivative of: pexidartinib, dasatinib, or PLX5622. In certain embodiments, R is a derivative of pexidartinib. In certain embodiments, R is a derivative of imatinib. In certain embodiments, R is a derivative of dasatinib. In certain embodiments, R is a derivative of PLX5622.In certain embodiments, R is a derivative of ARRY-382. In certain embodiments, R is a derivative of sotuletinib. In certain embodiments, R is a derivative of edicotinib. In certain embodiments, R is a derivative of Ki20227. In certain embodiments, R is a derivative of GW 2580.

[0205] In some embodiments, the derivative of: pexidartinib, imatinib, dasatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580, comprises Z2between Z and pexidartinib, imatinib, dasatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580; where Z2is a linker. Thus, in some embodiments, the compound of Formula (I) is of the formula:or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, Z2is a linker comprising a disulfide bond (i.e., -S-S-). In certain embodiments, Z2is -S-S-CH2-CH2- or -CH2-CH2-S-S-.

[0207] In some embodiments, Z2is a linker comprising a carbonyl. In some embodiments, Z2is a linker comprising an amine. In some embodiments, Z2is -NH-CH2-C(=O)- or -C(=O)- CH2-NH-.

[0208] In some embodiments, Z2is a linker comprising two rings. In some embodiments, Z2is of the formula:, wherein Ring A and Ring B are each independently a carbocyclylene, heterocyclylene, arylene, or heteroarylene. In some embodiments, Ring A is a carbocyclylene or heterocyclylene, and Ring B is an arylene or heteroarylene. In some embodiments, Ring A is a heterocyclylene, and Ring B is a heteroarylene. In some embodiments, Ring A is piperidinylene or piperazinylene, and Ring B is pyrazolylene. In some embodiments, Z2is,,In some embodiments, R is:some embodiments, R is:

[0214] In some embodiments, Z isIn some embodiments, Z is,

[0215] In some embodiments, Z is vbo-p1In some embodiments, Z isand f is 1-10, inclusive. In some embodiments, Z issome embodiments,O O embodiments, Z isIn certain embodiments, Z is, and I is 1. In some embodiments, Z is, and f is 3. In some embodiments, Z isinclusive, and g is 1-3, inclusive. In some embodiments, Z is, f is3, and g is 3.

[0216] In some embodiments, f is an integer from 1-20, inclusive. In some embodiments, f is an integer from 1-10, inclusive. In some embodiments, f is 10. In certain embodiments, f is 9. In some embodiments, f is 8. In some embodiments, f is 7. In some embodiments, f is 6. In some embodiments, f is 5. In some embodiments, f is 4. In some embodiments, f is 3. In some embodiments, f is 2. In some embodiments, f is 1.

[0217] As provided herein, in some embodiments, f is an integer from 1-3, inclusive. In some embodiments, f is 1. In certain embodiments, f is 2. In some embodiments, f is 3.

[0218] In some embodiments, g is an integer from 0-20, inclusive. As provided herein, in some embodiments, g is an integer from 0-10, inclusive. In certain embodiments, g is 1-3. In some embodiments, g is 1. In some embodiments, g is 2. In certain embodiments, g is 3.

[0219] In certain embodiments, f is 1-3, inclusive, and g is 1-3, inclusive. In some embodiments, f is 3, and g is 3.

[0220] In some embodiments, Z comprises Rz. In some embodiments, each instance of Rzis independently, hydrogen, -CH3, -OH, or -OCH3. In some embodiments, Rzis hydrogen. In some embodiments, each instance of Rzis hydrogen. In certain embodiments, one instance of Rzis -OH. In certain embodiments, one instance of Rzis -CH3. In certain embodiments, one instance

[0221] / 4s provided herein, D is a dendrimer. In some embodiments, the dendrimer, D, is a polyamidoamine (P AM AM), polypropylamine (POP AM), polyethylenimine, polylysine, polyester, iptycene, aliphatic poly(ether), or an aromatic polyether dendrimer. In some embodiments, the dendrimer, D, is a polypropylamine (POP AM) dendrimer. In some embodiments, the dendrimer, D, is a polyethylenimine dendrimer. In some embodiments, the dendrimer, D, is a polylysine dendrimer. In some embodiments, the dendrimer, D, is a polyester dendrimer. In some embodiments, the dendrimer, D, is an iptycene dendrimer. In some embodiments, the dendrimer, D, is an aliphatic poly(ether) dendrimer. In some embodiments, the dendrimer, D, is an aromatic polyether dendrimer.

[0222] In some embodiments, the dendrimer, D, is a polyamidoamine (PAMAM) dendrimer. In some embodiments, a PAMAM dendrimer comprises different cores with amidoamine building blocks. In some embodiments, a PAM AM dendrimer comprises carboxylic, amine, and / or hydroxyl terminal groups of any generation including, but not limited to, generation 1, generation 2, generation 3, generation 4, generation 5, generation 6, generation 7, generation 8, generation 9, or generation 10 PAMAM dendrimers. In some embodiments, a PAMAM dendrimer comprises an ethylenediamine with amidoamine building blocks. In some embodiments, the dendrimer, D, is a generation 4, generation 5, generation 6, generation 7, or generation 8 PAMAM dendrimer. In some embodiments, the dendrimer, D, is a generation 4 or generation 6 PAM AM: dendrimer. In some embodiments, the dendrimer, D, is a generation 3 PAMAM dendrimer. In certain embodiments, the dendrimer, D. is a generation 4 PAMAM dendrimer. In some embodiments, the dendrimer, D, is a generation 5 PAMAM dendrimer. In some embodiments, the dendrimer, D, is a generation 6 PAM AM dendrimer. In some embodiments, the dendrimer, D, is a generation 7 PAMAM dendrimer. In some embodiments, the dendrimer, D, is a generation 8 PAMAM dendrimer.

[0223] In some embodiments, the number of terminal sites on a dendrimer can depend on the particular dendrimeric scaffold and its generation. For example, in some embodiments, a dendrimer is based on a g Oeneration 0. 1, 2, 3, 4. 5, 6, 7, 8. 9, or 10 PAMAM dendrimericscaffold, which have 4, 8, 16, 32, 64, 128, 256, 512, 1024, 2048, and 4096 terminal sites, respectively. However, it should be appreciated that different dendrimeric scaffolds having a different number of terminal sites at each generation can be used in accordance with the disclosure. In some embodiments, all terminal sites of a dendrimer comprise hydroxyl groups. In some embodiments, each terminal site of a dendrimer comprises either a hydroxyl group or an amine group. In some embodiments, each terminal site of a dendrimer conjugate comprises a hydroxyl group, an amine group, or an agent conjugated to the dendrimer through an ether or amide bond. In some embodiments, each terminal site of a dendrimer conjugate comprises either a hydroxyl group or an agent conjugated to the dendrimer through an ether bond.

[0224] In some embodiments, at least 50% of terminal sites on a dendrimer conjugate comprise hydroxyl groups (e.g., at least 50% of terminal sites do not comprise either an amine group or an agent). For example, in some embodiments, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% of terminal sites on a dendrimer conjugate comprise hydroxyl groups. In some embodiments, about 50-99%, about 60-99%, about 70-99%, about 80-99%, about 90-99%, about 95-99%, about 98-99%, about 70-95%, about 70-90%, about 80-95%, or about 80-90% of terminal sites on a dendrimer conjugate comprise hydroxyl groups.

[0225] In some embodiments, one or more terminal sites on a dendrimer conjugate comprise a therapeutic agent. In some embodiments, at least 2, at least 3, at least 4, at least 5, at least 10, at least 15, at least 20, or more, terminal sites on a dendrimer conjugate comprise R. In some embodiments, at least 1% of terminal sites on a dendrimer conjugate comprise R. For example, in some embodiments, at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% of terminal sites on a dendrimer conjugate comprise R. In some embodiments, about 1-50%, about 1-40%, about 1-25%, about 1-10%, about 5-50%, about 5-40%, about 5-25%, about 5-10%, about 10-50%, about 10-40%, or about 10-25% of terminal sites on a dendrimer conjugate comprise R. In some embodiments, about 1%, about 2%, about 3%, about 4%, or about 5% of terminal sites on a dendrimer comprise R. In some embodiments, less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75% of terminal sites on a dendrimer comprise R.

[0226] In some embodiments, a desired R loading can depend on certain factors, including the choice of therapeutic agent, dendrimer structure and size, and cell or tissue to be treated.In some embodiments, a dendrimer conjugate is about 0.01% to about 45% by mass (m / m) of R. In some embodiments, a dendrimer conjugate is about 10% to about 20% by mass of R. In some embodiments, a dendrimer conjugate is about 0.1% to about 30%, about 0.1% to about 20%, about 0.1% to about 10%, about 1% to about 10%, about 1% to about 5%, about 3% to about 20%, about 3% to about 10% by mass of R.

[0227] As described herein, in some embodiments, a dendrimer conjugate can be characterized in terms of mass percentage (e.g., % by mass (m / m)) of agent. In some embodiments, mass percentage refers to a molecular weight (Da) percentage of Rin a dendrimer conjugate. In some embodiments, mass percentage can be determined by the general formula of: (agent Mw) / (conjugate Mw)x100. For example, in some embodiments, (agent Mw) can be determined by calculating or approximating the molecular weight of an agent as a single molecule or compound (conjugated or unconjugated), and multiplying this value by the number of terminal sites at which the agent is present in a dendrimer conjugate. In some embodiments, (agent Mw) can be determined by calculating or approximating the sum of the atomic mass of all atoms which form the agent in a dendrimer conjugate. The value for (agent Mw) can be taken as a fraction of total molecular weight of the dendrimer conjugate (conjugate Mw) and multiplied by 100 to provide a mass percentage. In some embodiments, mass percentage can be determined by experimental or empirical means. For example, in some embodiments, mass percentage can be determined using proton nuclear magnetic resonance I1!! NMR) or other analytical methods known in the art.

[0228] In som e embodiments, a dendrimer has a diameter of between about 1 nm and about 50 nm. For example, in some embodiments, the diameter is between about 1 nm and about 20 nm, between about 1 nm and about 10 nm, or between about 1 nm and about 5 nm. In some embodiments, the diameter is between about 1 nm and about 2 nm. In some embodiments, a dendrimer has a molecular weight of between about 500 Daltons (Da) and about 100,000 Da (e.g., between about 500 Da and about 50,000 Da, or between about 1,000 Da and about 20,000 Da).

[0229] In some embodiments, the therapeutic agent (e.g., R) is conjugated to a dendrimer through a linker, which is attached to the dendrimer and to the agent in a non-releasable manner (e.g., by ether and / or amide bonds). In some embodiments, a linker has a composition that is minimally releasable (e.g., minimally cleavable) under physiological conditions.

[0230] In some embodiments, a dendrimer is conjugated to an agent through covalent bonds that are stable under in vivo conditions. In some embodiments, the covalent bonds are minimally cleavable when administered to a subject and / or excreted intact from the body. Forexample, in some embodiments, less than 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or less than 0. 1% of the total dendrimer conjugates have agent cleaved within 24 hours, or 48 hours, or 72 hours after in vivo administration to a subject. In some embodiments, the covalent bonds comprise ether bonds. In some embodiments, the covalent bonds between dendrimer and agent are not hydrolytically or enzymatically cleavable bonds, such as ester bonds.

[0231] In some embodiments, the dendrimer is a generation 4 PAMAM. In some embodiments, the dendrimer is of the formula:wherein p terminal hydroxy groups are replaced with:and n terminal hydroxy groups are replaced with:

[0232] In some embodiments, the dendrimer is a generation 6 PAMAM. In some embodiments, the dendrimer is of the formula:wherein p terminal hydroxy groups are replaced with:and n terminal hydroxy groups are replaced with:

[0233] As provided herein, q is an integer from 0-50, inclusive. In some embodiments, q is an integer from 0-25, inclusive. In some embodiments, q is an integer from 0-10, inclusive. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0. In some embodiments, q is1. In some embodiments, q is 2.

[0234] / 4s provided herein, m is an integer from 16-4095, inclusive. In some embodiments, m is an integer from 50-250, inclusive. In certain embodiments, m is an integer from 50-70, inclusive. In certain embodiments, m is an integer from 54-63, inclusive. In some embodiments, m is 60. In some embodiments, m is an integer from 53-58, inclusive. In certain embodiments, m is an integer from 52-56, inclusive. In certain embodiments, m is an integer from 54-57, inclusive. In some embodiments, m is 54. In certain embodiments, m is an integer from 200-300, inclusive. In certain embodiments, m is an integer from 240-255,inclusive. In some embodiments, m is 251. In some embodiments, m is an integer from 240- 245, inclusive. In certain embodiments, m is 241.

[0235] As provided herein, p is an integer from 0-20, inclusive. In some embodiments, p is an integer from 1-10, inclusive. In certain embodiments, p is an integer from 1-5, inclusive. In some embodiments, p is an integer from 3-7, inclusive. In some embodiments, p is 7. In certain embodiments, p is 6. In some embodiments, p is 5. In certain embodiments, p is 4. In certain embodiments, p is 3. In some embodiments, p is 2. In certain embodiments, p is 1. In some embodiments, p is 0.

[0236] As provided herein, n is an integer from 1-20, inclusive. In some embodiments, n is an integer from 2-15, inclusive. In certain embodiments, n is an integer from 5-15, inclusive. In some embodiments, n is an integer from 1-5, inclusive. In some embodiments, n is 1. In some embodiments, n is 2. In certain embodiments, n is 3. In some embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, n is 7. In certain embodiments, n is 8. In certain embodiments, n is 9. In certain embodiments, n is 10. In certain embodiments, n is 11. In certain embodiments, n is 12. In certain embodiments, n is 13. In certain embodiments, n is 14. In certain embodiments, n is 15.

[0237] In some embodiments, the sum of p and n is from 5-15, inclusive. In certain embodiments, the sum of p and n is from 5-10, inclusive. In certain embodiments, the sum of p and n is from 5-10, inclusive. In certain embodiments, the sum of p and n is 5. In certain embodiments, the sum of p and n is 6. In certain embodiments, the sum of p and n is 7. In certain embodiments, the sum of p and n is 8. In certain embodiments, the sum of p and n is 9. In certain embodiments, the sum of p and n is 10. In certain embodiments, the sum of p and n is 1 1. In certain embodiments, the sum of p and n is 12. In certain embodiments, the sum of p and n is 13. In certain embodiments, the sum of p and n is 14. In certain embodiments, the sum of p and n is 15. In certain embodiments, the sum of p and n is 8 or 15.

[0238] In some embodiments, p is 0 and n is 8, or p is 1 and n is 7. In some embodiments, p is 0 and n is 8. In some embodiments, p is 1 and n is 7. In some embodiments, p is 2 and n is 6. In some embodiments, p is 3 and n is 5. In some embodiments, p is 4 and n is 4. In some embodiments, p is 5 and n is 3. In certain embodiments, p is 6 and n is 2. In some embodiments, p is 7 and n is 1.

[0239] In some embodiments, the sum of m, p, and n is 64. In some embodiments, the sum of m, p, and n is 128. In some embodiments, the sum of m, p, and n is 256.

[0240] In some embodiments, D is a generation 2, 3, 4, 5, 6, 7, 8, 9, or 10 PAMAM dendrimer, which has 16, 32, 64, 128, 256, 512, 1024, 2048, or 4096 terminal sites,respectively. Accordingly, in some embodiments, D is a generation 2, 3, 4, 5, 6, 7, 8, 9, or 10 PAMAM dendrimer, and the sum of m, p, and n is 16, 32, 64, 128, 256, 512, 1024, 2048, or 4096, respectively. In some embodiments, D is a generation 4 PAMAM dendrimer, and the sum of m, p, and n is 64. In some embodiments, D is a generation 5 PAMAM dendrimer, and the sum of m, p, and n is 128. In some embodiments, D is a generation 6 PAMAM dendrimer, and the sum of m, p, and n is 256.

[0241] In some embodiments, -Z-R is:or a pharmaceutically acceptable salt thereof.

[0243] .Also provided herein are dendrimer conjugates of the formula:pharmaceutically acceptable salt thereof.

[0244] In some embodiments, the dendrimer conjugate is of the formula:or a pharmaceutically acceptable salt thereof. In some embodiments, the dendrimer conjugate of the preceding formula is referred to herein as D-4517.2.

[0245] In some embodiments, the dendrimer conjugate is selected from dendrimer conjugates in FIGs. 10A-10D, 11A-11D, 12A-12F, and 13 A-13C, or a pharmaceutically acceptable salt thereof.

[0246] In certain embodiments, the dendrimer conjugate is of the formula:or a pharmaceutically acceptable salt thereof. In some embodiments, the dendrimer conjugate of the preceding formula is referred to herein as H74DS3M8.Therapeutic Agents

[0247] As provided herein, the dendrimer conjugate comprises a therapeutic agent. In some embodiments, the therapeutic agent (z.e., R) is selected from the group consisting of angiotensin II receptor blockers, Farnesoid X receptor (FXR) agonists, death receptor 5 agonists, sodium -glucose cotransporter type-2 (SGLT2) inhibitors, lysophosphatidic acid 1 receptor antagonists, endothelin-A receptor antagonist, peroxisome proliferator-activated receptor delta (PPAR5) agonists, ATI receptor antagonists, CCR5 / CCR2 antagonists, anti- fibrotic agents, anti-inflammatory agents, antioxidant agents, stimulator of interferon genes (STING) agonists, vascular endothelial growth factor receptor (VEGFR) inhibitors, colonystimulating factor 1 receptor (CSF1R) inhibitors, AXL inhibitors, c-Met inhibitors, poly(ADP -ribose) polymerase (PARP) inhibitors, receptor tyrosine kinase inhibitors, MEK inhibitors, PAK 1 inhibitors, glutaminase inhibitors, TIE II antagonists, chemokine receptor 2 (CXCR2) inhibitors, CD73 inhibitors, arginase inhibitors, phosphatidylinositol-3-kinase (PI3K) inhibitors, toll-like receptor 4 (TLR4) agonists, toll-like receptor 7 (TLR7) agonists, Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) inhibitors, chemotherapeutic agents, STING antagonists, JAK1 inhibitors, triggering receptor expressed on myeloid cells 2 (TREM2) inhibitors, and tyrosine kinase 2 (TYK2) inhibitors.

[0248] In some embodiments, the therapeutic agent (i.e., R) an angiotensin II receptor blocker. In some embodiments, the therapeutic agent {i.e., R) is a Farnesoid X receptor (FXR) agonist. In some embodiments, the therapeutic agent {i.e., R) is a death receptor 5 agonist. In some embodiments, the therapeutic agent {i.e., R) is a sodium -glucose cotransporter type-2(SGLT2) inhibitor. In some embodiments, the therapeutic agent (i.e., R) is a lysophosphatidic acid 1 receptor antagonist. In some embodiments, the therapeutic agent (i.e., R) is a endothelin-A receptor antagonist, peroxisome proliferator-activated receptor delta (PPAR5) agonist. In some embodiments, the therapeutic agent (i.e., R) is a ATI receptor antagonist. In some embodiments, the therapeutic agent (i.e., R) is a CCR5 / CCR2 antagonist. In some embodiments, the therapeutic agent (i.e., R) is an anti-fibrotic agent. In some embodiments, the therapeutic agent (i.e., R) is an anti-inflammatory agent. In some embodiments, the therapeutic agent (i.e., R) is an antioxidant agent. In some embodiments, the therapeutic agent (i.e., R) is a stimulator of interferon genes (STING) agonist. In some embodiments, the therapeutic agent (i.e., R) is a vascular endothelial growth factor receptor (VEGFR) inhibitor. In some embodiments, the therapeutic agent (i.e., R) is a colony-stimulating factor 1 receptor (CSF1 R) inhibitor. In some embodiments, the therapeutic agent (i.e., R) is an AXL inhibitor. In some embodiments, the therapeutic agent (i.e., R) is a c-Met inhibitor. In some embodiments, the therapeutic agent (i.e., R) is a poly(ADP -ribose) polymerase (PARP) inhibitor. In some embodiments, the therapeutic agent (i.e., R) is a receptor tyrosine kinase inhibitor. In some embodiments, the therapeutic agent (i.e., R) is a MEK inhibitor. In some embodiments, the therapeutic agent (i.e., R) is a P.AKI inhibitor. In some embodiments, the therapeutic agent (i.e., R) is a glutaminase inhibitor. In some embodiments, the therapeutic agent (i.e., R) is a TIE II antagonist. In some embodiments, the therapeutic agent (i.e., R) is a chemokine receptor 2 (CXCR2) inhibitor. In some embodiments, the therapeutic agent (i.e., R) is a CD73 inhibitor. In some embodiments, the therapeutic agent (i.e., R) is an arginase inhibitor. In some embodiments, the therapeutic agent (i.e., R) is a phosphatidylinositol-3- kinase (PI3K) inhibitor. In some embodiments, the therapeutic agent (i.e., R) is a toll-like receptor 4 (TLR4) agonist. In some embodiments, the therapeutic agent (i.e., R) is a toll-like receptor 7 (TLR7) agonist. In some embodiments, the therapeutic agent (i.e., R) is a Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) inhibitor. In some embodiments, the therapeutic agent (i.e., R) isa chemotherapeutic agent. In some embodiments, the therapeutic agent (i.e., R) is a STING antagonist. In some embodiments, the therapeutic agent (i.e., R) is a JAK1 inhibitor. In some embodiments, the therapeutic agent (i.e., R) is a triggering receptor expressed on myeloid cells 2 (TREM2) inhibitor. In some embodiments, the therapeutic agent (i.e., R) is a tyrosine kinase 2 (TYK2) inhibitor. In some embodiments, the receptor tyrosine kinase inhibitor is a vascular endothelial growth factor receptor (VEGFR) inhibitor or a colony stimulating factor-1 receptor (CSF1R) inhibitor.

[0249] In some embodiment, R is a derivative or analog of a known angiotensin II receptor blocker, Farnesoid X receptor (FXR) agonist, death receptor 5 agonist, sodium-glucose cotransporter type-2 (SGLT2) inhibitor, lysophosphatidic acid 1 receptor antagonist, endothelin- A receptor antagonist, peroxisome proliferator-activated receptor delta (PPAR6) agonist, ATI receptor antagonist, CCR5 / CCR2 antagonist, anti-fibrotic agent, antiinflammatory agent, antioxidant agent, stimulator of interferon genes (STING) agonist, vascular endothelial growth factor receptor (VEGFR) inhibitor, colony -stimulating factor 1 receptor (CSF1R) inhibitor, AXL inhibitor, c-Met inhibitor, poly(ADP-ribose) polymerase (PARP) inhibitor, receptor tyrosine kinase inhibitor, MEK inhibitor, PAK 1 inhibitor, glutaminase inhibitor, TIE II antagonist, chemokine receptor 2 (CXCR2) inhibitor, CD73 inhibitor, arginase inhibitor, phosphatidylinositol-3-kinase (PI3K) inhibitor, toll-like receptor 4 (TLR4) agonist, toll-like receptor 7 (TLR7) agonist, Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) inhibitor, chemotherapeutic agent, STING antagonist, JAK1 inhibitor, TREM2 inhibitor, or TYK2 inhibitor, wherein the derivative or analog comprises Z2between Z and core structure of the known therapeutic agent; where Z2is a linker. Thus, in some embodiments, the compound is of the formula:or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments, Z2is a linker comprising a disulfide bond (i.e., -S-S-). In certain embodiments, Z2is -S-S-CH2-CH2- or -CH2-CH2-S-S-.

[0251] In some embodiments, Z2is a linker comprising a carbonyl. In some embodiments, Z2is a linker comprising an amine. In some embodiments, Z2is -NH-CH2-C(=O)- or -C(:=:O)- CH2-NH-.

[0252] In some embodiments, Z2is a linker comprising two rings. In some embodiments, Z2is of the formula:, wherein Ring A and Ring B are each independently a carbocyclylene, heterocyclylene, arylene, or heteroarylene. In some embodiments, Ring A is a carbocyclylene or heterocyclylene, and Ring B is an arylene or heteroarylene. In some embodiments, Ring A is a heterocyclylene, and Ring B is a heteroarylene. In someembodiments, Ring A is piperidinylene or piperazinylene, and Ring B is pyrazolylene. In some embodiments,

[0253] In some embodiments, such dendrimer-drug conjugates have a therapeutic index that is increased relative to the unconjugated drug (e.g., therapeutic agent in absence of the dendrimer). In some embodiments, the dendrimer-drug conjugate has a therapeutic index of greater than 10% of the therapeutic index of the unconjugated drug. In some embodiments, the dendrimer-drug conjugate has a therapeutic index of greater than 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the therapeutic index of the unconjugated drug.

[0254] The therapeutic index (TI) of a therapeutic agent is a comparison of the amount of the therapeutic agent that causes the therapeutic effect to the amount that causes toxicity. In some embodiments, a therapeutic index can be expressed as the ratio, LD50 / ED50, where ED50 corresponds to a dose that is therapeutically effective in 50% of the population, and LD50 corresponds to the dose that is lethal to 50% of the population. In some embodiments, therapeutic efficacy and toxicity of drugs and dendrimer-drug conjugates can be determined by standard pharmaceutical procedures in cell cultures or experimental animals.

[0255] In some embodiments, a therapeutic agent is any of the compounds described below or a pharmaceutically acceptable derivative, analog, or prodrug of any of the compounds described below. Prodrugs are compounds that, when metabolized z>? vivo, undergo conversion to compounds having the desired pharmacological activity. Prodrugs can be prepared by replacing appropriate functionalities present in a therapeutic agent with “pro- moieties” as described in the art (see, e.g., H. Bundgaar, Design of Prodrugs (1985)). Examples of prodrugs include ester, ether or amide derivatives of a therapeutic agent described herein, polyethylene glycol derivatives of a therapeutic agent described herein, N- acyl amine derivatives, dihydropyridine pyridine derivatives, amino-containing derivatives conjugated to polypeptides, 2-hydroxybenzamide derivatives, carbamate derivatives, N- oxides derivatives that are biologically reduced to the active amines, and N-Mannich base derivatives. For further discussion of prodrugs, see, for example, Rautio, J. et al. Nature Reviews Drug Discovery. 7:255-270 (2008).

[0256] In some embodiments, the therapeutic agent is an immunomodulatory agent. In some embodiments, an immunomodulatory agent refers to an agent that elicits a specific effect upon the immune system of the recipient. Immunomodulation can include, in some embodiments, suppression, reduction, enhancement, prolonging, or stimulation of one ormore physiological processes of the innate or adaptive immune response to antigen, as compared to a control. In some embodiments, immunomodulatory agents can modulate immune microenvironment for a desired immunological response (e.g., increasing anti-tumor activity, or increasing anti-inflammatory activities sites in need thereof in autoimmune diseases) by targeting one or more immune cells or cell types at a target site. In some embodiments, immunomodulatory agents are delivered to kill, inhibit, or reduce activity or quantity of suppressive immune cells such as tumor-associated macrophages for an enhanced anti-tumor response at a tumor site. In other embodiments, immunomodulatory agents are delivered to kill, inhibit, or reduce activity or quantity of pro-inflammatory immune cells (e.g., Ml -type macrophages) for reducing pro-inflammatory immune environment at pathogenic sites associated with autoimmune diseases. Examples of immunomodulatory agents for use in accordance with the disclosure include, without limitation, STING agonists, STING antagonists, Janus kinase 1 (JAKI) inhibitors, CSF1R inhibitors, AXL inhibitors, c- Met inhibitors, PARE inhibitors, receptor tyrosine kinase inhibitors, MEK inhibitors, PAK1 inhibitors, glutaminase inhibitors, TIE II antagonists, CXCR2 inhibitors, CD73 inhibitors, arginase inhibitors, PI3K inhibitors, TLR4 agonists, TLR7 agonists, SHP2 inhibitors, TREM2 inhibitors, TYK2 inhibitors, anti-inflammatory agents, and derivatives or analogs thereof.

[0257] In some embodiments, the therapeutic agent is a STING agonist selected from a cyclic dinucleotide GMP-AMP and DMXAA, and derivatives or analogs thereof. In some embodiments, the therapeutic agent is a STING antagonist selected from C-178, C-176, Cl 8, Astin C, NO2-CLA, H-151, and alpha-mangostin, and derivatives or analogs thereof.

[0258] In some embodiments, the therapeutic agent is a JAKI inhibitor selected from tofacitinib, ruxolitinib, baricitinib, peficitinib, decernotiniba, filgotinib, solcitinibb, itacitinib, SHR0302, upadacitinib, PF-04965842, Target-007, and Target-006, and derivatives or analogs thereof.

[0259] In some embodiments, the therapeutic agent is a CSF1R inhibitor selected from PLX3397, PLX108-01, ARRY-382, PLX7486, BLZ945, JNJ-40346527, and GW 2580, and derivatives or analogs thereof.

[0260] In some embodiments, the therapeutic agent is a PARP inhibitor selected from Olaparib, Veliparib, Niraparib, and Rucaparib, and derivatives or analogs thereof.

[0261] In some embodiments, the therapeutic agent is a receptor tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR) or epidermal growth factor receptor (EGFR).

[0262] In some embodiments, the therapeutic agent is an AXL inhibitor (e.g., bemcentinib (R428), or dubermatinib (TP-0903), or a derivative or analog thereof).

[0263] In some embodiments, the therapeutic agent is a c-Met inhibitor (e.g., cabozantinib, or a derivative or analog thereof).

[0264] In some embodiments, the therapeutic agent is a receptor tyrosine kinase (e.g., VEGFR, CSF1R, AXL, and / or c-Met) inhibitor selected from sunitinib, sorafenib, pazopanib, vandetanib, axitinib, cediranib, vatalanib, dasatinib, bemcentinib (R428), dubermatinib (TP- 0903), nintedanib, cabozantinib, and motesanib, and derivatives or analogs thereof. In some embodiments, the receptor tyrosine kinase inhibitor is N, A-didesethyl sunitinib or a derivative or analog thereof.

[0265] In some embodiments, the therapeutic agent is a MEK inhibitor selected from Trametinib, Cobimetinib, Binimetinib, Selumetinib, PD325901, PD035901, PD032901, and TAK-733, and derivatives or analogs thereof.

[0266] In some embodiments, the therapeutic agent is a PAK1 inhibitor. In some embodiments, the PAK1 inhibitor is Frax-1036 (6-[2-chloro-4-(6-methyl-2- pyrazinyl)phenyl]-8-ethyl-2-[[2-(l-methyl-4-piperidinyl)ethyl]amino]-pyrido[2,3- d]pyrimidin-7(8H)-one), or a derivative or analog thereof.

[0267] In some embodiments, the therapeutic agent is a glutaminase inhibitor selected from Bis-2-(5-phenylacetimido-l,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), azaserine, acivicin, and CB-839, and derivatives or analogs thereof.

[0268] In some embodiments, the therapeutic agent is a CXCR2 inhibitor selected from Navarixin, SB225002, and SB332235, and derivatives or analogs thereof.

[0269] In some embodiments, the therapeutic agent is a CD73 inhibitor selected from APCP, quercetin, and tenofovir, and derivatives or analogs thereof.

[0270] In some embodiments, the therapeutic agent is an arginase inhibitor, such as 2-(S)- amino-6-boronohexanoic acid, or a derivative or analog thereof.

[0271] In some embodiments, the therapeutic agent is a PI3K inhibitor selected from alpelisib, serabelisib, pilaralisib, WX-037, dactolisib, prexasertib, voxtalisib, PX-866, ZSTK474, buparlisib, pictilisib, and copanlisib, and derivatives or analogs thereof.

[0272] In some embodiments, the therapeutic agent is an anti-inflammatory agent. In some embodiments, an anti-inflammatory agent reduces inflammation and can include steroidal and non-steroidal drugs. Examples of steroidal drugs include, without limitation, glucocorticoids, progestins, mineralocorticoids, and corticosteroids. Examples of nonsteroidal anti-inflammatory drugs (NSAIDs) include, without limitation, mefenamic acid,aspirin, Diflunisal, Salsalate, Ibuprofen, Naproxen, Fenoprofen, Ketoprofen, Deacketoprofen, Flurbiprofen, Oxaprozin, Loxoprofen, Indomethacin, Sulindac, Etodolac, Ketorolac, Diclofenac, Nabumetone, Piroxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam, Meclofenamic acid, Flufenamic acid, Tolfenamic acid, elecoxib, Rofecoxib, Valdecoxib, Parecoxib, Lumiracoxib, Etoricoxib, Firocoxib, Sulphonanilides, Nimesulide, Niflumic acid, and Licofelone, and derivatives or analogs thereof. Additional examples of anti-inflammatory agents include, without limitation, triamcinolone acetonide, fluocinolone acetonide, methylprednisolone, prednisolone, prednisone, dexamethasone, loteprendol, fluoromethoIone, ibuprofen, aspirin, naproxen, cyclosporine, tacrolimus, rapamycin, and metformin, and derivatives or analogs thereof. In some embodiments, the therapeutic agent is triamcinolone acetonide, prednisone, or dexamethasone, or a derivative or analog thereof.

[0273] In some embodiments, the therapeutic agent is a cytotoxic agent. In some embodiments, the therapeutic agent is a chemotherapeutic agent. Examples of cytotoxic agents for use in accordance with the disclosure include, without limitation, amsacrine, bevacizumab, bleomycin, busulfan, camptothecin, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clofarabine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epipodophyllotoxins, epirubicin, etoposide, etoposide phosphate, fludarabine, fluorouracil, gemcitabine, hydroxycarb amide, idarubicin, ifosfamide, innotecan, leucovorin, daunorubicin, lomustine, mechlorethamine, melphalan, mercaptopurine, mertansine, mesna, methotrexate, mitomycin, mitoxantrone, monomethyl auristatin E, oxaliplatin, paclitaxel, pemetrexed, pentostatin, procarbazine, raltitrexed, satraplatin, streptozocin, teniposide, tegafur-uracil, temozolomide, teniposide, thiotepa, tioguanine, topotecan, treosulfan, vinblastine, vincristine, vindesine, vinorelbine, vorinostat, taxol, trichostatin A, trastuzumab, cetuximab, and rituximab, and derivatives or analogs thereof.

[0274] In some embodiments, the therapeutic agent is an anti-cancer agent, such as a cytotoxic agent described herein. In some embodiments, the therapeutic agent is a histone deacetylase (HD AC) inhibitor, such as vorinostat, or a derivative or analog thereof. In some embodiments, the therapeutic agent is a topoisomerase I and / or II inhibitor, such as etoposide or camptothecin, or a derivative or analog thereof. Additional examples of anti -cancer agents include, without limitation, irinotecan, exemestane, octreotide, carmofur, clarithromycin, zinostatin, tamoxifen, tegafur, toremifene, doxifluridine, nimustine, vindensine, nedaplatin, pirarubicin, flutamide, fadrozole, prednisone, medroxyprogesterone, mitotane, mycophenolate mofetil, and mizoribine, and derivatives or analogs thereof.

[0275] In some embodiments, the therapeutic agent is an anti-angiogenesis agent. Examples of anti-angiogenesis agents include, without limitation, bevacizumab (AVASTIN®), rhuFAb V2 (ranibizumab, LUCENTIS®), aflibercept (EYLEA®), MACUGEN® (pegaptanim sodium, anti-VEGF aptamer or EYE001), pigment epithelium derived factor(s) (PEDF), celecoxib (CELEBREX®), rofecoxib (VIOXX®), interferon alpha, interleukin- 12 (IL-12), thalidomide (THALOMID®), lenalidomide (REVLIMID®), squalamine, endostatin, angiostatin, ANGIOZYME® (Sima Therapeutics), NEOVASTAT® (AE-941) (Aeterna Laboratories, Quebec City, Canada), sunitinib (SUTENT®), sorafenib (Nexavar®), erlotinib (Tarceva®), panitumumab (VECTIBIX®), and cetuximab (ERBITUX®), and derivatives or analogs thereof. Additional examples of anti-angiogenesis agents include agents targeting members of the platelet-derived growth factor family, epidermal growth factor family, fibroblast growth factor family, transforming growth factor-P superfamily (TGF-pl, activins, follistatin and bone morphogenetic proteins), angiopoietin-like family, galectins family, integrin superfamily, as well as pigment epithelium derived factor, hepatocyte growth factor, angiopoietins, endothelins, hypoxia-inducible factors, insulin-like growth factors, cytokines, matrix metalloproteinases and their inhibitors, and glycosylation proteins.

[0276] In some embodiments, the therapeutic agent is an agent that can be used to treat one or more conditions or diseases associated with the liver and / or associated diseases or conditions such as infections, sepsis, diabetic complications, hypertension, obesity, high blood pressure, heart failure, kidney diseases, and cancers. Examples of such therapeutic agents include, without limitation, angiotensin II receptor blockers, FXR agonists, death receptor 5 agonists, SGLT2 inhibitors, lysophosphatidic acid 1 receptor antagonists, endothelin-A receptor antagonist, PPAR5 agonists, ATI receptor antagonists, CCR5 / CCR2 antagonists, insulin sensitizer, pioglitazone, anti-fibrotic agents, antioxidant agents, anti- angiogenic agents, anti-excitotoxic agents (e.g., valproic acid, D-aminophosphonovalerate, D-aminophosphonoheptanoate), inhibitors of glutamate formation / release (e g., baclofen, NMD A receptor antagonists, ranibizumab, anti-VEGF agents), and immunomodulatory and cytotoxic agents described herein.

[0277] In some embodiments, the therapeutic agent is an angiotensin II receptor blocker, such as telmisartan, a telmisartan-amide derivative, or a telmisartan-ester derivative. In some embodiments, the therapeutic agent is an FXR agonist, such as chenodeoxycholic acid, a chenodeoxycholic acid-amide derivative, or a chenodeoxycholic acid-ester derivative. In some embodiments, the therapeutic agent is an SGLT2 inhibitor selected from phlorizin, T- 1095, canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, empagliflozin, luseogliflozin,ertugliflozin, and remogliflozin etabonate. In some embodiments, the therapeutic agent is a PPAR5 agonist, such as GW0742, a GW0742-amide derivative, or a GW0742 -ester derivative. In some embodiments, the therapeutic agent is an antioxidant agent, such as vitamin E.

[0278] In some embodiments, the therapeutic agent is N-acetyl-L-cysteine. In some embodiments, N-acetyl-L-cysteine is conjugated to a hydroxyl-terminated dendrimer via non- cleavable linkage for minimal release of free N-acetyl-cysteine in vivo after administration. In some embodiments, a non-cleavable form of a dendrimer / N-acetyl-cysteine conjugate provides enhanced therapeutic efficacy as compared to a releasable or cleavable form of the dendrimer / 'N-acetyl-cysteine complex.

[0279] In some embodiments, the therapeutic agent is polysialic acid (e.g., low molecular weight polySia with an average degree of polymerization 20 (polySia avDP20)), Translocator Protein Ligands (e.g., Diazepam binding inhibitor (DBI)), Interferon-p (IFN-p), or minocycline.

[0280] In some embodiments, the therapeutic agent is an anti-infective agent. Examples of anti-infective agents include, without limitation, antiviral agents, antibacterial agents, antiparasitic agents, and anti-fungal agents. In some embodiments, the therapeutic agent is selected from moxifloxacin, ciprofloxacin, erythromycin, levofloxacin, cefazolin, vancomycin, tigecycline, gentamycin, tobramycin, ceftazidime, ofloxacin, gatifloxacin, amphotericin, voriconazole, and natamycin.

[0281] Therapeutic agents suitable for use in accordance with the disclosure are described in additional detail in co-pending International Application Numbers PCT / US2020 / 063332, PCT / US2020 / 063347, PCT / US2020 / 063342, and PCT / US2021 / 029139, the relevant contents of each of which are incorporated by reference herein in their entireties.

[0282] In some embodiments, R comprises a PAK1 inhibitor. In some embodiments, R comprises Frax-1036. In some embodiments, R is of the formula:

[0283] In some embodiments, R comprises a MEK inhibitor. In some embodiments, R comprises selumetinib. In some embodiments, R is of the formula:some embodiments, R comprises trametinib. In some embodiments, R is of the formula:some embodiments, R comprises cobimetinib. In some embodiments, Rsome embodiments, R is of the formula:

[0284] In some embodiments, R comprises a receptor tyrosine kinase inhibitor. In some embodiments, R comprises dasatinib. In some embodiments, R is of the formula:some embodiments, R comprises bemcentinib (R428).In some embodiments, R is of the formula:embodiments, R comprises dubermatinib (TP-0903). In some embodiments, R is of theformula:in some embodiments, R comprises cabozantinib. In some embodiments, R is of the formula:

[0285] In some embodiments, Ris a colony stimulating factor- 1 receptor (CSFIR) inhibitor. In some embodiments, Ris pexidartinib, imatinib, dasatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580, or a derivative or analog thereof. In some embodiments, Ris pexidartinib, dasatinib, or PLX5622, or a derivative or analog thereof. In some embodiments, Ris pexidartinib, dasatinib, or PLX5622. In some embodiments, Ris pexidartinib. In some embodiments, Ris imatinib. In some embodiments, Ris dasatinib. In some embodiments, Ris PLX5622. In some embodiments, Ris ARRY-382. In some embodiments, Ris sotuletinib. In some embodiments, Ris edicotinib. In some embodiments, Ris Ki20227. In some embodiments, Ris GW 2580.

[0286] In certain embodiments, Ris a derivative of: pexidartinib, imatinib, dasatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580. In certain embodiments, Ris a derivative of: pexidartinib, dasatinib, or PLX5622. In certain embodiments, Ris a derivative of pexidartinib. In certain embodiments, Ris a derivative of imatinib. In certain embodiments, Ris a derivative of dasatinib. In certain embodiments, Ris a derivative of PLX5622.In certain embodiments, Ris a derivative of ARRY-382. In certain embodiments, Ris a derivative of sotuletinib. In certain embodiments, Ris a derivative of edicotinib. In certain embodiments, Ris a derivative of Ki20227. In certain embodiments, R is a derivative of GW 2580.

[0287] In some embodiments, the derivative or analog of pexidartinib, imatinib, dasatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580, comprises Z2between Z and the core structure of pexidartinib, imatinib, dasatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580; where Z2is a linker. Thus, in some embodiments, the compound is of the formula:or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments, Z2is a linker comprising a disulfide bond (i.e., -S-S-). In certain embodiments, Z2is -S-S-CH2-CH2- or -CH2-CH2-S-S-.

[0289] In some embodiments, Z2is a linker comprising a carbonyl. In some embodiments, Z2is a linker comprising an amine. In some embodiments, Z2is -NH-CH2-C(=O)- or -C(=O)- CH2-NH-.

[0290] In some embodiments, Z2is a linker comprising two rings. In some embodiments, Z2is of the formula:, wherein Ring A and Ring B are each independently a carbocyclylene, heterocyclylene, arylene, or heteroarylene. In some embodiments, Ring A is a carbocyclylene or heterocyclylene, and Ring B is an arylene or heteroaryiene. In some embodiments, Ring A is a heterocyclylene, and Ring B is a heteroaryiene. In some embodiments, Ring A is piperidinylene or piperazinylene, and Ring B is pyrazolylene. In,,In some embodiments, Rissome embodiments, RisComposition Preparation and Fonmilation

[0293] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmaceutics. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient” (i.e., the dendrimer conjugate comprising the therapeutic agent) into association with an excipient, such as N-(8-[2- hydroxybenzoyl]amino)caprylic acid, caprylic acid, capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and / or a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0294] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0295] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w / w) active ingredient.

[0296] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents or fillers, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0297] Exemplary diluents or fillers include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, starches (such as dsy starch, cornstarch), sugars (such as powdered sugar), calcium trisulfate, carboxymethylcellulose calcium, dextrate, dextrin, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium, maltitol, maltodextrin, maltose, sucrose, glucose, mannitol, silicic acid, xylitol, and mixtures thereof.

[0298] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar,bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0299] Exemplary' surface active agents and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myij® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, pol oxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0300] Exemplary disintegrating agents or disintegrants include agar, algin, alginic acid, sodium alginate, silicates, sodium carbonate, calcium carbonate, carboxymethylcellulose, cellulose, clay, colloidal silicon dioxide, croscarmellose sodium, crospovidone, rubber, magnesium silicate, methylcellulose, potassium krillin, hydroxypropylcellulose (e.g., low substituted Hydroxypropylcellulose), crosslinked polyvinylpyrrolidone, hydroxypropylcellulose, and starch (e.g., sodium glycolate starch, potato or tapioca starch).

[0301] Exemplary binding agents include starch (e.g., glycolate starch, cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, polyvinylpyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0302] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0303] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0304] Exemplary’ chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.

[0305] Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0306] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0307] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0308] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, betacarotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0309] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, NeoIone®, Kathon®, and Euxyl®.

[0310] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen- free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof.

[0311] Exemplar}' lubricating agents include agar, ethyl oleate, ethyl laurate, glycerin, blyceryl palmitostearate, magnesium oxide, magnesium stearate, mannitol, poloxamer, glycol, sodium stearyl, sorbitol, zinc stearate, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0312] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplar}' syntheticoils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyl dodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0313] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0314] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0315] In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a ready -to-use (“RTU”) preparation that can be directly administered to a subject. In some embodiments, the RTU preparation is a suspension. In some embodiments, the RTU preparation is a solution. In some embodiments, the RTU preparation is an emulsion. In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a solid that is reconstituted prior to administration. In some embodiments, the solid is a lyophilized solid. In some embodiments, injectable preparationsof the compositions disclosed herein are in the form of a liquid or suspension that is diluted prior to administration.

[0316] In some embodiments, the pharmaceutical compositions disclosed herein comprise a bulking agent. Bulking agents can be used, e.g., to improve the appearance of a solid composition, to provide visible “bulk” to demonstrate product quality or to facilitate preparation, e.g., of a solid composition prepared for reconstitution prior to administration. Bulking agents can be used for low dose (high potency) drugs that do not have the necessary bulk to support their own staicture or provide a visible composition in a unit dosage form. Bulking agents are used in lyophilized formulations. Bulking agents provide a desirable structure for a lyophilized cake comprising pores that provide the means for vapor to escape from the product during lyophilization cycles and facilitate dissolution on reconstitution. In some embodiments, the bulking agent is mannitol, lactose, sucrose, dextran, trehalose, povidone, dextran, glycine, isoleucine, methionine, or a cyclodextrin (e.g., (2- hydroxypropyl)-p-cyclodextrin).

[0317] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0318] In order to prolong the effect of a therapeutic agent, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0319] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0320] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol,and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0321] Solid compositions of a similar type can be employed as fdlers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0322] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0323] Dosage forms for topical and / or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0324] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and / or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder / particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0325] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0326] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation suitable for pulmonary' administration via the buccal cavity. Such a formulation may comprise dry / particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and / or using a self-propellingsolvent / powder dispensing container such as a device comprising the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. .Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0327] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally, the propellant may constitute 50 to 99.9% (w / w) of the composition, and the active ingredient may constitute 0.1 to 20% (w / w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0328] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and / or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and / or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0329] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0330] Formulations for nasal administration may, for example, comprise from about as little as 0. 1% (w / w) to as much as 100% (w / w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for buccal administration.Such formulations may, for example, be in the form of tablets and / or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w / w) active ingredient, the balance comprising an orally dissolvable and / or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Such powdered, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0331] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1 -1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and / or one or more other of the additional ingredients described herein. Other ophthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are also contemplated as being within the scope of this disclosure.

[0332] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0333] Compositions provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician wdthin the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of thespecific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0334] The compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the composition described herein is suitable for topical administration to the eye of a subject.

[0335] The exact amount of a dendrimer conjugate required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the mul tiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to asubject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 ug and 1 pg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a dendrimer conjugate described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0336] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0337] A composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and / or in inhibiting the activity of a protein kinase in a subject or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve differenteffects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects.

[0338] The composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactic ally active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing a disease (e g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder). Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or composition described herein in a single dose or composition or administered separately in different doses or compositions. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0339] The additional pharmaceutical agents include, but are not limited to, anti -proliferative agents, anti -cancer agents, anti-angiogenesis agents, steroidal or non-steroidal anti- inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti -allergic agents,contraceptive agents, pain-relieving agents, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, analgesics, anti-pyretics, hormones, and prostaglandins. In certain embodiments, the additional pharmaceutical agent is an anti -proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti -cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of a protein kinase. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, a\\-trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the compounds or pharmaceutical compositions described herein can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy. Additional pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the US Food and Drug Administration as provided in the Code of Federal Regul ations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.Kits

[0340] In one aspect, provided herein are kits comprising a composition as provided herein; and instructions for using the composition.

[0341] In some embodiments, the kit compri ses a single dose or a plurality of doses of a composition comprising a dendrimer conjugate of the disclosure, and instructions for administering the composition. In some embodiments, the instructions direct that an effective amount of the composition be administered to an individual with a particular condition / disease as indicated and in accordance with the disclosure. The composition can beformulated as described above with reference to a particular treatment method and can be packaged in any convenient manner.

[0342] In some embodiments, a kit comprises one or more containers, such as a vial, test tube, flask, bottle, syringe, or other container means into which a component may be placed, where at least one container comprises a composition of the disclosure. In some embodiments, the kit comprises a single container comprising a composition of the disclosure. In some embodiments, the kit comprises two or more (e.g., 2, 3, 4, 5, or more) containers comprising the composition. In some embodiments, the components of a kit are packaged in solution or lyophilized form. In some embodiments, the kit comprises at least one container comprising the composition in lyophilized form, and at least one container comprising a liquid component for reconstituting the composition in solution form. In some embodiments, the kit comprises at least one container comprising one or more stabilizers, bulking agents (e.g., mannitol), or other additives known in the art.Methods

[0343] Provided herein are methods of modulating biological processes, as well as methods of treating and preventing diseases. The methods of modulating biological processes may lead to treating and preventing diseases.

[0344] Thus, in one aspect, provided herein are methods of modulating a target in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a composition provided herein, wherein the target is an angiotensin II receptor, Farnesoid X receptor (FXR), death receptor 5, sodium-glucose cotransporter type-2 (SGLT2), lysophosphatidic acid 1 receptor, endothelin-A receptor, peroxisome proliferator-activated receptor delta (PPAR8), ATI receptor, CCR5 / CCR2, stimulator of interferon genes (STING), vascular endothelial growth factor receptor (VEGFR), colony-stimulating factor 1 receptor (CSF1R), AXL, c-Met, poly(ADP-ribose) polymerase (PARP), receptor tyrosine kinase, MEK, PAK1, glutaminase, TIE II, chemokine receptor 2 (CXCR2), CD73, arginase, phosphatidylinositol-3-kinase (PI3K), toll-like receptor 4 (TLR4), toll-like receptor 7 (TLR7), Src homology -2 domain-containing protein tyrosine phosphatase-2 (SHP2), STING, JAK1, TREM2, and TYK2. In some embodiments, the modulation is inhibition. In certain embodiments, the method treats a disease or disorder. In some embodiments, the modulation is in vitro or ex vivo.

[0345] In another aspect, provided herein are methods of modulating a target in a subject, the method comprising administering to the subject an effective amount of a compositionprovided herein, wherein the target is an angiotensin II receptor, Farnesoid X receptor (FXR), death receptor 5, sodium-glucose cotransporter type-2 (SGLT2), lysophosphatidic acid 1 receptor, endothelin-A receptor, peroxisome proliferator-activated receptor delta (PPAR8), ATI receptor, CCR5 / CCR2, stimulator of interferon genes (STING), vascular endothelial growth factor receptor ( VEGFR), colony-stimulating factor 1 receptor (CSF1R), AXL, c-Met, poly(ADP -ribose) polymerase (PARP), receptor tyrosine kinase, MEK, PAK1, glutaminase, TIE II, chemokine receptor 2 (CXCR2), CD73, arginase, phosphatidylinositol-3-kinase (PI3K), toll-like receptor 4 (TLR4), toll-like receptor 7 (TLR7), Src homology-2 domaincontaining protein tyrosine phosphatase-2 (SHP2), STING, JAK1, TREM2, and TYK2. In some embodiments, the modulation is inhibition. In certain embodiments, the method treats a disease or disorder. In some embodiments, the modulation is in vitro or ex vivo.

[0346] In one aspect, provided herein are methods of modulating receptor tyrosine kinase in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a composition provided herein. In some embodiments, the modulation is inhibition. In certain embodiments, the method treats a disease or disorder. In some embodiments, the modulation is in vitro or ex vivo.

[0347] In another aspect, provided herein are methods of modulating receptor tyrosine kinase in a subject, the method comprising administering to the subject an effective amount of a composition provided herein. In some embodiments, the modulation is inhibition. In certain embodiments, the method treats a disease or disorder. In some embodiments, the modulation is in vitro or ex vivo.

[0348] In one aspect, provided herein are methods of modulating VEGFR in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a composition provided herein. In some embodiments, the modulation is inhibition. In certain embodiments, the method treats a disease or disorder. In some embodiments, the modulation is in vitro or ex vivo.

[0349] In another aspect, provided herein are methods of modulating VEGFR in a subject, the method comprising administering to the subject an effective amount of a composition provided herein. In some embodiments, the modulation is inhibition. In certain embodiments, the method treats a disease or disorder. In some embodiments, the modulation is in vitro or ex vivo.

[0350] In one aspect, provided herein are methods of modulating CSF1R in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a composition provided herein. In some embodiments, themodulation is inhibition. In certain embodiments, the method treats a disease or disorder. In some embodiments, the modulation is in vitro or ex vivo.

[0351] In another aspect, provided herein are methods of modulating CSF1R in a subject, the method comprising administering to the subject an effective amount of a composition provided herein. In some embodiments, the modulation is inhibition. In certain embodiments, the method treats a disease or disorder. In some embodiments, the modulation is in vitro or ex vivo.

[0352] In another aspect, provided herein are methods of treating a disease or disorder in a subject, the method comprising administering to the subject an effective amount of a composition provided herein.

[0353] In some embodiments, the disease or disorder is a disease or disorder of the eye, a neurological disorder, an inflammatory disease, an autoimmune disorder, a cancer, a central nervous system disease, a painful condition, a bone disease, or a tumor.

[0354] In certain embodiments, the disease or disorder is a disease or disorder of the eye. In some embodiments, the disease or disorder of the eye is an inflammatory or angiogenic disease of the eye. In certain embodiments, the disease or disorder of the eye is selected from the group consisting of age-related macular degeneration (AMD), macular edema, retinitis pigmentosa, optic neuritis, uveitis, retinal detachment, temporal arteritis, retinal ischemia, arteriosclerotic retinopathy, hypertensive retinopathy, retinal artery blockage, retinal vein blockage, diabetic retinopathy, retinal neovascularization, and choroidal neovascularization. In some embodiments, the disease or disorder of the eye is wet AMD. In certain embodiments, the disease or disorder of the eye is diabetic macular edema (DME).

[0355] In some embodiments, the disease or disorder is a neurological disorder, an inflammatory disease, an autoimmune disorder, a cancer, a central nervous system disease, a painful condition, a bone disease, or a tumor.

[0356] In some embodiments, the disease or disorder is a neurological disorder. In certain embodiments, the neurological disorder is a neurodegenerative disorder. In certain embodiments, the neurodegenerative disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. In certain embodiments, the neurodegenerative disorder is amyotrophic lateral sclerosis (ALS). In certain embodiments, the neurodegenerative disorder is multiple sclerosis (MS). In certain embodiments, the multiple sclerosis is relapsing remitting MS, primary progressive multiple sclerosis, or secondary progressive MS. In certain embodiments, the neurodegenerative disorder isAlzheimer’s disease. In certain embodiments, the neurodegenerative disorder is Parkinson’s disease. In certain embodiments, the neurodegenerative disorder is Huntington’s disease. In certain embodiments, the neurological disorder is epilepsy.

[0357] In certain embodiments, the disease or disorder is an inflammatory disease.

[0358] In some embodiments, the disease or disorder is an autoimmune disorder.

[0359] In some embodiments, the inflammatory disease or autoimmune disease is selected from the group consisting of arthritis, inflammatory bowel disease, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison’s disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune thrombocytopenic purpura, Bechet’s disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, cicatricial pemphigoid, cold agglutinin disease, Crest syndrome, Crohn’s disease, Degos disease, dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura, IgA nephropathy, insulin-dependent diabetes, Meniere’s disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud’s phenomenon, Reiter’s syndrome, rheumatic fever, sarcoidosis, scleroderma, Sjogren’s syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener’s granulomatosis. In some embodiments, the arthritis is rheumatoid arthritis or psoriatic arthritis.

[0360] In certain embodiments, the disease or disorder is a cancer. In certain embodiments, the cancer is brain cancer, breast cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, gastric cancer, esophagus cancer, lung cancer, liver cancer, renal cell cancer, skin cancer, colon cancer, a sarcoma, a lymphoma, a leukemia, or a malignant tumor. In some embodiments, the skin cancer is melanoma. In certain embodiments, the melanoma is acral melanoma or mucosal melanoma. In certain embodiments, the brain cancer is glioblastoma. In some embodiments, the lymphoma is Hodgkin lymphoma or non-Hodgkin lymphoma. In certain embodiments, the leukemia is chronic myeloid leukemia chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (.ALL).

[0361] In some embodiments, the disease or disorder is a central nervous system disease. In certain embodiments, the central nervous system disease is Charcot-Marie-Tooth disease type 1.

[0362] In certain embodiments, the disease or disorder is a painful condition. In some embodiments, the painful condition is neuropathic pain.

[0363] In some embodiments, the disease or disorder is a bone disease. In some embodiments, the bone disease is osteoporosis or osteolysis.

[0364] In certain embodiments, the disease or disorder is a tumor. In some embodiments, the tumor is a solid tumor, diffuse-type tenosynovial giant cell tumor, or neurofibroma.

[0365] In some embodiments, the composition is administered to the subject systemically. In certain embodiments, the composition is administered to the subject intraperitoneally, intravenously, intrathecal ly, intratum orally, or orally. In certain embodiments, the composition is administered to the subject orally.

[0366] In some embodiments, the effective amount is from about 1 mg / kg to about 50 mg / kg of the subject. In some embodiments, the effective amount is from about 1 mg / kg to about 30 mg / kg of the subject. In some embodiments, the effective amount is from about 1 mg / kg to about 5 mg / kg, from about 5 mg / kg to about 15 mg / kg, from about 10 mg / kg to about 20 mg / kg, or from about 20 mg / kg to about 30 mg / kg of the subject. In some embodiments, the effective amount is about 2 mg / kg, about 5 mg / kg, about 17 mg / kg, or about 26.5 mg / kg of the subject.EXAMPLES

[0367] In order that the present disclosure may be more fully understood, the following examples are set forth. The examples described in this Application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.Example 1

[0368] Male C57B1 / 6 mice (n=8) were enrolled into each of 9 groups and underwent laser- induced choroidal neovascularization (CNV) in both eyes (OU) on Day 0. Animals receiving intravitreal (IVT) treatment OU (Groups 1 and 2) were dosed immediately following CNV. Animals dosed subcutaneously (SQ; Group 3) or via oral gavage (OG; Groups 4-9) received treatment 24 hours post-CNV. Group 1 animals received a 1 pL IVT injection of vehicle;Group 2 animals received a 1 pL, 40 pg (40 mg / mL) IVT injection of aflibercept (positivecontrol); Group 3 animals received a 200 pL, 40 pg (2 mg / kg) SQ injection of D-4517.2;Group 4 animals received a 100 pL, 40 pg (2 mg / kg) OG dose of Oral Formulation 1; Group 5 animals received a 100 pL, 200 pg (10 mg / kg) OG dose of Oral Formulation 1 ; Group 6 animals received a 100 pL, 40 pg (2 mg / kg) OG dose of Oral Formulation 2; Group 7 animals received a 100 pL, 200 pg (10 mg / kg) OG dose of Oral Formulation 2; Group 8 animals received a 100 pL, 40 pg (2 mg / kg) OG dose of Oral Formulation 3; and Group 9 animals received a 100 pL, 200 pg (10 mg / kg) OG dose of Oral Formulation 3. Ocular examinations (OEs) were performed at baseline for enrollment. Color fundus imaging was performed on Day 0 following CNV. Fluorescein angiography (FA) was performed on Days 7 and 14. On Day 14, the animals were euthanized, and all eyes were collected and processed for RPE choroid flat-mount analysis of isolectin lesion area.Table 1. Experimental DesignAbbreviations: CNV -- choroidal neovascularization; ROA - route of administration; Gr - group; N - number of mice; Tx - treatment; IVT - intravitreal; SQ - subcutaneous; OG - oral gavage; OE - ocular exam

[0369] Following study start, there was one change to the protocol. Groups 3-9 were dosed 24 hours after CNV to harmonize with previous study designs.Test Articles

[0370] Aflibercept is commercially available and was injected neat without dilution. The test articles (TAs) and excipients were stored at 2-8°C upon receipt.

[0371] For SQ dosing, a stock solution of D-4517.2 at 200 mg / mL (ABZ 2934) was diluted with a formulation buffer containing 6.3% trehalose dihydrate and 10 mM histidine (pH 5.5; Lot # SKT-880-028 Buffer) to prepare the formulation solution at 0.2 mg / mL. Two 0.5 mL aliquots were used for dose concentration analysis.

[0372] For OG dosing, D-4517.2 (SKT-880-027.1) was reconstituted in excipients for oral gavage prior to dosing. A stock solution of D-4517.2 (SKT-880-027.1) in water at 30 mg / mL was prepared and split into 3 equal parts for each of the oral formulations. D-4517.2 dissolved easily at 30 mg / mL with vortex and sonication. Two 0.5 mL aliquots were set aside and used for concentration analysis. The appropriate permeation enhancers were weighed and diluted into water for injection (WFI) per Table 2, then vortexed and sonicated to mix until no solids were left. The compound dissolved easily under these conditions; exact times were not recorded. The dissolved permeation enhancers were added to the D-4517.2 resuspended in water to obtain the desired concentration. The solution was vortexed for 2 minutes to obtain a clear orange solution, which was checked visually to ensure that no solids remained. Two 0.5 mL aliquots were set aside and used for concentration analysis.Table 2. Test Article FormulationsDosing and ProceduresLaser-Induced Choroidal Neovascularization

[0373] On Day 0, mice were given buprenorphine 0.01-0.05 mg / kg SQ. Atopical mydriatic (1.0% tropicamide HG and 2.5% phenylephrine HC1) were applied at least 15 minutes prior to the laser procedure. The mice were tranquilized with an intraperitoneal (IP) injection of ketamine / xyl azine. The cornea was kept moistened using topical eyewash, and body temperature was maintained using hot pads. An 810 nm diode laser delivered through a slitlamp was used to create 4 single laser spots surrounding the optic nerve. Both mouse eyes underwent laser treatment according to the experimental design table. vitreal Injection

[0374] On Day 0 prior to injection, mice in Groups 1 and 2, while remaining anesthetized from the CNV procedure, were given one drop of 0.5% proparacaine HC1 OU. The conjunctiva was gently grasped with Dumont #4 forceps, and the injection was made using a 33 G needle and a Hamilton syringe. After dispensing the syringe contents, the syringe needle was slowly withdrawn. Following the injection procedure, 1 drop of Ofloxacin ophthalmic solution was applied topically to the ocular surface with eye lube. The animal was returned to its cage and allowed to recover normally.Subcutaneous Injection

[0375] Twenty-four (24) hours after the CNV procedure, while manually restrained, a 30G needle was used to administer 200 uL of TA into the loose skin between the shoulders to animals in Group 3. Following dosing, mice were returned to their cages. There were no abnormal observations regarding SQ dosing noted in the study records.Oral Gavage

[0376] Twenty-four (24) hours after the CNV procedure, each mouse in Groups 4-9 was gently scruffed and tilted slightly away from the handler. Using a rodent feeding needle / tube(18-24g), each mouse was given the TA designated in the experimental design table in a dosing volume of no more than 10 mL / kg. The animal was gently restrained to imm obilize the head. The distance from the oral cavity to the xiphoid process was measured to ascertain the distance of insertion for the feeding needle. While maintaining the animal in an upright (vertical) position, the gavage needle was passed along the left side of the mouth (following the roof of the mouth) and advanced into the esophagus and toward the stomach. After the needle was passed to the correct length, the TA was injected. Following dosing, mice were returned to their cage. There were no abnormal observations regarding OG dosing noted in the study records.ResultsCage-Side Examinations

[0377] Morbidity and mortality were observed daily along with cage-side observations with particular attention paid to both eyes.Ocular Examination

[0378] OEs were done using a slit-lamp biomicroscope to evaluate ocular surface morphology at baseline to determine enrollment into the study.

[0379] Due to the change in procedure noted previously, the mice in Group 3 that were lasered and dosed on the same day were humanely euthanized and replaced with all existing spares, which precluded exclusion of mice in Groups 3- 9 based on baseline ocular findings as no spares remained.Color Fundus Imaging

[0380] While remaining under sedation from the CNV procedure, color fundus imaging was performed on all enrolled eyes post-laser to visualize the lesions and assist with exclusions based on failure to rupture Bruch’s membrane. In addition to the 1.0% tropicamide HC1 and 2.5% phenylephrine HC1 administered pre-laser to dilate and proptose the eyes, animals were given 0.5% phenylephrine HC1 or similar.Fluorescein Angiography

[0381] On Days 7 and 14, FA was performed to visualize vascular leakage and, subsequently, measure the leakage area. Mydriasis for FA was achieved using a tropical mydriatic (1.0% tropicamide HC1 and 2.5% phenylephrine HC1; 1 drop in each eye 15 minutes prior to examination). Mice were tranquilized with an IP injection of ketamine / xylazine. Retinal photography was performed approximately 1 minute after intraperitoneal sodium fluorescein injection (50 mg / kg of 1% fluorescein stock).

[0382] At the Day 7 post-laser timepoint, animals in Groups 1, 5, and 8 had the largest lesion area (FIG. 1 and FIG. 2) while animals in Groups 3, 4, 6, and 7 had the smallest lesion area. In all groups, lesion area decreased from Day 7 to Day 14. On Day 14, Group 1 animals had the largest lesion area, while animals in Groups 3, 6, 7, and 9 had the lowest lesion area.

[0383] Statistical analysis of the FA lesion area between vehicle-treated eyes and experimental eyes was performed. On Day 7, vehicle-treated eyes had significantly larger lesion area than eyes of animals receiving 2 mg / kg D-4517.2 SQ (Group 3), 2 mg / kg Oral Formulation 1 (Group 4), and 10 mg / kg Oral Formulation 3 at p<0.05 (Group 9), and significantly larger lesion area than eyes of animals receiving 2 mg / kg and 10 mg / kg Oral Formulation 2 (Groups 6 and 7; p<0.01). There was no significant difference between the lesion area of vehicle-treated eyes and eyes treated with aflibercept or the eyes of animals treated with 10 mg / kg Oral Formulation 1, and 2 mg / kg Oral Formulation 3 (FIG. I).

[0384] On Day 14, vehicle-treated eyes had significantly larger lesion area than eyes of animals receiving 2 mg / kg D-4517.2 SQ (Group 3) at / ?<0.05, and 2 mg / kg and 10 mg / kg Oral formulation 2 (Groups 6 and 7; p < 0.01 ) and 10 mg / kg Oral Formulation 3 (Group 9) at p<0.01. There was no significant difference between the lesion area of vehicle-treated eyes (Group 1) and eyes treated with aflibercept (Group 2) or the eyes of animals treated with, 2 mg / kg and 10 mg / kg Oral Formulation 1 (Groups 4 and 5), and 2 mg / kg Oral Formulation 3 (Group 8; FIG. 2).

[0385] Statistical comparisons of the lesion area between vehicle-treated eyes (Group 1), aflibercept (Group 2), D-4517.2 (Group 3), and 2 mg / kg and 10 mg / kg Oral Formulation 2 (Groups 6 and 7) was also performed. There was no significant difference in lesion area between vehicle-treated eyes and IVT aflibercept-treated eyes (FIG. 3). The lesion area of vehicle-treated eyes was significantly larger than eyes from animals receiving 2 mg / kg D- 4517.2 SQ at p<0.05, and significantly larger than eyes from animals receiving 2 mg / kg and 10 mg / kg Oral Formulation 2 at p<0.01; the 2 and 10 mg / kg doses were not significantly different from each other.

[0386] For representative images of Day 7 FA, see FIG. 4. For representative images of Day 14 FA, see FIG. 5.Euthanasia and Tissue Collection

[0387] Following FA on Day 14, animals were euthanized via carbon dioxide asphyxiation and death was confirmed by cervical dislocation. All eyes were collected for RPE choroid flatmount analysis.RPE Choroid Flat-Mounts

[0388] Eyes were enucleated and immediately fixed in 4% paraformaldehyde (PFA) in phosphate- buffered saline (PBS) overnight at 4°C. The following day, the eyes were transferred to cold immunocytochemistry (ICC) buffer (PBS containing 0.5% bovine serum albumin [BSA] and 0.2% Tween 20) until processing. Following overnight fixation and using a dissecting microscope, the eyes were trimmed of extraneous tissue and the anterior segment and lens were removed. The retina was detached and removed from the optic nerve head with fine curved scissors. Eye cups were rinsed with cold ICC buffer.

[0389] Eye cups were placed in cold ICC buffer containing 4’,6-diamidino-2-phenylindole (D.API; nuclear stain), isolectin IB4 DyLight 649 (marks all vasculature; Vector Labs DL- 1208-.5), and AlexaFluor 488 Phalloidin (f-actin; ThermoFisher cat# A12379). Eye cups were incubated at 4°C with gentle rotation for 4 hours and then washed with cold ICC buffer. Radial cuts were then made toward the optic nerve head avoiding lesions, and the sclera- choroid / retinal pigment epithelium (RPE) complexes were flat-mounted, covered, and sealed. Two-dimensional (2D) fluorescent microscopy images were acquired, digitized, and analyzed using an Olympus Bx63 upright fluorescent microscope and CellSens (Olympus) software and post-acquisition analysis was performed with CellSens software. Isolectin 1B4 is a lectin that binds to the cell surface of endothelial cells and was used as a marker for choroid neovascularization following laser induced Bruch’s membrane disruption. To quantify neoformed vessels, the isolectin IB4 area was measured in pm2.

[0390] On Day 14, the lesion area was largest in Groups 1, 2, and 5 (FIG. 6), and Groups 4, 7, and 8 had the smallest lesion area.

[0391] Statistical analysis was performed on the Day 14 isolectin IB4 lesion area measurements. The lesion area of vehicle-treated eyes was significantly larger than eyes from animals treated with 2 mg / kg D-4517.2 SQ (Group 3; p<0.01) 2 mg / kg Oral Formulation 2 (Group 6; / ?<0.01), 2 mg / kg Oral Formulation 1 (Group 4; / ?<0.001), 10 mg / kg Oral Formulation 3 (Group 9; p<0.001), 10 mg / kg Oral Formulation 2 (Group 7; / ?<0.0001) and the 2 mg / kg Oral Formulation 3 (Group 8; / ?<0.0001). There were no significant differences between vehicle-treated eyes and eyes from animals receiving IVT aflibercept (Group 2) or 10 mg / kg Oral Formulation 1 (Group 5; FIG. 6).

[0392] Statistical analysis was performed of the isolectin IB4 lesion area between vehicle- treated eyes and eyes from animals receiving 2 mg / kg Oral Formulations 1, 2, and 3 (FIG. 7). The lesion area of vehicle-treated eyes was significantly larger than the lesion area of eyes from animals receiving 2 mg / kg D-4517.2 SQ (Group 3; p<0.01) and 2 mg / kg OralFormulation 2 (Group 6; / ?<0.01), 2 mg / kg Oral Formulation 1 (Group 4; p<0.001), and the 2 mg / kg Oral Formulation 3 (Group 8; p<0.0001). There was no significant difference in the lesion area between vehicle-treated eyes and aflibercept-treated eyes (FIG. 7).

[0393] Statistical analysis on the isolectin IB4 lesion area between vehicle-treated eyes and eyes from animals receiving 2 mg / kg and 10 mg / kg Oral Formulation 2 was performed (FIG. 8). The lesion area of vehicle-treated eyes was significantly larger than in eyes from animals receiving 2 mg / kg D-4517.2 SQ (Group 3; p<0.01), 2 mg / kg Oral Formulation 2 (Group 6; <0.01) and the 10 mg / kg Oral Formulation 2 (Group 7; p<0.0001). The lesion area of eyes from animals receiving 2 mg / kg Oral Formulation 2 (Group 6) was larger than the lesion area of eyes from animals receiving 10 mg / kg Oral Formulation 2 (Group 7); the difference approached significance (p=0.07).Conclusion

[0394] Presented herein is an evaluation of the efficacy of different formulations and routes of administration in a laser-induced model of CNV in the mouse. On Day 0, mice underwent laser-induced CNV OU. Immediately post-laser, Group 1 animals received vehicle IVT OU and Group 2 animals received 40 mg / kg aflibercept IVT OU. On Day 1, Group 3 animals received 0.2 mg / kg D-4517.2 SQ. On Day 1, animals in Groups 4-9 received OG doses of the Sponsor’s TAs: Group 4 received 2 mg / kg Oral Formulation 1; Group 5 received 10 mg / kg Oral Formulation 1; Group 6 received 2 mg / kg Oral Formulation 2; Group 7 received 10 mg / kg Oral Formulation 2; Group 8 received 2 mg / kg Oral Formulation 3; and Group 9 received 10 mg / kg Oral Formulation 3.

[0395] Ocular examinations (OEs) were performed at baseline for enrollment. With the exception of 401 OD, which was excluded for a corneal opacity, all other eyes with baseline ocular findings were enrolled into the study due to a lack of available spare animals following a change in study design post-study start.

[0396] Color fundus imaging was performed on Day 0 following CNV These images provided documentation of successful disruption of Bruch’s membrane and served as a reference for subsequent analysis of area either as a measure of leakage (i.e. fluorescein angiography) or neovascularization (i.e. isolectin staining on flat-mounts). Fluorescein angiography (FA) was performed on Days 7 and 14, which allowed vessel leakage area to be monitored over time. On Day 7, animals in Groups 1, 5, and 8 (vehicle, 10 mg / kg Oral Formulation 1, and 2 mg / kg Oral Formulation 3, respectively) had the largest lesion area while animals in Groups 6 and 7 (2 mg / kg Oral Formulation 2 and 10 mg / kg Oral Formulation 2, respectively) had the smallest lesion area. In all groups, lesion area decreasedfrom Day 7 to Day 14. On Day 14, Group 1 animals had the largest lesion area, while animals in Groups 6 (2 mg / kg Oral Formulation 2), 7 (10 mg / kg Oral Formulation 2), and 9 (10 mg / kg Oral Formulation 3) had the smallest lesion area. On Day 14, the animals were euthanized, and all eyes were collected and processed for RPE choroid flat-mount analysis of isolectin lesion area. The flat-mount analysis of isolectin staining allows for visualization of the neovascular morphological structure; measurement of lesion area is considered a primary endpoint in this model. Similar to the Day 14 FA lesion area measurements, on Day 14, the isolectin lesion area was largest in Groups 1, 2, and 5 (vehicle, aflibercept, and 10 mg / kg Oral Formulation 1, respectively); in contrast to the Day 14 FA data, Groups 7 and 8 (10 mg / kg Oral Formulation 2 and 2 mg / kg Oral Formulation 3, respectively) had the smallest isolectin area.

[0397] Groups 6 (2 mg / kg Oral Formulation 2) and 7 (10 mg / kg Oral Formulation 2) consistently outperformed aflibercept in both the FA leakage area and isolectin measurements of neovascularization. While 2 mg / kg Oral Formulation 1 and 10 mg / kg Oral Formulation 3 also outperformed aflibercept at Day 14 via FA, both had higher variability when compared to Oral Formulation 2.Example 2

[0398] Ocular diseases such as neovascular (wet) age-related macular degeneration (AMD) and diabetic macular edema (DME) have been treated with anti-VEGF therapies (such as aflibercept and ranibizumab) through direct injection into the vitreous of the eye. These approaches require aseptic techniques and a trained retinal ophthalmologist to administer the drug. The administration of anti-VEGF therapies by direct injection to the eye creates a large burden on the patients and treating retinal ophthalmologists due to the frequency of injection (every 4 to 12 weeks) and the increasing number of wet AMD and DME patients. Therefore, D-4517.2 has been designed to target wet AMD and DME as a systemic therapy. D-4517.2 showed to reduce choroidal neovascular lesions after a single subcutaneous injection to a comparable or greater extent than an intravitreal injection of aflibercept (scaled from human dose) in a mouse model of wet AMD. Safety of D-4517.2 in chronic rat and dog studies has already been well established with subcutaneous dosing.Dose Formulation

[0399] Details of Dosing formulations are included in Table 3Table 3. Dose Formulation DetailsExperimental Design

[0400] Experimental design is described in Table 4.Table 4. Experimental Design and Study Groups*For group 4-6, each animal was dosed with 2 mini capsules (within 2-5 minutes interval), **Rats from groups#4 and 5 were dosed with each capsule containing 3.3mg of D-4517.2, leads to 6.6mg D-4517.2 / animal which is equivalent to 26.4mg / kg of 250gm rat.****Rats from groups#6 were dosed with each capsule containing 2.1mg of D-4517.2, leads to 4.2mg D-4517.2 / animal which is equivalent to 17.1mg / kg of 250gm rat.

[0401] Male Sprague Dawley rats were received by an approved vendor and allowed to acclimate to the Test Facility for at least 2 days. Animals were fasted overnight. Food was returned following the 4 hours post dose blood collection, or approximately 4 hours post dose.

[0402] The formulation was administered once on Day 1 as specified in the experimental design. Intravenous administration was administered via direct stick into a lateral tail vein in Group 1. Oral capsule administration was done via appropriately sized capsule dosing apparatus for size 9el capsules. Each animal received 2 capsules at 2-5-minute intervals in Groups 4-6.

[0403] The following parameters and endpoints were evaluated: mortality, clinical observations, and body weights. Animal body weights were collected prior to dosing. All serial bleeds were scheduled based on the time of the first dose. Serial blood samples were collected via sublingual vein or by another approved method. The method of each collection was recorded. Blood samples were collected into K2EDTA tubes and stored on wet ice until processed. Whole blood samples were processed to plasma by centrifugation (3500rpm for 10 minutes at 5°C) within 30 minutes of collection . Plasma was transferred into cluster tubes and stored at -80°C until transferred. The cellular fraction was discarded. Samples were shipped on dry ice for analysis.Table 5. Individual Dose AdministrationNAA: not applicable; animal not dosed due to limited test article availability* Assumes a formulation density of Ig / mL**Capsules were dosed at a 2-5-minute interval to respective group and considered as single dose.Bioanalysis Evaluation

[0404] Approximately 250 pL of blood samples were collected into K2EDTA tubes and stored on wet ice until processed. Blood was collected for all groups at 0.5, 2, 4, 8, and 24 hours post dose. Whole blood samples were processed to plasma by centrifugation (3500rpm for 10 minutes at 5°C) within 30 minutes of collection. Plasma was transferred into cluster tubes and stored at -80°C until transferred. The cellular fraction was discarded. Samples were shipped on dry ice for analysis.

[0405] Blood samples were collected into K2EDTA tubes from the sublingual vein at 0.5, 2, 4, 8 and 24 hours after dosing. Alturas Analytical (Moscow, ID) determined plasma D-4517.2 concentrations using a qualified LC / MS / MS assay with a lower limit of quantification of 0.05 to 0.25 pg / mL. Pacific BioDevelopment performed noncompartmental pharmacokinetic analysis using Phoenix WinNonlin (version 8.3). FIG. 9 shows a plasma exposure graph showing the plasma exposure levels of the different oral formulations of D-4517.2 from rat plasma at different timepoints (0.5, 2, 4, 8 and 24-hours post injection).

[0406] Maximum plasma concentrations (Cmax), the area under the plasma concentration versus time curve (AUC) and dose-normalized AUG are shown in Table 6. The fraction of drug absorbed (F) was calculated from the ratio of the dose normalized AUC to that for the IV dose group.Table 6. D-4517.2 PK ParametersConclusion

[0407] The rats treated with SNAC containing formulations demonstrated improved oral bioavailability.Example 3

[0408] The efficacy evaluation of H74DS3M8 in a mouse model of multiple sclerosis (MS) i.e., Experimental Autoimmune Encephalomyelitis (EAE) is described in this example.

[0409] Neuroinflammation is a major contributor to disease progression in multiple sclerosis and is driven by activated myeloid cells. Hydroxyl-dendrimer nanoparticles can selectively target these activated myeloid cells to deliver both therapeutics and imaging agents. Targeting colony stimulating factor 1 receptor (CSF1R) with selective tyrosine kinase inhibitors such as dasatinib and masitinib lowers experimental autoimmune encephalomyelitis (E.AE) severity and decreases the progression of progressive multiple sclerosis. These effects are associated with a dramatic reduction in microgliosis and neuroinflammation, and targeting these mechanisms may have significant implications for the inflammation-driven disease processes in MS. However, these drugs have been shown to be associated with serious hepatic and renal toxicity in preclinical species and in humans. A novel nanomedicine was developed that is a hydroxyl dendrimer conjugated to a CSF1R tyrosine kinase inhibitor, an analog of dasatinib, which selectively targets only activated myeloid cells, thus avoiding systemic toxicity. This molecule, H74DS3M8, was previously tested in the same mouse model of EAE alongside 3 other lead candidates. The current study aimed to determine oral efficacy of H74DS3M8 administered twice a week at various dose levels.Study Design for Example 3

[0410] 8-week-old C57bl / 6 female mice were injected subcutaneously (v.c.) with MOG35-55 peptide emulsified in CFA (H37RA in Incomplete Freud’s Adjuvant) at day 0. Booster injections with Pertussis toxin (PTX) were given day 0 and day 2 to induce disease. Disease progression was followed macroscopically from day 5 throughout the study. Once a mean score of 1.5 was reached, the animals were divided into groups and the treatment was initiated the following day (day 11 after the inoculation). Vehicle and H74DS3M8 / SNAC (20mg / kg, 60 mg / kg, 200mg / kg, 400mg / kg and 580mg / kg) were administrated twice a week to the animals via oral gavage. H74DS3M8 (4.4% Trehalose -l OmM Histidine) (60mg / kg) was administrated daily via intraperitoneal (i.p.) injection or twice a week subcutaneously (s.c.). Fingolimod (3 mg / kg) and Dasatinib (30 mg / kg) were administrated to the animals via oral gavage (p.o.).

[0411] The blood was collected via sublingual vein 4h post treatment on day 22 of the treatment from all animals, except for Fingolimod group. Obtained serum was aliquoted into single tubes and stored at -20°C.

[0412] The termination was divided over 3 days: set 1 contained groups 2, 3, 4, 5 and 6; set 2 contained groups 7, 9 and 10; set 3 contained groups 1 and 8. On the day of termination of set 1 all the animals received the treatment.

[0413] Spinal cords from all animals were collected, except for the Fingolimod and Dasatinib groups, snap frozen in isopentane on dry ice and transferred to tubes. Kidneys and two lobes of the liver were collected at the termination and snap frozen in liquid nitrogen. The weight of the liver and spleen was taken. The liver for Fingolimod and Dasatinib groups was discarded after the weight measurement. The collected organs were stored at -80°C.

[0414] Experimental Autoimmune Encephalomyelitis (EAE) in mice is a CD4+ T cell mediated autoimmune disease and the most widely accepted animal model of the human disease Multiple Sclerosis (MS) with inflammatory lesions of the CNS causing peripheral paralysis. Disease is induced with one single injection of CNS proteins emulsified in adjuvant and is followed by highly reproducible disease onset about one week after induction. The most severe phase of disease is often observed between 15-20 days after induction and the experiment can be terminated at day 25-30. Inflammatory lesions of the CNS causing peripheral paralysis are characteristic for EAE in mice.Materials and Methods for Example 3

[0415] D-PBS (Life Technologies, 14190169). Stored at RT.

[0416] MOG35-55 (MDBioproducts, 3038001 lot# Y411). Stored at -20°C.

[0417] M tuberculosis H37RA (Difco, 231141, lot# 3026415). Stored at 4°C.

[0418] Incomplete Freund’s Adjuvant (IFA) (Difco, 263910, lot# 2349622). Stored at 4°C.

[0419] IsoFlo vet (Orion Pharma, Apoteket 002185). Stored at RT.

[0420] Test compound H74DS3M8-3, 60mg / ml in water. Stored at 4°C.

[0421] Test compound H74DS3M8-3, 6mg / ml 4.4% Trehalose Histidine. Stored at 4°C.

[0422] Salcaprozate sodium powder. Stored at 4°C.

[0423] Dasatinib (Sigma Aldrich, SML2589, lot#0000241365) Stored at -20°C.

[0424] DMSO (Sigma Aldrich, H0887). Stored at RT.

[0425] Pertussin toxin from Bordetella pertussis (Sigma- Aldrich, 516560, lot# 4047235). Stored at 4°C.

[0426] Animals and Husbandry. C57B1 / 6 mice (females, 7 weeks at delivery) were acquired from Janvier, France. Mice were housed in the animal facility, Medicon Village, Lund, Sweden and kept at 12h light / dark cycles, in polystyrene cages (type III cages, 10 mice per cage) containing wood shavings and fed standard rodent chow and water ad libitum . The mice were acclimatized for approximately one week before initiation of experiment. The mice were ear marked for identification at day 0. Treatment groups were mixed within cages to avoid cage effects.

[0427] Determination of Mean Weight and Group Assignments. All mice were ’weighed at day 0 for determination of mean weight of the mice included in the study. The mean weight of all mice included in the experiment was determined to be 20.65 ± 0.09 grams on day 0. Mice were assigned to the treatment groups when the average disease score reached 3.05 at day 11. In addition to the disease score at day 11, mean weight of the mice at day 11 (18.14± 0. 18 grams) provided the basis for treatment group assignment. Groups were mixed within cages to avoid cage effects. Data is presented as mean ±SEM.

[0428] Disease Induction. EAE was induced day 0 with an emulsion containing 0.2 mg MOG35-55 peptide dissolved in PBS to a concentration of 4 mg / ml. The MOG peptide solution was emulsified with Complete Freund’s Adjuvant (CFA) containing 6 mg / ml H37RA. The emulsion was prepared by adding the oil phase and the water phase to two separate syringes connected with a BD Connecta. The emulsion was pushed through the syringes until a white solid emulsion appeared. The emulsion was kept on ice during the preparation. Mice were anaesthetized with IsoFlo vet, the injection site was cleaned with EtOH, and the emulsion was injected subcutaneously (volume lOOpl) at the flank. A slight pressure was applied on the injection site for 10 seconds after the injection to prevent leakage of emulsion. The mice were removed from anaesthetics and health status, includingbreathing, was monitored until the mice were awake and until recovery' from anaesthetics was ensured. A systemic adjuvant, Pertussis toxin (PTX) 200 ng, was given i.p. day 0 and day 2 after disease induction. The day 0 booster was given 2 hours after immunization. The Pertussis toxin (PTX) was resuspended in MQH2O to a concentration of 50 pg / ml and was further diluted in PBS to a final concentration of I pg / ml.

[0429] Compound and Formulation. The test compound H74DS3M8 for group 9 and 10, ready to use (6mg / ml, 4.4% Trehalose Histidine) was stored at 4°C. The test compound H74DS3M8 (60 mg / ml, in water) for group 4-8 was stored at 4°C. Salcaprozate sodium (SNAC) was provided as a powder, and resuspended in water at 50 mg / ml. The H74DS3M8 was further diluted with SNAC according to Table 7. Dasatinib was first dissolved in 100% DMSO at the concentration 165 mg / ml, aliquoted in small tubes and stored at -20°C. On the day of the treatment 4.4% Trehalose / 1 OmM Histidine was added to the tube to the final concentration of 3mg / ml for dosage of 30mg / kg.

[0430] The stock solution for Fingolimod lOmg / ml was prepared by dissolving Fingolimod in mqH20 and further diluted in mqH20 for the dosage of 3 mg / kg. Daily left-over formulated test items used in the animal facility were discarded upon use. The stock solutions were saved and kept at 4°C.

[0431] Experimental Groups and Administration of Test Compounds. The Vehicle (SNAC) and H74DS3M8 / SNAC (20, 60, 200, 400 and 580mg / kg) were administrated via oral gavage (p.o.) twice a week from day 11 to 25. H74DS3M8 (4.4% Trehalose- Histidine 60 mg / kg) was administrated via subcutaneous injection (s.c.) twice a week from day 11 to 25. In addition, H74DS3M8 (4.4% Trehalose- Histidine 60 mg / kg) was administrated via intraperitoneal injection (i.p.) daily from day 11 to 25. The Fingolimod (3 mg / kg) and Dasatinib (30mg / kg) were administrated via oral gavage (p.o.) daily from day 11 to 25.

[0432] Disease Evaluation. Disease was evaluated daily in a blinded fashion starting day 5 until the end of the experiment according to the following criteria: 0 = healthy, 1 = tail weakness, 2 = tail paralysis, 3 = tail paralysis and mild waddle, 4 = tail paralysis and severe waddle, 5:= tail paralysis and paralysis of one limb, 6 = Tail paralysis and paralysis of a pair of limbs, 7 = tetraparesis or paralysis of three limbs and 8 = premorbid or dead.

[0433] Weight. The animals were weighed on day 0 for the determination of mean weight of the mice included in the experiment. The mice were weighed two times per week betweenday 0 and treatment start on day 11. From the start of the treatment day 11, the animals were weighed every day or twice a week depending on the treatment regiment.

[0434] Health Evaluation. The general health of the mice was evaluated daily after disease induction. All mice were weighed two times per week as part of the general health assessment and for mice in groups 2, 3 and 10 daily after initiation of treatment for determination of dose volumes. Mice K3 (Group 10, H74DS3M8 4.4% Trehalose- Histidine 60 mg / kg i.p) and C3 (Group 4, H74DS3M8 SNAC 20 mg / kg p.o.) were found dead on day 18 and 23 of the study, respectively. Mouse CIO (Group 3, Dasatinib 30 mg / kg p.o.) was removed on day 24 of the study, due to reaching humane end points, i.e. restricted breathing and kyphotic posture.

[0435] Blood Samples. Blood was collected 4h post treatment from all the animals except group 2 (Fingolimod) and mouse K3 (found dead day 18) via sublingual vein on day 22. Serum obtained was collected into single tubes and stored at -20°C.

[0436] Tissue / Organ Collection. Both kidneys, two liver lobes, spleen and spinal cord were collected from animals in groups 1 and 4-9. Spinal cords were collected, snap frozen in isopentane on dry ice, transferred to tubes and put on dry ice until stored -80 °C. The weight of the two liver lobes and spleens was measured for all animals, for group 2 (Fingolimod) and 3 (Dasatinib) the tissues were later discarded. Kidneys and liver lobes were snap frozen in liquid nitrogen and transiently put on dry ice until stored at -80 °C. Spleens were weighed and discarded.Results for Example 3

[0437] FIGs. 14A-18B and Table 9 describe the results of this example.1Cumulative incidence. A mouse was considered to have developed disease if receiving a score of 1 or higher on two consecutive scoring days.2Mean EAE score for all scoring time points.3Area under curve for animals from d5 to d25. Three animals that were pre-terminated are included in the calculations up to the day of the removal.Conclusion for Example 3

[0438] Experimental Autoimmune Encephalomyelitis (EAE) in mice is a widely used model for investigating the effects of potential drugs against multiple sclerosis. In the present study, vehicle-treated animals developed moderate to severe disease. Once the mean clinical score exceeded 1.5, treatment was initiated the following day (Day 11 post-inoculation).

[0439] Administration of the clinically approved fmgolimod, as well as dasatinib (small molecule analog of H74DS3M8), resulted in a significant inhibition of disease progression. Notably, H74DS3M8-SNAC twice weekly p.o. administration significantly ameliorated disease severity at doses of 20 mg / kg, 60 mg / kg, and 400 mg / kg. See, for example, the results shown in FIGs. 17A-17B. As shown in FIG. 17A, H74DS3M8-SNAC (twice / week p.o.) resulted in a significant improvement in disease severity compared to Vehicle (positive control, fmgolimod (FTY720), is further shown for comparative purposes). FIG. 17B shows a bar chart depicting area under the curve (AUC) of disease scores, demonstrating that the total burden of the disease was significantly lower with the H74DS3M8-SNAC treatment.Additionally, daily i.p. administration of H74DS3M8 at 60 mg / kg also significantly reduced disease severity, consistent with previous findings.

[0440] Body weight measurements show fingolimod, dasatinib, and H74DS3M8, i.p. at 60mg / kg enhanced body weight recovery whereas all H74DS3M8 p.o. and s.c. treatments did not impact body weights throughout the study. In terms of organ weights, fingolimod and H74DS3M8-i.p. groups showed significantly higher liver weight which may be due to the corresponding increased body weight. The H74DS3M8-p.o. 20mg / kg group showed significantly higher spleen weight in comparison to the vehicle.

[0441] Three animals that were pre-terminated are included in the calculations of disease parameters: Max, Mean and AUC up to the day of the removal.

[0442] Serum H74DS3M8 concentration was quantified on the last study day at 4 hours after drug administration. 100% of animals receiving H74DS3M8 via i.p. and s.c. routes demonstrated high serum drug concentrations 4 hours after dosing of approximately 30000 ng / mL and 5000 ng / mL, respectively.

[0443] Of the oral administration groups, animals receiving H74DS3M8-SNAC via p.o. at the lowest (20 mg / kg) and highest (580 mg / kg) doses showed detectable drug levels. This may be due to the fact that SNAC dose level, and more importantly, the ratio between theactive drug and SNAC dose levels, differed between the groups, such that the 20 mg / kg H74DS3M8 group received the highest SNAC dose proportional to its drug dose (1 :24 H74DS3M8:SNAC ratio). With increasing H74DS3M8 dose, the SNAC ratio decreased; however drug was still detected in the 580 mg / kg dose group, likely due to a sufficiently high drug concentration. These results highlight the importance of administering SNAC, permeation enhancer, proportionally to the active drug, and that SNAC can have a significant effect on enhancing oral bioavailability especially at low drug dose levels.

[0444] Efficacy was observed at multiple dose levels of oral H74DS3M8 administered twice a week even in the absence of measurable drug 4 hours post-dosing.Example 4

[0445] Ocular diseases such as neovascular (wet) age-related macular degeneration (AMD) and diabetic macular edema (DME) have been treated with anti-VEGF therapies (such as aflibercept and ranibizumab) through direct injection into the vitreous of the eye. These approaches require aseptic techniques and a trained retinal ophthalmologist to administer the drug. The administration of anti-VEGF therapies by direct injection to the eye creates a large burden on the patients and treating retinal ophthalmologists due to the frequency of injection (every 4 to 12 weeks) and the increasing number of wet AMD and DME patients. Therefore, D-4517.2 has been designed to target wet AMD and DME as a systemic therapy. D-4517.2 showed to reduce choroidal neovascular lesions after a single subcutaneous injection to a comparable or greater extent than an intravitreal injection of aflibercept (scaled from human dose) in a mouse model of wet AMD. Safety of D-4517.2 in chronic rat and dog studies has already been well established with subcutaneous dosing. The oral pharmacokinetics (PK) of D-4517.2 in rats has been investigated (Example 2) where the SNAC containing formulations showed oral bioavailability ranging from approximately 16% to 53%. The aim of this study is to determine the oral PK of D-4517.2 in rats.

[0446] Experimental design is described in Table 10, and formulation ingredients are shown in Table 11.Table 10. Experimental Design and Study Groups* For group 7 only: SNAC was sourced from DRL, however, for rest of groups, SNAC (if used) was procured from AK Scientific, CA.Table 11. Formulations* D-4517.2: SNAC (1:6) - Fl: Formulation was prepared by absorbing D-4517.2 on Prosolv-730 followed by addition of SNAC.** D-4517.2: SNAC (1:6) - F2: Formulation was prepared by mixing D-4517.2 and SNAC followed by adsorption of D-4517.2: SNAC mixture on Prosolv-730.

[0447] Male Sprague Dawley rats were received from an approved vendor and allowed to acclimate to the Test Facility for at least 2 days. All animals were fasted overnight. Food was returned approximately 4 hours post dose, after the 4 hour blood collection.

[0448] Capsules were administered orally via appropriately sized capsule dosing apparatus for 9EL capsules according to Test Facility Guidance documents. Group 4 and 5 animals received 1, the rest of the groups received 2 capsules with 2-5 minutes in between each capsule dose. Each dosing was followed by an oral gavage flush of ~0.5 -1.0 mL of water.

[0449] The following parameters and endpoints were evaluated in this study: mortality, clinical observations, and body weights. Animal body weights were collected prior to dosing. All serial bleeds w7ere scheduled based on the time of the first dose. Serial blood samples were collected via sublingual vein or by another approved method. The method of each collection was recorded. Blood samples were collected into K2EDTA tubes and stored on wet ice until processed. Whole blood samples were processed to plasma by centrifugation (3500rpm for 10 minutes at 5°C) within 30 minutes of collection. Plasma was transferred into cluster tubes and stored at -80°C until transferred. The cellular fraction was discarded.Samples were shipped on dry ice for analysis.Table 12. Individual Dose Administration*Time elapsed between capsule doses was 5.37 minutes **Time elapsed between capsule doses was 9.40 minutes

[0450] Bioanalysis

[0451] Approximately 250 pL of blood sample (from each animal, from the sublingual vein) was collected into K2ED TA tubes and stored on wet ice until processed. Blood was collected for all groups at 0.5-, 2-, 4-, 8-, and 24-hours post dose. Whole blood samples were processed to plasma by centrifugation (3500rpm for 10 minutes at 5°C) within 30 minutes of collection. Plasma was transferred into cluster tubes and stored at -80°C until transferred. The cellular fraction was discarded. Samples were shipped on dry ice for analysis.

[0452] Plasma D-4517.2 concentrations were determined using a qualified LC / MS / MS assay with a lower limit of quantification of 0.05 to 0.25 pg / mL. The plasma concentration graph is shown in FIG. 19. Group 2 showed a similar bioavailability compared to the rat study of Example 2. There was no significant difference observed between different source(s) of SNAC, but the 1 :6 SNAC formulation of Group 2 performed better than the 1 :6 SNAC formulation of Group 1. The formulation of Group 6 showed good exposure, and the sodium caprate containing formulation of Group 3 appeared to perform similarly to SNAC groups.

[0453] Conclusions

[0454] This study evaluated the oral PK of D-4517.2 in rats when administered capsules containing various formulations. A number of changes were made to the formulations from the oral PK study of Example 2: 1) the order of addition of formulation ingredients, 2) the manufacturing source of SNAC, 3) the use of different permeability enhancers, and 4) the use of new formulations containing lipiodol excipients.

[0455] The results surprisingly showed that the order of ingredient addition to prepare the formulation is critical for optimal exposure. Increased exposure was observed with the Group2 formulation, prepared by addition of drug to permeability enhancer (PE) followed by adsorption of Drug:PE mixture to a earner, as compared to the Group 1 formulation, which was prepared by absorbing drug on carrier followed by addition of PE. Group 6 containing Capmul exhibited favorable bioavailability, and all formulations containing PE or lipoidal excipients performed better than those without. Minimal impact on exposure was observed bychanging the source(s) of SNAC. Formulations containing PE (SNAC, Sodium Caprate) and Lipid (Capmul) showed favorable results.Example 5

[0456] Test Article Migaldendranib (D-45I7.2) was designed to target ocular inflammation and inhibit angiogenesis in neovascular ocular diseases such neovascular (wet) age-related macular degeneration (AMD) and diabetic macular edema (DME). D-4517.2 was renally excreted due to its size (~19 kDa; 4 nm) and lack of plasma protein binding. Historically, wet AMD and DME were treated with anti-VEGF therapies (such as aflibercept and ranibizumab) through direct injection into the vitreous of the eye. These approaches require aseptic techniques and a trained retinal ophthalmologist to administer the drug. The administration of anti-VEGF therapies by direct injection to the eye creates a large burden on the patients and treating retinal ophthalmologists due to the frequency of injection (every 4 to 12 weeks) and the increasing number of wet AMD and DME patients.

[0457] D-4517.2 has been evaluated as a systemic therapy, which has reduced choroidal neovascular lesions after a single subcutaneous injection to a comparable or greater extent than an intravitreal injection of aflibercept (scaled from human dose) in a mouse model of wet AMD. Safety in chronic rat and dog studies has already been well established with subcutaneous dosing.

[0458] The objective of this non-GLP study was to evaluate the pharmacokinetics (PK) of different formulations of a single oral dose of D-4517.2 in non-naive, fasted Beagle dogs. Additionally, one group received an oral dose of D-4517.2 administered three times at two- hour intervals, for a total of three (3) doses.

[0459] Tables 13 and 14 provide formulation descriptions for oral capsules (Table 13) and liquid formulations (Table 14).Table 13. Test Article Identification - Oral CapsulesTable 14. Test Article Identification - Liquid Formulations

[0460] Table 15 shows dose group assignment information for this study.Table 15. Dose Group AssignmentaOnce daily with pentagastrin pre -treatment at least 30 mins prior to dose."Once daily without pentagastrin pre -treatment prior to dose.cThree times daily, every 2-hours (three total doses) with pentagastrin pre-treatment at least 30 mins prior to each dose."Animals with smallest body weights were selected for Group 1 and the same animals were used for Group 5 of Phase 2 in order to target as close to a 20 mg / kg dose per an...

Claims

CLAIMSWhat is claimed is:

1. A composition comprising: a dendrimer conjugate, or a pharmaceutically acceptable salt thereof, wherein the dendrimer conjugate comprises a dendrimer conjugated to a therapeutic agent; andN-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

2. The composition of claim 1, wherein the composition comprises a sodium salt or a potassium salt of N-(8-[2-hydroxybenzoyl]amino)caprylic acid.

3. The composition of claim 1 or 2, wherein the composition comprises a sodium salt of N-(8-[2-hydroxybenzoyl]amino)caprylic acid.

4. The composition of any one of claims 1-3, wherein the composition comprises a monosodium salt of N-(8-[2~hydroxybenzoyl]amino)caprylic acid (salcaprozate sodium, “SNAC”).

5. The composition of any one of claims 1-4, wherein the dendrimer comprises a plurality of terminal hydroxyl groups, wherein at least one terminal hydroxyl group is optionally substituted.

6. The composition of claim 5, wherein the substituent comprises the therapeutic agent.

7. The composition of claim 6, wherein the substituent is attached to the dendrimer via an ether bond.

8. The composition of claim 6 or 7, wherein the therapeutic agent is attached to the dendrimer via a linker between the at least one terminal hydroxyl group and the therapeutic agent.

9. The composition of claim 8, wherein the therapeutic agent is attached to the linker via an amide bond.

10. The composition of claim 8 or 9, wherein the linker comprises polyethylene glycol.

11. The composition of any one of claims 1-10, wherein the dendrimer is a poly(amidoamine) ( PAM AM) dendrimer.

12. The composition of any one of claims 1-11, wherein the dendrimer is a generation 4, generation 5, or generation 6 dendrimer.

13. The composition of any one of claims 1-12, wherein the dendrimer is a generation 4, generation 5, or generation 6 poly(amidoamine) (PAMAM) dendrimer.

14. The composition of any one of claims 1-13, wherein the therapeutic agent is selected from the group consisting of angiotensin II receptor blockers, Famesoid X receptor (FXR) agonists, death receptor 5 agonists, sodium -glucose cotransporter type-2 (SGLT2) inhibitors, lysophosphatidic acid 1 receptor antagonists, endothelin-A receptor antagonist, peroxisome proliferator-activated receptor delta (PPAR8) agonists, ATI receptor antagonists, CCR5 / CCR2 antagonists, anti-fibrotic agents, anti-inflammatory agents, antioxidant agents, stimulator of interferon genes (STING) agonists, vascular endothelial growth factor receptor (VEGFR) inhibitors, colony-stimulating factor 1 receptor (CSF1R) inhibitors, AXL inhibitors, c-Met inhibitors, poly(ADP-ribose) polymerase (PARP) inhibitors, receptor tyrosine kinase inhibitors, MEK inhibitors, PAK1 inhibitors, glutaminase inhibitors, TIE II antagonists, chemokine receptor 2 (CXCR2) inhibitors, CD73 inhibitors, arginase inhibitors, phosphatidylinositol-3-kinase (PI3K) inhibitors, toll-like receptor 4 (TLR4) agonists, toll-like receptor 7 (TLR7) agonists, Src homology -2 domain-containing protein tyrosine phosphatase-2 (SHP2) inhibitors, chemotherapeutic agents, STING antagonists, JAKI inhibitors, TREM2 inhibitors, and TYK2 inhibitors.

15. The composition of any one of claims 1-14, wherein the therapeutic agent is a receptor tyrosine kinase inhibitor.

16. The composition of claim 15, wherein the receptor tyrosine kinase inhibitor is a vascular endothelial growth factor receptor (VEGFR) inhibitor or a colony stimulating factor- 1 receptor (CSF1R) inhibitor.

17. The composition of claim 15 or 16, wherein the receptor tyrosine kinase inhibitor is selected from sunitinib, dasatinib, sorafenib, pazopanib, vandetanib, axitinib, cediranib, vatalanib, nintedanib, motesanib, and derivatives or analogs thereof.

18. The composition of any one of claims 15-17, wherein the receptor tyrosine kinase inhibitor is N, A'-didesethyl sunitinib or a derivative or analog thereof.

19. The composition of any one of claims 1-18, wherein the dendrimer conjugate is of Formula (0):or a pharmaceutically acceptable salt thereof, wherein:D is the dendrimer;A is a first click-chemistry handle;L1and L2are independently a linker or a bond;X is a moiety resulting from a click-chemislry reaction between the first clickchemistry handle and a second click-chemistry handle;R is the therapeutic agent; m is an integer from 16-4095, inclusive; n is an integ Oer from 1-20, 7 inclusive; 7 and p is an integer from 0-20, inclusive.

20. The composition of claim 19, wherein the dendrimer conjugate of Formula (0) is ofFormula (I):or a pharmaceutically acceptable salt thereof, wherein: q is an integer from 0-50, inclusive;f is an integ Oer from 1-20, 7 inclusive; 7 g is an integer from 0-20, inclusive; and each instance of Rzis independently, hydrogen, -CH3, -OH, or -OCH3.

21. The composition of claim 19, wherein the dendrimer conjugate of Formula (0) is of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: q is an integer from 0-50, inclusive;f is an integer from 1-3, inclusive; and g is an integer from 0-10, inclusive.

22. The composition of claim 19, wherein the dendrimer conjugate of Formula (0) is of Formula (III):(Ill), or a pharmaceutically acceptable salt thereof, wherein: p is an integer from 3-7, inclusive;f is an integer from 1 -20, inclusive; and g is an integer from 0-20, inclusive.

23. The composition of any one of claims 19-22, wherein R is sunitinib, dasatinib, sorafenib, pazopanib, vandetanib, axitinib, cediranib, vatalanib, nintedanib, motesanib, pexidartinib, imatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580, or a derivative or analog thereof.

24. The composition of any one of claims 19-23, wherein R is a derivative or analog of sunitinib, dasatinib, sorafenib, pazopanib, vandetanib, axitinib, cediranib, vatalanib, nintedanib, motesanib, pexidartinib, imatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580.

25. The composition of claim 24, wherein the derivative or analog of sunitinib, dasatinib, sorafenib, pazopanib, vandetanib, axitinib, cediranib, vatalanib, nintedanib, motesanib, pexidartinib, imatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580 comprises Z2between Z and sunitinib, dasatinib, sorafenib, pazopanib, vandetanib, axitinib, cediranib, vatalanib, nintedanib, motesanib, pexidartinib, imatinib, PLX5622, ARRY-382, sotuletinib, edicotinib, Ki20227, or GW 2580; wherein Z2is a linker.

26. The composition of any one of claims 19-22, wherein R is of the formula:

27. The composition of claim 20, wherein the dendrimer conjugate of Formula (I) is of the formula:or a pharmaceutically acceptable salt thereof.28, The composition of claim 19, wherein the dendrimer conjugate of Formula (0) is selected from dendrimer conjugates in FIGs. 10A-10D, 11A-11D, 12A-12F, and 13A-13C, or a pharmaceutically acceptable salt thereof.

29. The composition of any one of claims 19-22, wherein R is of the formula:

30. The composition of claim 19, wherein the dendrimer conjugate of Formula (0) is of the formula:or a pharmaceutically acceptable salt thereof.

31. The composition of any one of claims 1-30, wherein the composition is in the form of a solid or liquid.

32. The composition of any one of claims 1-31, wherein the composition is formulated as a solid.

33. The composition of any one of claims 1-32, wherein the composition is in the form of a capsule, tablet, pill, powder, or granule.

34. The composition of any one of claims 1-33, wherein the composition is in the form of a tablet or a capsule.

35. The composition of any one of claims 32-34, wherein the composition comprises the dendrimer conjugate, or a pharmaceutically acceptable salt thereof, in an amount from about 0.1% to about 80% w / w.

36. The composition of any one of claims 32-35, wherein the composition comprises N- (8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in an amount from about 1% to about 60% w / w.

37. The composition of any one of claims 32-36, wherein the composition comprises: from about 5% to about 25%, from about 10% to about 20%, from about 13% to about 17%, from about 20% to about 40%, from about 25% to about 35%, from about 25% to about 60%, from about 30% to about 55%, from about 35% to about 45%, or from about 10% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 5% to about 25%, from about 10% to about 20%, from about 13% to about 17%, from about 15% to about 45%, from about 20% to about 40%, from about 25% to about 35%, from about 28% to about 32%, from about 30% to about 60%, from about 40% to about 50%, or from about 42% to about 46% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

38. The composition of any one of claims 32-36, wherein the composition comprises: from about 25% to about 60%, from about 30% to about 55%, or from about 35% to about 45% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; andfrom about 5% to about 25%, from about 10% to about 20%, or from about 13% to about 17% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof39. The composition of any one of claims 32-36, wherein the composition comprises: from about 10% to about 50%, from about 20% to about 40%, or from about 25% to about 35% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 15% to about 45%, from about 20% to about 40%, from about 25% to about 35%, or from about 28% to about 32% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

40. The composition of any one of claims 32-36, wherein the composition comprises: from about 5% to about 25%, from about 10% to about 20%, or from about 13% to about 17% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 30% to about 60%, from about 40% to about 50%, or from about 42% to about 46% w / w of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

41. The composition of any one of claims 32-40, further comprising an adsorbent.

42. The composition of claim 41, wherein the composition comprises from about 20% to about 60%, from about 25% to about 55%, from about 30% to about 50%, or from about 35% to about 45% w / w of the adsorbent.

43. The composition of claim 41 or 42, wherein the adsorbent is PROSOLV® 730, ABISORB-DC™, microcrystalline cellulose (MCC), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), silicon dioxide, or a combination thereof.

44. The composition of any one of claims 41-43, wherein the composition comprises: from about 10% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof;from about 10% to about 50% w / w of N-(8-[2-hydroxybenzoyl]amino)capiylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 20% to about 60% w / w of the adsorbent.

45. The composition of any one of claims 41-43, wherein the composition comprises: from about 10% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 10% to about 50% w / w of SNAC; and from about 20% to about 60% w / w of a mixture of microcrystalline cellulose, silicon dioxide, and copovidone.

46. The composition of any one of claims 41 -43, wherein the composition comprises: from about 40% to about 50% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 10% to about 20% w / w of SNAC; and from about 35% to about 45% w / w of a mixture of microcrystalline cellulose, silicon dioxide, and copovidone.

47. The composition of any one of claims 41-43, wherein the composition comprises: from about 25% to about 35% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 25% to about 35 w / w of SNAC; and from about 35% to about 45% w / w of a mixture of microcrystalline cellulose, silicon dioxide, and copovidone.

48. The composition of any one of claims 41 -43, wherein the composition comprises: from about 10% to about 20% w / w of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 35% to about 45% w / w of SNAC; and from about 35% to about 45% w / w of a mixture of microcrystalline cellulose, silicon dioxide, and copovidone.

49. The composition of any one of claims 1-31, wherein the composition is formulated as a liquid.

50. The composition of any one of claims 1-31 and 49, wherein the composition is in the form of an emulsion, microemulsion, solution, suspension, or liquid capsule.

51. The composition of any one of claims 1-31 and 49-50, wherein the composition is in the form of a solution or a suspension.

52. The composition of any one of claims 49-51, wherein the composition comprises: from about 0.001% to about 0.5%, from about 0.01% to about 0.09%, from about0.01% to about 1%, from about 0.01% to about 5%, from about 0.02% to about 0.06%, from about 0.05% to about 0.7%, from about 0. 1% to about 0.3%, from about 0. 1% to about 4%, or from about 1% to about 3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 10%, from about 2% to about 8%, from about 3% to about 9%, from about 5% to about 7%, or from about 3% to about 7% w / v of N-(8-[2- hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

53. The composition of any one of claims 49-51, wherein the composition comprises: from about 0.001% to about 0.5%, from about 0.01% to about 0.09%, or from about0.02% to about 0.06% w / v of the dendrim er conjugate, or a pharm aceutically acceptable salt thereof; and from about 1% to about 10%, from about 3% to about 9%, or from about 5% to about 7% w / v of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

54. The composition of any one of claims 49-51, wherein the composition comprises: from about 0.01% to about 1%, from about 0.05% to about 0.7%, or from about 0.1% to about 0.3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 10%, from about 3% to about 9%, or from about 5% to about 7% w / v of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

55. The composition of any one of claims 49-51, wherein the composition comprises: from about 0.01% to about 5%, from about 0.1% to about 4%, or from about 1% to about 3% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; and from about 1% to about 10%, from about 2% to about 8%, or from about 3% to about 7% w / v of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

56. The composition of any one of claims 49-51, wherein the composition comprises: from about 0.01% to about 5% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 1% to about 10% w / v of N-(8-[2-hydroxybenzoyl]amino)caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and from about 85% to about 99% w / v of water.

57. The composition of any one of claims 49-51, wherein the composition comprises: from about 0.01% to about 2% w / v of the dendrimer conjugate, or a pharmaceutically acceptable salt thereof; from about 1% to about 10% w / v of SNAC; and from about 89% to about 99% w / v of water.

58. A composition comprising: a dendrimer conjugate, or a pharmaceutically acceptable salt thereof, wherein the dendrimer conjugate comprises a dendrimer conjugated to a therapeutic agent; and caprylic acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

59. The composition of claim 58, wherein the composition comprises a sodium salt or a potassium salt of caprylic acid.

60. The composition of claim 58 or 59, wdierein the composition comprises a sodium salt of caprylic acid, optionally wherein the sodium salt is a monosodium salt of caprylic acid (sodium caprylate).

61. A composition comprising:a dendrimer conjugate, or a pharmaceutically acceptable salt thereof, wherein the dendrimer conjugate comprises a dendrimer conjugated to a therapeutic agent; and capric acid, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

62. The composition of claim 61 , wherein the composition comprises a sodium salt or a potassium salt of capric acid.

63. The composition of claim 61 or 62, wherein the composition comprises a sodium salt of capric acid, optionally wherein the sodium salt is a monosodium salt of capric acid (sodium caprate).

64. A kit compri sing : the composition of any one of claims 1-63; and instructions for using the composition.

65. A method of modulating a receptor tyrosine kinase in a subject in need thereof, the method comprising administering to the subject an effective amount of the composition of any one of claims 1-63.

66. The method of claim 65, wherein the modulation is inhibition.

67. The method of claim 65 or 66, wherein the method treats a disease or disorder.

68. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of the composition of any one of claims 1-63.

69. The method of claim 68, wherein the disease or disorder is a disease or disorder of the eye.

70. The method of claim 69, wherein the disease or disorder of the eye is an inflammatory or angiogenic disease of the eye.

71. The method of claim 69, wherein the disease or disorder of the eye is selected from the group consisting of age-related macular degeneration (AMD), macular edema, retinitis pigmentosa, optic neuritis, uveitis, retinal detachment, temporal arteritis, retinal ischemia, arteriosclerotic retinopathy, hypertensive retinopathy, retinal artery blockage, retinal vein blockage, diabetic retinopathy, retinal neovascularization, and choroidal neovascularization.

72. The method of claim 69, wherein the disease or disorder of the eye is wet AMD.

73. The method of claim 69, wherein the disease or disorder of the eye is diabetic m acular edema (DME).

74. The method of claim 68, wherein the disease or disorder is a neurological disorder, an inflammatory disease, an autoimmune disorder, a cancer, a central nervous system disease, a painful condition, a bone disease, or a tumor.

75. The method of claim 74, wherein the central nervous system disease is Charcot- Marie-Tooth disease type 1.

76. The method of claim 74, wherein the painful condition is neuropathic pain.

77. The method of claim 74, wherein the bone disease is osteoporosis or osteolysis.

78. The method of claim 74, wherein the neurological disorder is a neurodegenerative disorder.

79. The method of claim 78, wherein the neurodegenerative disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.

80. The method of claim 79, wherein the multiple sclerosis is relapsing remitting MS, primary progressive multiple sclerosis, or secondary progressive MS.

81. The method of claim 74, wherein the cancer is brain cancer, breast cancer, ovarian cancer, uterine cancer, prostate cancer, testicular cancer, gastric cancer, esophagus cancer,lung cancer, liver cancer, renal cell cancer, skin cancer, colon cancer, a sarcoma, a lymphoma, a leukemia, or a malignant tumor.

82. The method of claim 81, wherein the skin cancer is melanoma.

83. The method of claim 82, wherein the melanoma is acral melanoma or mucosal melanoma.

84. The method of claim 81, wherein the brain cancer is glioblastoma.

85. The method of claim 81, wherein the lymphoma is Hodgkin lymphoma or non¬Hodgkin lymphoma.

86. The method of claim 81, wherein the leukemia is chronic myeloid leukemia chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL).

87. The method of claim 74, wherein the tumor is a solid tumor, diffuse-type tenosynovial giant cell tumor, or neurofibroma.

88. The method of claim 74, wherein the inflammatory' disease or autoimmune disease is selected from the group consisting of arthritis, inflammatory bowel disease, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison’s disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune thrombocytopenic purpura, Bechet’s disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue syndrome, chronic inflammatory' demyelinating polyneuropathy, cicatricial pemphigoid, cold agglutinin disease, Crest syndrome, Crohn’s disease, Degos disease, dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura, IgA nephropathy, insulin-dependent diabetes, Meniere’s disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary' biliary cirrhosis, psoriasis, Raynaud’s phenomenon, Reiter’ssyndrome, rheumatic fever, sarcoidosis, scleroderma, Sjogren’s syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener’s granulomatosis.

89. The method of claim 88, wherein the arthritis is rheumatoid arthritis or psoriatic arthritis.

90. The method of claim 74, wherein the neurological disorder is epilepsy.

91. The method of any one of claims 65-90, wherein the composition is administered to the subject systemically.

92. The method of any one of claims 65-90, wherein the composition is administered to the subject intraperitoneally, intravenously, intrathecal ly, intratum orally, or orally.

93. The method of any one of claims 65-90, wherein the composition is administered to the subject orally.

94. The method of any one of claims 65-93, wherein the effective amount is from about 1 mg / kg to about 50 mg / kg of the subject.

95. The method of any one of claims 65-94, wherein the effective amount is from about 1 mg / kg to about 30 mg / kg of the subject.

96. The method of any one of claims 65-95, wherein the effective amount is from about 1 mg / kg to about 5 mg / kg, from about 5 mg / kg to about 15 mg / kg, from about 10 mg / kg to about 20 mg / kg, or from about 20 mg / kg to about 30 mg / kg of the subject.

97. The method of any one of claims 65-95, wlierein the effective amount is about 2 mg / kg, about 5 mg / kg, about 17 mg / kg, or about 26.5 mg / kg of the subject.

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