Dendrimer-based lipid nanoparticles for organ-selective mRNA transfection

Abstract

The present disclosure provides compounds of the formulae herein (e.g., Formula (I), Formula (I')), and pharmaceutically acceptable salts thereof, and compositions and kits comprising the compounds, or pharmaceutically acceptable salts thereof, which are useful for mRNA delivery to immune cells (e.g., tumor-infiltrating monocytes (TIMs), myeloid-derived suppressor cells (MDSCs)). The present disclosure also provides methods of treating or preventing diseases or disorders (e.g., diseases or disorders associated with TIMs, MDSCs) by administering the compounds, or pharmaceutically acceptable salts thereof, or compositions thereof, to a subject in need thereof, and methods of preparing the compounds, or pharmaceutically acceptable salts thereof.

Description

DENDRIMER-BASED LIPID NANOPARTICLES FOR ORGAN-SELECTIVE MRNA TRANSFECTIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Number 63 / 620,447, filed January 12, 2024, titled DENDRIMER-BASED LIPID NANOPARTICLES FOR ORGAN-SELECTIVE MRNA TRANSFECTION, the contents of which are incorporated herewith by reference in their entirety.GOVERNMENT SUPPORT

[0002] This invention was made with government support under R21 CA277263 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE INVENTION

[0003] The rapid clinical progression of mRNA-lipid nanoparticles (LNPs) highlighted the need to expand their applications beyond vaccine. Most traditional LNPs accumulate in the liver, limiting mRNA transfection in other organs, including the spleen and lungs. As a secondary lymphoid organ containing high numbers of antigen-presenting cells (APCs), the spleen serves as a target for delivery of mRNA for immune related applications. For instance, in the context of mRNA vaccines, selective transfection of APCs in the spleen may facilitate a more efficient immune response.

[0004] Likewise, the spleen contains other types of immune cells such as myeloid-derived suppressor cells (MDSCs) and tumor-infiltrating monocytes (TIMs). MDSCs are pathologically activated neutrophils and monocytes that are a significant contributor to immunosuppression. MDSCs increase under certain conditions such as cancer (solid tumors) and chronic illness associated with sepsis and trauma (infection). MDSCs also play a role in establishing immune tolerance in transplantation, and in autoimmune disorders. In order to target and modulate MDSCs with mRNA transfection for disease treatment, an LNP exhibiting spleen tropism (spleen selectivity) would be beneficial to enhance the transfection efficacy.

[0005] In addition to the challenges associated with spleen-selective transfection, monocytes are difficult to transfect. Current disclosed LNP formulations can only mediate 1 -4% of RNA release into the cytoplasm1, 2- an important step in mediating RNA transfection. Therefore, developing mRNA- LNP formulations that efficiently transfect monocytes in vivo is needed.SUMMARY OF THE INVENTION

[0006] The present disclosure provides a library of dendrimer-based lipids and a library of dendrimer-based lipid nanoparticles (DLNPs), which can deliver mRNA in an organ-selective manner. Dendrimers possess the same high degree of molecular uniformity as small molecules as wellas broad theoretical space for flexible structural-tuning, allowing for the establishment of the structure-function relationship between DLNP formulations and mRNA delivery.

[0007] Ior pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, Q, n, p, x, y, and z are as defined herein.

[0008] In another aspect, the present disclosure provides compounds of Formula (I'):or pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, Q, n, p, x, y, and z are as defined herein.

[0009] In another aspect, the present disclosure provides compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof; a helper lipid; cholesterol; and a PEGylated lipid. In some embodiments, the composition further comprises a nucleic acid.

[0010] In another aspect, the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a provided composition. In some embodiments, the disease is cancer. In some embodiments, the therapeutically effective amount is an amount effective for delivering a nucleic acid (e.g., RNA (e.g., mRNA)) to the subject.

[0011] In another aspect, the present disclosure provides methods of cellular engineering, the method comprising administering to a subject in need thereof or contacting a cell, tissue, or biological sample with an effective amount of a provided composition. In some embodiments, the therapeutically effective amount is an amount effective for delivering a nucleic acid (e.g., RNA (e.g., mRNA)) to the subject or the cell, tissue, or biological sample.

[0012] In another aspect, the present disclosure provides methods of preparing compounds of Formula (I) or Formula (I'), or pharmaceutically acceptable salts thereof.

[0013] In another aspect, the present disclosure provides kits comprising a provided compound or composition and instructions for its use.

[0014] It should be appreciated that the foregoing concepts, and the additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in thisrespect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1 shows the construction of a library of dendrimer formulations for mRNA delivery to myeloid-derived suppressor cells (MDSCs). Starting with 6 initiator cores, referred to as generation 0 (GO) dendrimers, a two-step reaction produced two additional generations (G1 and G2), obtaining a total of 18 dendrimers. These 18 dendrimers contain primary (1°) and tertiary (3°) amine functional groups and initially have no lipid modification (0% lipid conjugation). The 1° amines of these dendrimers are selectively modified with four different types of lipid-terminated epoxides to yield dendrimer-based lipids. Consequently, 72 dendrimer-based lipids were obtained that contain both secondary (2°) amines and 3° amines (representing 50% lipid conjugation), and an additional 72 dendrimer-based lipids featuring exclusively 3° amines (representing 100% lipid conjugation). These dendrimer-based lipids are dissolved in ethanol and mixed with l,2-distearoyl-sn-glycero-3- phosphocholine (DSPC), cholesterol, DMG-PEG 2000, and luciferase FLuc mRNA to form dendrimer-based lipid nanoparticles (dLNPs). The nanoparticle library screening method is used to identify the formulations capable of mediating organ-selective mRNA expression.

[0016] FIG. 2 shows transfection efficiency vs. percent viability for a library of nanoparticles comprising the indicated dendrimer. The in vitro screening of dLNPs containing FLuc mRNA identified several dLNP formulations with transfection efficiency and cell viability comparable to or superior to those of FDA-approved LNP formulations, such as SM-102 or DLin-MC3-DMA.

[0017] FIG. 3 shows in vivo biodistribution for formulations of the present disclosure compared to SM-102. Five formulations showed higher overall in vivo transfection than SM-102. Data shown are associated percentage of total FLuc signal in the, spleen, liver, lungs, bone, heart, and kidneys of mice treated with intravenous doses of 0.5mg / kg luciferase-mRNA dLNPs. (Data presented as mean ± SD (n = 3).

[0018] FIGs. 4A-4B show the biodistribution of nanoparticle formulations of the present disclosure compared to SM-102. FIG. 4A shows nanoparticle formulations that showed in vivo tropism toward spleen (spleen-targeting). FIG. 4B shows nanoparticle formulations that showed in vivo tropism toward liver (liver-targeting). Data shown are associated percentage of total FLuc signal in the, spleen, liver, lungs, bone, heart, and kidneys of mice treated with intravenous doses of 0.5mg / kg luciferase-mRNA dLNPs. (Data presented as mean (n = 3).

[0019] FIGs. 5A-5E show the physicochemical properties of nine nanoparticle formulations of the present disclosure: zeta potential (FIG. 5A), particle size (FIG. 5B), polydispersity index (FIG. 5C), encapsulation efficiency (FIG. 5D), and apparent pKa (FIG. 5E).

[0020] FIG. 6 shows the relationship between apparent pKa and mRNA expression in the spleen, liver, and lung for nanoparticle formulations of the present disclosure, in which the ionizable lipid contains 3° amine (100% lipid graft), or the ionizable lipid contains both 2° and 3° amines (50% lipid graft).

[0021] FIG. 7 shows a comparison of the mRNA expression of two DLNP formulations of the present disclosure with SM-102.

[0022] FIG. 8 shows the chemical structures of dendrimers used for the formulation of twelve nanoparticle formulations of the present disclosure.

[0023] FIGs. 9A-9G show >H NMR spectra for ClGl-L8-50% (FIG. 9A), C3G0-LB-50% (FIG. 9B), ClGl-UNL-100% (FIG. 9C), C4G0-UNL-100% (FIG. 9D), C5G0-L12-100% (FIG. 9E), C5G0-L12-50% (FIG. 9F), C1G1-L12-1OO% (FIG. 9G).

[0024] FIGs. 10A-10B show Surface Lipophilicity Assay for lead dLNP formulations characterized by PRODAN and DPH fluorescent dye.

[0025] FIG. 11 shows that the lipophilicity / hydrophobicity synergistically determines the liver vs. spleen tropism of dLNP.

[0026] FIG. 12 shows validatation of the tissue tropism using a new mRNA / mouse system: cre- mRNA and tdTomato transgenic mouse. Immunofluorescent analysis of tdTomato expression in the lungs, liver, and spleen of Ail4 transgenic mice following intravenous administration of 0.5mg / kg Cre-recombinase mRNA-dLNPs. (Representative images of n=3).

[0027] FIG. 13 shows that 50 and 100 series localize in different splenic zones.

[0028] FIGs. 14A-14C show dLNP transfection efficiency in key myeloid cell tissues: peripheral blood (FIG. 14A), spleen (FIG. 14B), and bone marrow (FIG. 14C). Data are presented as mean ± s.e.m. (n = 3 biologically independent animals). C1G1-L8-50 (triangle) and C1G1-L8-100 (circle).

[0029] FIGs. 15A-15C show dLNP Cellular Targets: peripheral blood (FIG. 15A), spleen (FIG.15B), and bone marrow (FIG. 15C). Data are presented as mean ± s.e.m. (n = 3 biologically independent animals). C1G1-L8-50 (triangle) and C1G1-L8-100 (circle).

[0030] FIG. 16 shows particle uptake by cell subset. Data are presented as mean, (n = 3 biologically independent animals). Pie charts represent how much each cell subset contribute to particle uptake.DEFINITIONS

[0031] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Michael B. Smith, March’s AdvancedOrganic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0032] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0033] 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^t, C1-3, C1-2, C2-6, C2-5, C2 4, C2-3, C3-6, C3-5, C s 4, C4-6, C4-5, and C5-6 alkyl.

[0034] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“Ci-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“Ci-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“Ci-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“Ci^t alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of Ci-6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n- pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2- butanyl, tert-amyl), and hexyl (Ce) (e.g., n-hexyl). Additional examples of alkyl groups include n- heptyl (C7), n-octyl (Cs), n-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substitutedalkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted Ci-12 alkyl (such as unsubstituted Ci-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (z'-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted / / -butyl (zz-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (z'-Bu)). In certain embodiments, the alkyl group is a substituted Ci-12 alkyl (such as substituted Ci-6 alkyl, e.g., -CH2F, -CHF2, -CF3, - CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).

[0035] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo.

[0036] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“Ci-20 heteroalkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“Ci-i2heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“Ci-11 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“Ci-10 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-9 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“Ci-8 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-7 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“Ci-6 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C1-5 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain (“Ci^ heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“C1-3 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“C1-2 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“Ci heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C2-6 heteroalkyl”). Unless otherwise specified, each instance ofa heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted Ci-12 heteroalkyl. In certain embodiments, the heteroalkyl group is a substituted Ci-12 heteroalkyl.

[0037] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“Ci-20 alkenyl”). In some embodiments, an alkenyl group has 1 to 12 carbon atoms (“Ci-12 alkenyl”). In some embodiments, an alkenyl group has 1 to 11 carbon atoms (“Ci-11 alkenyl”). In some embodiments, an alkenyl group has 1 to 10 carbon atoms (“Ci-10 alkenyl”). In some embodiments, an alkenyl group has 1 to 9 carbon atoms (“C1-9 alkenyl”). In some embodiments, an alkenyl group has 1 to 8 carbon atoms (“C1-8 alkenyl”). In some embodiments, an alkenyl group has 1 to 7 carbon atoms (“C1-7 alkenyl”). In some embodiments, an alkenyl group has 1 to 6 carbon atoms (“Ci-6 alkenyl”). In some embodiments, an alkenyl group has 1 to 5 carbon atoms (“C1-5 alkenyl”). In some embodiments, an alkenyl group has 1 to 4 carbon atoms (“Ci^t alkenyl”). In some embodiments, an alkenyl group has 1 to 3 carbon atoms (“C1-3 alkenyl”). In some embodiments, an alkenyl group has 1 to 2 carbon atoms (“C1-2 alkenyl”). In some embodiments, an alkenyl group has 1 carbon atom (“Ci alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of Ci 4 alkenyl groups include methylidenyl (Ci), ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of Ci-6 alkenyl groups include the aforementioned C24 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted Ci-20 alkenyl. In certain embodiments, the alkenyl group is a substituted Ci-20 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH3 or) may be in the (E)- or(Z) -configuration.

[0038] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain.

[0039] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“Ci -20 alkynyl”).

[0040] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain.

[0041] The term “carbocyclyl” or “carbocyclic” refers to a radical 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.

[0042] 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”).

[0043] 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 > electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ctu aryl”).

[0044] 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”).

[0045] The term “unsaturated bond” refers to a double or triple bond.

[0046] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0047] 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.

[0048] 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, heteroalkylene is the divalent moiety of heteroalkyl, and heteroalkenylene is the divalent moiety of heteroalkenyl.

[0049] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, heteroalkyl, and heteroalkenyl groups are optionally substituted. “Optionally substituted” refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either thesame or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The disclosure is not limited in any manner by the exemplary substituents described herein.

[0050] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X-, -N(ORcc)Rbb, -SH, -SRaa, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORCC)2, -CO2Raa, -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, -Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa,-P(ORCC)3+X’, -P(RCC)4, -P(ORCC)4, -OP(RCC)2, -OP(RCC)3+X’, -OP(ORCC)2, -OP(ORCC)3+X-, -OP(RCC)4, -OP(ORcc)4, -B(Raa)2, -B(ORCC)2, -BRaa(ORcc), Ci20alkyl, Ci20perhaloalkyl, Ci20alkenyl, Ci-20 alkynyl, heteroCi-2o alkyl, heteroCi-2o alkenyl, heteroCi-2o alkynyl, C3-10 carbocyclyl, 3- 14 membered heterocyclyl, Ce i4aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X“ is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORCC; wherein: each instance of Raais, independently, selected from Ci-20 alkyl, Ci-20 perhaloalkyl, Ci-2o alkenyl, Ci-20 alkynyl, heteroCi-2o alkyl, heteroCi-2oalkenyl, heteroCi-2oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce i4aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, -OH, -OR311, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SOB'1'1. -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, CI 20 alkyl, Ci20perhaloalkyl,Ci-20 alkenyl, Ci-20 alkynyl, heteroCi-2oalkyl, heteroCi-2oalkenyl, heteroCi-2oalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from hydrogen, Ci-20 alkyl, Ci-20 perhaloalkyl, Ci-20 alkenyl, Ci-20 alkynyl, heteroCi-20 alkyl, heteroCi-20 alkenyl, heteroCi-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce -14 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3+X“, -N(ORee)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, C1-10 alkyl, Ci-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-ioalkyl, heteroCi-ioalkenyl, heteroCi- loalkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce 10 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents are joined to form =0 or =S; wherein X“ is a counterion; each instance of Reeis, independently, selected from Ci-10 alkyl, Ci-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-10 alkyl, heteroCi-10 alkenyl, heteroCi-10 alkynyl, C3-10 carbocyclyl, Ce 10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, Ci-10 alkyl, Ci-10 perhaloalkyl, Ci-10 alkenyl, Ci-10 alkynyl, heteroCi-10 alkyl, heteroCi-10 alkenyl, heteroCi-10 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce 10 aryl, and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups;heterocyclyl, or 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; and each X" is a counterion.

[0051] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -C1), bromine (bromo, -Br), or iodine (iodo, -I).

[0052] The term “hydroxyl” or “hydroxy” refers to the group -OH. The term “substituted hydroxyl” or “substituted hydroxy,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups

[0053] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents includealkyl, C1-20perhaloalkyl, C 1-20 alkenyl, C 1-20 alkynyl, hetero C 1-20 alkyl, hetero C 1-20 alkenyl, hetero Ci-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.

[0054] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include -OH, -ORaa, -N(RCC)2, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SOFT. -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, Ci-10 alkyl, Ci-20 alkenyl, Ci-20 alkynyl, hetero Ci-20 alkyl, hetero Ci-20 alkenyl, hetero Ci-20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce -14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0055] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-10 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-10 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-10 alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted Ci-6 alkyl or an oxygen protecting group.

[0056] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3, -P(RCC)2, -P(RCC)3+X’, -P(ORCC)2, -P(ORCC)3+X-, -P(=O)(Raa)2, -P(=O)(ORCC)2, and -P(=O)(N(Rbb) 2)2, wherein X“, Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0057] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may bemonovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F", Cl", Br , I"), NO3 , CIO4 , OH , H2PO4 , HCOr HSO4 , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5- sulfonate, ethan-1 -sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4~, PF4 , PFe", AsFe", SbFe", B[3,5-(CF3)2CeH3]4]-, B(CeF5)4“, BPh4 , A1(OC(CF3)3)4", and carborane anions (e.g., CB| I H I or (HCB i i MciBi'r,) ). Exemplary counterions which may be multivalent include COA. HPO42-, PO43-. B4O72-, SO42-, S2O32-, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0058] A “leaving group” (EG) is an art-understood term referring to an atomic or molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. As used herein, a leaving group can be an atom or a group capable of being displaced by a nucleophile. See e.g., Smith, March Advanced Organic Chemistry 6th ed. (501-502). In some embodiments, the leaving group is an internal leaving group such as an epoxide.

[0059] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0060] A “non-hydrogen group” refers to any group that is defined for a particular variable that is not hydrogen.

[0061] The term “heteroatom” refers to an atom that is not hydrogen or carbon. In certain embodiments, the heteroatom is nitrogen. In certain embodiments, the heteroatom is oxygen. In certain embodiments, the heteroatom is sulfur.

[0062] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The present disclosure is not limited in any manner by the above exemplary listing of substituents.

[0063] 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, ormalonic 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, 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, 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.

[0064] 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 well 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, 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 pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, 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 usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0065] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

[0066] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (z.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0067] The terms “composition” and “formulation” are used interchangeably.

[0068] A “subject” to which administration is contemplated refers to a human (z.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 nonhuman 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.

[0069] 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.

[0070] The term “target 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 be treated. A target tissue may alsobe 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.

[0071] 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.

[0072] 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.

[0073] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0074] 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, pharmacokinetics, 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).

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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 the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for delivering a nucleic acid (e.g., RNA (e.g., mRNA)) to a subject or a cell, tissue, or biological sample. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating cancer (e.g., a solid tumor (e.g., brain tumor (e.g., glioblastoma), pancreatic cancer, ovarian cancer)). In certain embodiments, a therapeutically effective amount is an amount sufficient for delivering a nucleic acid (e.g., RNA (e.g., mRNA)) to a subject or a cell, tissue, or biological sample and treating cancer (e.g., a solid tumor (e.g., brain tumor (e.g., glioblastoma), pancreatic cancer, ovarian cancer)).

[0079] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for delivering a nucleic acid (e.g., RNA (e.g., mRNA)) to a subject or a cell, tissue, or biological sample. In certain embodiments, a prophylactically effective amount is an amount sufficient for treating cancer (e.g., a solid tumor (e.g., brain tumor (e.g., glioblastoma), pancreatic cancer, ovarian cancer)). In certain embodiments, a prophylactically effective amount is an amount sufficient for delivering a nucleic acid (e.g., RNA (e.g., mRNA)) to a subject or a cell, tissue, or biological sample and treating cancer (e.g., a solid tumor (e.g., brain tumor (e.g., glioblastoma), pancreatic cancer, ovarian cancer)).

[0080] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.

[0081] A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990). A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (z.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.

[0082] The term “angiogenesis” refers to the physiological process through which new blood vessels form from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development. Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis may be chemically stimulated by angiogenic proteins, such as growth factors (e.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and / or is associated with a disease.

[0083] 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. Exemplary benign 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. Incontrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction 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.

[0084] 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., Stedman’s 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., leukemia such 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, Burkittlymphoma, 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); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (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), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).

[0085] 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 stimulationof 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, andnecrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation.

[0086] 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 inflammatory condition (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.

[0087] An “autoimmune disease” refers 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 other words, the immune system mistakes some part of the body as a pathogen and attacks its own 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.

[0088] The term “liver disease” or “hepatic disease” refers to damage to or a disease of the liver. Non-limiting examples of liver disease include intrahepatic cholestasis e.g., alagille syndrome, biliary liver cirrhosis), fatty liver (e.g., alcoholic fatty liver, Reye’s syndrome), hepatic vein thrombosis, hepatolenticular degeneration (i.e., Wilson’s disease), hepatomegaly, liver abscess (e.g., amebic liver abscess), liver cirrhosis (e.g., alcoholic, biliary, and experimental liver cirrhosis), alcoholic liver diseases (e.g., fatty liver, hepatitis, cirrhosis), parasitic liver disease (e.g., hepatic echinococcosis, fascioliasis, amebic liver abscess), jaundice (e.g., hemolytic, hepatocellular, cholestatic jaundice), cholestasis, portal hypertension, liver enlargement, ascites, hepatitis (e.g., alcoholic hepatitis, animal hepatitis, chronic hepatitis (e.g., autoimmune, hepatitis B, hepatitis C, hepatitis D, drug induced chronic hepatitis), toxic hepatitis, viral human hepatitis (e.g., hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E), granulomatous hepatitis, secondary biliary cirrhosis, hepatic encephalopathy, varices, primary biliary cirrhosis, primary sclerosing cholangitis, hepatocellular adenoma, hemangiomas, bile stones, liver failure (e.g., hepatic encephalopathy, acute liver failure), angiomyolipoma, calcified liver metastases, cystic liver metastases, fibrolamellar hepatocarcinoma, hepatic adenoma, hepatoma, hepatic cysts (e.g., Simple cysts, Polycystic liver disease, hepatobiliary cystadenoma, choledochal cyst), mesenchymal tumors (mesenchymal hamartoma, infantile hemangioendothelioma, hemangioma, peliosis hepatis, lipomas, inflammatory pseudotumor), epithelial tumors (e.g., bile duct hamartoma, bile duct adenoma), focal nodular hyperplasia, nodular regenerative hyperplasia, hepatoblastoma, hepatocellular carcinoma, cholangiocarcinoma, cystadenocarcinoma, tumors of blood vessels, angiosarcoma, Karposi’s sarcoma, hemangioendothelioma, embryonal sarcoma, fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma, carcinosarcoma, teratoma, carcinoid, squamous carcinoma, primary lymphoma, peliosis hepatis,erythrohepatic porphyria, hepatic porphyria (e.g., acute intermittent porphyria, porphyria cutanea tarda), and Zellweger syndrome.

[0089] Immune disorders, such as auto-immune disorders, include, but are not limited to, arthritis (including rheumatoid arthritis, spondyloarthopathies, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjogren’s syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet’s disease, haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amylosis, acute painful shoulder, psoriatic, and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), enuresis, eosinophilic disease, 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, ischaemic colitis, diversion colitis, Behcet’s syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), and disorders ameliorated by a gastroprokinetic agent (e.g., ileus, postoperative ileus and ileus during sepsis; gastroesophageal reflux disease (GORD, or its synonym GERD); eosinophilic esophagitis, gastroparesis such as diabetic gastroparesis; food intolerances and food allergies and other functional bowel disorders, such as non-ulcerative dyspepsia (NUD) and non-cardiac chest pain (NCCP, including costo-chondritis)).

[0090] The term “particle” refers to a small object, fragment, or piece of a substance that may be a single element, inorganic material, organic material, or mixture thereof. Examples of particles include polymeric particles, single-emulsion particles, double -emulsion particles, coacervates, liposomes, microparticles, nanoparticles, macroscopic particles, pellets, crystals, aggregates, composites, pulverized, milled or otherwise disrupted matrices, and cross-linked protein or polysaccharide particles, each of which have an average characteristic dimension of about less than about 1 mm and at least 1 nm, where the characteristic dimension, or “critical dimension,” of the particle is the smallest cross-sectional dimension of the particle. A particle may be composed of a single substance or multiple substances. In certain embodiments, the particle is not a viral particle. In other embodiments, the particle is not a liposome. In certain embodiments, the particle is not a micelle. In certain embodiments, the particle is substantially solid throughout. In certain embodiments, the particle is a nanoparticle. In certain embodiments, the particle is a microparticle.

[0091] The term “nanoparticle” refers to a particle having an average (e.g., mean) dimension (e.g., diameter) of between about 1 nanometer (nm) and about 1 micrometer (pm) (e.g., between about 1 nm and about 300 nm, between about 1 nm and about 100 nm, between about 1 nm and about 30 nm, between about 1 nm and about 10 nm, or between about 1 nm and about 3 nm), inclusive.

[0092] The term “microparticle” refers to a particle having an average (e.g., mean) dimension (e.g., diameter) of between about 1 micrometer (pm) and about 1 millimeter (mm) (e.g., between about 1pm and about 100 pm, between about 1 pm and about 30 pm, between about 1 pm and about 10 pm, or between about 1 pm and about 3 pm), inclusive.

[0093] The term “sterol” refers to a subgroup of steroids also known as steroid alcohols, i.e., a steroid containing at least one hydroxyl group. Sterols are usually divided into two classes: (1) plant sterols also known as “phytosterols,” and (2) animal sterols also known as “zoosterols.” The term “sterol” includes, but is not limited to, cholesterol, sitosterol, campesterol, stigmasterol, brassicasterol (including dihydrobrassicasterol), desmosterol, chalinosterol, poriferasterol, clionasterol, ergosterol, coprosterol, codisterol, isofucosterol, fucosterol, clerosterol, nervisterol, lathosterol, stellasterol, spinasterol, chondrillasterol, peposterol, avenasterol, isoavenasterol, fecosterol, pollinastasterol, and all natural or synthesized forms and derivatives thereof, including isomers.

[0094] The “hydrodynamic diameter” of a particle refers to the diameter of a solid sphere that would exhibit the same hydrodynamic friction as the particle (e.g., the diameter of a solid sphere that diffuses at the same rate as the particle). Hydrodynamic diameter can be measured through various techniques including dynamic light scattering (DLS) and nanoparticle tracking analysis (NT A).

[0095] The terms “polydispersity index” or “PDI” refer to the degree of non-uniformity of a size distribution of particles (e.g., the broadness of a molecular weight distribution). PDI can be measured through various techniques including dynamic light scattering (DLS).

[0096] The term “zeta potential” refers to the potential difference between the surface of a particle and the surrounding liquid the particles are dispersed in (e.g., the surface charge of nanoparticles in solution). Zeta potential can be measured through various techniques including electrophoretic light scattering and electroacoustic phenomenon.

[0097] The term “pKa” refers to the negative decadic logarithm of the ionization constant (Ka) of an acid; equal to the pH value at which equal concentrations of the acid and conjugate base forms of a substance (often a buffer) are present.

[0098] The term “apparent pKa” refers to the experimentally determined pH at which the numbers of ionized (protonated) and deionized groups are equal in a molecule or nanoparticle. The apparent pKa of a nanoparticle is the result of the average ratio of all the ionized to deionized groups in the nanoparticle. The surface charge and ionic interaction of assembled nanomaterials in nanoparticles can be estimated according to apparent pKa. Apparent pKa can be measured through various techniques including acid-base titration and and 2-(p-toluidino)-6-naphthalene sulfonic acid (TNS) fluorescent methods.

[0099] 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.

[0100] The term “gene” refers to a nucleic acid fragment that expresses a protein, including regulatory sequences preceding (5 ’ non-coding sequences) and following (3 ’ non-coding sequences)the coding sequence. “Native gene” refers to a gene as found in nature with its own regulatory sequences. “Chimeric gene” or “chimeric construct” refers to any gene or a construct, not a native gene, comprising regulatory and coding sequences that are not found together in nature. Accordingly, a chimeric gene or chimeric construct may comprise regulatory sequences and coding sequences that are derived from different sources, or regulatory sequences and coding sequences derived from the same source, but arranged in a manner different than that found in nature. “Endogenous gene” refers to a native gene in its natural location in the genome of an organism. A “foreign” gene refers to a gene not normally found in the host organism, but which is introduced into the host organism by gene transfer. Foreign genes can comprise native genes inserted into a non-native organism, or chimeric genes. A “transgene” is a gene that has been introduced into the genome by a transformation procedure.

[0101] The terms “polynucleotide”, “nucleotide sequence”, “nucleic acid”, “nucleic acid molecule”, “nucleic acid sequence”, and “oligonucleotide” refer to a series of nucleotide bases (also called “nucleotides”) in DNA and RNA, and mean any chain of two or more nucleotides. The polynucleotides can be chimeric mixtures or derivatives or modified versions thereof, single-stranded or double-stranded. The oligonucleotide can be modified at the base moiety, sugar moiety, or phosphate backbone, for example, to improve stability of the molecule, its hybridization parameters, etc. The antisense oligonuculeotide may comprise a modified base moiety which is selected from the group including, but not limited to, 5-fluorouracil, 5-bromouracil, 5 -chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5- carboxymethylaminomethyl-2-thiouridine, 5- carboxymethylaminomethyluracil, dihydrouracil, beta- D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1 -methylinosine, 2,2- dimethylguanine, 2-methyladenine, 2-methylguanine, 3 -methylcytosine, 5- methylcytosine, N6- adenine, 7-methylguanine, 5 -methylaminomethyluracil, 5- methoxyaminomethyl-2-thiouracil, beta-D- mannosylqueosine, 5 ’-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6- isopentenyladenine, wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2- thiouracil, 4-thiouracil, 5-methyluracil, uracil- 5-oxyacetic acid methylester, uracil-5 -oxy acetic acid, 5-methyl-2- thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, a thio-guanine, and 2,6- diaminopurine. A nucleotide sequence typically carries genetic information, including the information used by cellular machinery to make proteins and enzymes. These terms include double- or singlestranded genomic and cDNA, RNA, any synthetic and genetically manipulated polynucleotide, and both sense and antisense polynucleotides. This includes single- and double-stranded molecules, i.e., DNA-DNA, DNA-RNA and RNA-RNA hybrids, as well as “protein nucleic acids” (PNAs) formed by conjugating bases to an amino acid backbone. This also includes nucleic acids containing carbohydrate or lipids. Exemplary DNAs include single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), plasmid DNA (pDNA), genomic DNA (gDNA), complementary DNA (cDNA), antisense DNA, chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA(mtDNA or mDNA), kinetoplast DNA (kDNA), provirus, lysogen, repetitive DNA, satellite DNA, and viral DNA. Exemplary RNAs include single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), small interfering RNA (siRNA), messenger RNA (mRNA), precursor messenger RNA (pre-mRNA), small hairpin RNA or short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer RNA (tRNA), antisense RNA (asRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or IncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, and viral satellite RNA.

[0102] “RNA transcript” refers to the product resulting from RNA polymerase-catalyzed transcription of a DNA sequence. When the RNA transcript is a complementary copy of the DNA sequence, it is referred to as the primary transcript, or it may be an RNA sequence derived from post- transcriptional processing of the primary transcript and is referred to as the mature RNA. “Messenger RNA (mRNA)” refers to the RNA that is without introns and can be translated into polypeptides by the cell. “cRNA” refers to complementary RNA, transcribed from a recombinant cDNA template. “cDNA” refers to DNA that is complementary to and derived from an mRNA template. The cDNA can be single-stranded or converted to double-stranded form using, for example, the Klenow fragment of DNA polymerase I.

[0103] The terms “nucleic acid” or “nucleic acid sequence”, “nucleic acid molecule”, “nucleic acid fragment” or “polynucleotide” may be used interchangeably with “gene”, “mRNA encoded by a gene” and “cDNA”.

[0104] The term “mRNA” or “mRNA molecule” refers to messenger RNA, or the RNA that serves as a template for protein synthesis in a cell. The sequence of a strand of mRNA is based on the sequence of a complementary strand of DNA comprising a sequence coding for the protein to be synthesized.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0105] The aspects described herein are not limited to specific embodiments, systems, compositions, methods, or configurations, and as such can, of course, vary. The terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.Compounds

[0106] In one aspect, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted heteroalkyl;each instance of R2is independently hydrogen or OH each instance of R3is independentlyn is 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, or 5; wherein the sum of n and p equals the number of attachment points in Q; each x is independently 0 or 1 ; each y is independently 0 or 1 ; and each z is independently 0 or 1 ;provided that within each instance ofeach x is 0, each y is 0, and each z is 0; each x is 1, each y is 0, and each z is 0; each x is 1, each y is 1, and each z is 0; or each x is 1 , each y is 1 , and each z is 1.

[0107] In another aspect, the present disclosure provides a compound of Formula (I'):or a pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted heteroalkyl;each instance of R2is independently hydrogen or OH each instance of R3is independentlyn is 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, or 5; wherein the sum of n and p equals the number of attachment points in Q; each x is independently 0 or 1 ; each y is independently 0 or 1 ; and each z is independently 0 or 1 ; provided that within each instance ofeach x is 0, each y is 0, and each z is 0; each x is 1, each y is 0, and each z is 0; each x is 1, each y is 1, and each z is 0; or each x is 1 , each y is 1 , and each z is 1 ; provided that the compound of Formula (I') is not of formula:

[0108] In some embodiments, the compound of Formula (I) or Formula (I') comprises at least oneR1

[0109] As generally described herein, each instance of R1is independently optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted heteroalkyl.

[0110] In some embodiments, each instance of R1is independently optionally substituted alkyl or optionally substituted alkenyl. In some embodiments, each instance of R1is independently optionally substituted alkyl or optionally substituted heteroalkyl. In some embodiments, each instance of R1is independently optionally substituted alkenyl or optionally substituted heteroalkyl.

[0111] In some embodiments, each instance of R1is independently substituted alkyl, substituted alkenyl, or substituted heteroalkyl. In some embodiments, each instance of R1is independently unsubstituted alkyl, unsubstituted alkenyl, or unsubstituted heteroalkyl.

[0112] In some embodiments, at least one instance of R1is substituted alkyl, substituted alkenyl, or substituted heteroalkyl. In some embodiments, at least one instance of R1is unsubstituted alkyl, unsubstituted alkenyl, or unsubstituted heteroalkyl.

[0113] In some embodiments, at least one instance of R1is optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted heteroalkyl.

[0114] In some embodiments, at least one instance of R1is optionally substituted alkyl or optionally substituted alkenyl. In some embodiments, at least one instance of R1is optionally substituted alkyl oroptionally substituted heteroalkyl. In some embodiments, at least one instance of R1is optionally substituted alkenyl or optionally substituted heteroalkyl.

[0115] In some embodiments, at least one instance of R1is optionally substituted alkyl.

[0116] In some embodiments, at least one instance of R1is optionally substituted Cm alkyl. In some embodiments, at least one instance of R1is optionally substituted C3-12 alkyl. In some embodiments, at least one instance of R1is optionally substituted Ce 12 alkyl. In some embodiments, at least one instance of R1is optionally substituted C3-10 alkyl. In some embodiments, at least one instance of R1is optionally substituted Ce 10 alkyl. In some embodiments, at least one instance of R1is optionally substituted Ce alkyl. In some embodiments, at least one instance of R1is optionally substituted C10 alkyl.

[0117] In some embodiments, at least one instance of R1is unsubstituted alkyl.

[0118] In some embodiments, at least one instance of R1is unsubstituted Ci-12 alkyl. In some embodiments, at least one instance of R1is unsubstituted C3-12 alkyl. In some embodiments, at least one instance of R1is unsubstituted Ce 12 alkyl. In some embodiments, at least one instance of R1is unsubstituted C3-10 alkyl. In some embodiments, at least one instance of R1is unsubstituted Ce 10 alkyl. In some embodiments, at least one instance of R1is unsubstituted Ce alkyl. In some embodiments, at least one instance of R1is unsubstituted C10 alkyl.

[0119] In some embodiments, at least one instance of R1is unsubstituted linear alkyl.

[0120] In some embodiments, at least one instance of R1is unsubstituted linear Ci-12 alkyl. In some embodiments, at least one instance of R1is unsubstituted linear C3-12 alkyl. In some embodiments, at least one instance of R1is unsubstituted linear Ce 12 alkyl. In some embodiments, at least one instance of R1is unsubstituted linear C3-10 alkyl. In some embodiments, at least one instance of R1is unsubstituted linear Ce 10 alkyl. In some embodiments, at least one instance of R1is unsubstituted linear Ce alkyl. In some embodiments, at least one instance of R1is unsubstituted linear C10 alkyl.

[0121] In some embodiments, at least one instance of R1is n-hexyl, n-heptyl, n-octyl, n-nonyl, or n- decyl. In some embodiments, at least one instance of R1is / z-hcxyl or n-decyl. In some embodiments, at least one instance of R1is / z-hcxyl. In some embodiments, at least one instance of R1is n-decyl.

[0122] In some embodiments, each instance of R1is independently optionally substituted alkyl.

[0123] In some embodiments, each instance of R1is independently optionally substituted Ci-12 alkyl. In some embodiments, each instance of R1is independently optionally substituted C3-12 alkyl. In some embodiments, each instance of R1is independently optionally substituted Ce 12 alkyl. In some embodiments, each instance of R1is independently optionally substituted C3-10 alkyl. In some embodiments, each instance of R1is independently optionally substituted Ce 10 alkyl. In some embodiments, each instance of R1is independently optionally substituted Ce alkyl. In some embodiments, each instance of R1is independently optionally substituted C10 alkyl.

[0124] In some embodiments, each instance of R1is independently unsubstituted alkyl.

[0125] In some embodiments, each instance of R1is independently unsubstituted Ci-12 alkyl. In some embodiments, each instance of R1is independently unsubstituted C3-12 alkyl. In some embodiments, each instance of R1is independently unsubstituted Ce 12 alkyl. In some embodiments, each instance of R1is independently unsubstituted C3-10 alkyl. In some embodiments, each instance of R1is independently unsubstituted Ce 10 alkyl. In some embodiments, each instance of R1is independently unsubstituted Ce alkyl. In some embodiments, each instance of R1is independently unsubstituted C10 alkyl.

[0126] In some embodiments, each instance of R1is independently unsubstituted linear alkyl.

[0127] In some embodiments, each instance of R1is independently unsubstituted linear Ci-12 alkyl. In some embodiments, each instance of R1is independently unsubstituted linear C3-12 alkyl. In some embodiments, each instance of R1is independently unsubstituted linear Ce 12 alkyl. In some embodiments, each instance of R1is independently unsubstituted linear C3-10 alkyl. In some embodiments, each instance of R1is independently unsubstituted linear Ce 10 alkyl. In some embodiments, each instance of R1is independently unsubstituted linear Ce alkyl. In some embodiments, each instance of R1is independently unsubstituted linear C10 alkyl.

[0128] In some embodiments, each instance of R1is independently n-hexyl, n-heptyl, n-octyl, n- nonyl, or n-decyl. In some embodiments, each instance of R1is independently / z-hcxyl or n-decyl. In some embodiments, each instance of R1is independently / z-hcxyl. In some embodiments, each instance of R1is independently n-decyl.

[0129] In some embodiments, at least one instance of R1is optionally substituted alkenyl.

[0130] In some embodiments, at least one instance of R1is optionally substituted C2-12 alkenyl. In some embodiments, at least one instance of R1is optionally substituted C4-12 alkenyl. In some embodiments, at least one instance of R1is optionally substituted Ce 12 alkenyl. In some embodiments, at least one instance of R1is optionally substituted C4-10 alkenyl. In some embodiments, at least one instance of R1is optionally substituted Ce 10 alkenyl. In some embodiments, at least one instance of R1is optionally substituted Cs alkenyl.

[0131] In some embodiments, at least one instance of R1is unsubstituted alkenyl.

[0132] In some embodiments, at least one instance of R1is unsubstituted C2-12 alkenyl. In some embodiments, at least one instance of R1is unsubstituted C4-12 alkenyl. In some embodiments, at least one instance of R1is unsubstituted Ce 12 alkenyl. In some embodiments, at least one instance of R1is unsubstituted C4-10 alkenyl. In some embodiments, at least one instance of R1is unsubstituted Ce 10 alkenyl. In some embodiments, at least one instance of R1is unsubstituted C« alkenyl.

[0133] In some embodiments, at least one instance of R1is unsubstituted linear alkenyl.

[0134] In some embodiments, at least one instance of R1is unsubstituted linear C2-12 alkenyl. In some embodiments, at least one instance of R1is unsubstituted linear C4-12 alkenyl. In some embodiments, at least one instance of R1is unsubstituted linear Ce 12 alkenyl. In some embodiments, at least one instance of R1is unsubstituted linear C4-10 alkenyl. In some embodiments, at least one instance of R1isunsubstituted linear Ce-io alkenyl. In some embodiments, at least one instance of R1is unsubstituted linear Cs alkenyl.

[0135] In some embodiments, at least one instance of R1is octenyl. In some embodiments, at least one instance of R1is 7-octenyl. In some embodiments, at least one instance of R1is

[0136] In some embodiments, each instance of R1is independently optionally substituted alkenyl.

[0137] In some embodiments, each instance of R1is independently optionally substituted C2-12 alkenyl. In some embodiments, each instance of R1is independently optionally substituted C4-12 alkenyl. In some embodiments, each instance of R1is independently optionally substituted Ce 12 alkenyl. In some embodiments, each instance of R1is independently optionally substituted C4-10 alkenyl. In some embodiments, each instance of R1is independently optionally substituted Ce 10 alkenyl. In some embodiments, each instance of R1is independently optionally substituted C« alkenyl.

[0138] In some embodiments, each instance of R1is independently unsubstituted alkenyl.

[0139] In some embodiments, each instance of R1is independently unsubstituted C2-12 alkenyl. In some embodiments, each instance of R1is independently unsubstituted C4-12 alkenyl. In some embodiments, each instance of R1is independently unsubstituted Ce 12 alkenyl. In some embodiments, each instance of R1is independently unsubstituted C4-10 alkenyl. In some embodiments, each instance of R1is independently unsubstituted Ce 10 alkenyl. In some embodiments, each instance of R1is independently unsubstituted Cs alkenyl.

[0140] In some embodiments, each instance of R1is independently unsubstituted linear alkenyl.

[0141] In some embodiments, each instance of R1is independently unsubstituted linear C2-12 alkenyl. In some embodiments, each instance of R1is independently unsubstituted linear C4-12 alkenyl. In some embodiments, each instance of R1is independently unsubstituted linear Ce 12 alkenyl. In some embodiments, each instance of R1is independently unsubstituted linear C4-10 alkenyl. In some embodiments, each instance of R1is independently unsubstituted linear Ce 10 alkenyl. In some embodiments, each instance of R1is independently unsubstituted linear C« alkenyl.

[0142] In some embodiments, each instance of R1is independently octenyl. In some embodiments, each instance of R1is independently 7-octenyl. In some embodiments, each instance of R1is independently

[0143] In some embodiments, at least one instance of R1is optionally substituted heteroalkyl.

[0144] In some embodiments, at least one instance of R1contains 1 or 2 oxygen atoms. In some embodiments, at least one instance of R1contains 1 oxygen atom.

[0145] In some embodiments, at least one instance of R1is optionally substituted Ci-12 heteroalkyl. In some embodiments, at least one instance of R1is optionally substituted C3-12 heteroalkyl. In some embodiments, at least one instance of R1is optionally substituted Ce 12 heteroalkyl. In some embodiments, at least one instance of R1is optionally substituted C3-10 heteroalkyl. In someembodiments, at least one instance of R1is optionally substituted Ce 10 heteroalkyl. In some embodiments, at least one instance of R1is optionally substituted C9 heteroalkyl.

[0146] In some embodiments, at least one instance of R1is unsubstituted heteroalkyl.

[0147] In some embodiments, at least one instance of R1is unsubstituted Ci-12 heteroalkyl. In some embodiments, at least one instance of R1is unsubstituted C3-12 heteroalkyl. In some embodiments, at least one instance of R1is unsubstituted Ce 12 heteroalkyl. In some embodiments, at least one instance of R1is unsubstituted C3-10 heteroalkyl. In some embodiments, at least one instance of R1is unsubstituted Ce 10 heteroalkyl. In some embodiments, at least one instance of R1is unsubstituted C9 heteroalkyl.

[0148] In some embodiments, at least one instance of R1is unsubstituted branched heteroalkyl.

[0149] In some embodiments, at least one instance of R1is unsubstituted branched Ci-12 heteroalkyl. In some embodiments, at least one instance of R1is unsubstituted branched C3-12 heteroalkyl. In some embodiments, at least one instance of R1is unsubstituted branched Ce 12 heteroalkyl. In some embodiments, at least one instance of R1is unsubstituted branched C3-10 heteroalkyl. In some embodiments, at least one instance of R1is unsubstituted branched Ce 10 heteroalkyl. In some embodiments, at least one instance of R1is unsubstituted branched C9 heteroalkyl.

[0150] In some embodiments, at least one instance of R1is unsubstituted branched heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0151] In some embodiments, at least one instance of R1is unsubstituted branched Ci-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. In some embodiments, at least one instance of R1is unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. In some embodiments, at least one instance of R1is unsubstituted branched Ce 12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. In some embodiments, at least one instance of R1is unsubstituted branched C3-10 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. In some embodiments, at least one instance of R1is unsubstituted branched Ce 10 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. In some embodiments, at least one instance of R1is unsubstituted branched C9 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0152] In some embodiments, at least one instance of R1is

[0153] In some embodiments, each instance of R1is independently optionally substituted heteroalkyl.

[0154] In some embodiments, each instance of R1independently contains 1 or 2 oxygen atoms. In some embodiments, each instance of R1independently contains 1 oxygen atom.

[0155] In some embodiments, each instance of R1is independently optionally substituted Cm heteroalkyl. In some embodiments, each instance of R1is independently optionally substituted C3-12 heteroalkyl. In some embodiments, each instance of R1is independently optionally substituted Ce 12 heteroalkyl. In some embodiments, each instance of R1is independently optionally substituted C3-10heteroalkyl. In some embodiments, each instance of R1is independently optionally substituted Ce-io heteroalkyl. In some embodiments, each instance of R1is independently optionally substituted C9 heteroalkyl.

[0156] In some embodiments, each instance of R1is independently unsubstituted heteroalkyl.

[0157] In some embodiments, each instance of R1is independently unsubstituted Cm heteroalkyl. In some embodiments, each instance of R1is independently unsubstituted C3-12 heteroalkyl. In some embodiments, each instance of R1is independently unsubstituted Ce 12 heteroalkyl. In some embodiments, each instance of R1is independently unsubstituted C3-10 heteroalkyl. In some embodiments, each instance of R1is independently unsubstituted Ce 10 heteroalkyl. In some embodiments, each instance of R1is independently unsubstituted C9 heteroalkyl.

[0158] In some embodiments, each instance of R1is independently unsubstituted branched heteroalkyl.

[0159] In some embodiments, each instance of R1is independently unsubstituted branched Ci-12 heteroalkyl. In some embodiments, each instance of R1is independently unsubstituted branched C3-12 heteroalkyl. In some embodiments, each instance of R1is independently unsubstituted branched Ce 12 heteroalkyl. In some embodiments, each instance of R1is independently unsubstituted branched C3-10 heteroalkyl. In some embodiments, each instance of R1is independently unsubstituted branched Ce 10 heteroalkyl. In some embodiments, each instance of R1is independently unsubstituted branched C9 heteroalkyl.

[0160] In some embodiments, each instance of R1is independently unsubstituted branched heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0161] In some embodiments, each instance of R1is independently unsubstituted branched Ci-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. In some embodiments, each instance of R1is independently unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. In some embodiments, each instance of R1is independently unsubstituted branched Ce 12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. In some embodiments, each instance of R1is independently unsubstituted branched C3-10 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. In some embodiments, each instance of R1is independently unsubstituted branched Ce 10 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. In some embodiments, each instance of R1is independently unsubstituted branched C9 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0162] In some embodiments, each instance of R1is independently

[0163] As generally described herein, each instance of R2is independently hydrogen or OH

[0164] In some embodiments, at least one instance of R2is hydrogen or

[0165] In some embodiments, at least one instance of R2is hydrogen. In some embodiments, each instance of R2is independently hydrogen.

[0166] In some embodiments, at least one instance of R2is OH . in some embodiments, each instance of R2is independently

[0167] In some embodiments, each instance of R2is independently OH , and each instance ofR1is independently optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted heteroalkyl.

[0168] In some embodiments, at least one instance of R2is OH , and at least one instance ofR1is optionally substituted Ce 12 alkyl. In some embodiments, at least one instance of R2isOH ,and at least one instance of R1is optionally substituted Ce 10 alkyl. In someembodiments, at least one instance of R2is OH , and at least one instance of R1is optionally substituted Ce alkyl or Cio alkyl.

[0169] In some embodiments, at least one instance of R2is OH , and at least one instance ofR1is unsubstituted Ce 12 alkyl. In some embodiments, at least one instance of R2is OH , and at least one instance of R1is unsubstituted Ce 10 alkyl. In some embodiments, at least one instance ofR2is OH , and at least one instance of R1is unsubstituted Ce alkyl or Cio alkyl.

[0170] In some embodiments, at least one instance of R2is OH , and at least one instance ofR1is unsubstituted linear Ce 12 alkyl. In some embodiments, at least one instance of R2is OH and at least one instance of R1is unsubstituted linear Ce 10 alkyl. In some embodiments, at least oneinstance of R2is OH , and at least one instance of R1is unsubstituted linear Ce alkyl or C10 alkyl.

[0171] In some embodiments, at least one instance of R2is OH . In someembodiments, at least one instance of R2is OH

[0172] In some embodiments, each instance of R2is independently OH , and each instance ofR1is independently optionally substituted Ce 12 alkyl. In some embodiments, each instance of R2isindependently OH , and each instance of R1is independently optionally substituted Ce 10R1alkyl. In some embodiments, each instance of R2is independently OH , and each instance of R1is independently optionally substituted Ce alkyl or C10 alkyl.

[0173] In some embodiments, each instance of R2is independently OH , and each instance ofR1is independently unsubstituted Ce 12 alkyl. In some embodiments, each instance of R2isindependently OH , and each instance of R1is independently unsubstituted Ce 10 alkyl. Insome embodiments, each instance of R2is independently OH , and each instance of R1is independently unsubstituted Ce alkyl or C10 alkyl.

[0174] In some embodiments, each instance of R2is independently OH , and each instance of R1is independently unsubstituted linear Ce 12 alkyl. In some embodiments, each instance of R2isindependently OH , and each instance of R1is independently unsubstituted linear Ce 10 alkyl.In some embodiments, each instance of R2is independently OH , and each instance of R1is independently unsubstituted linear Ce alkyl or C10 alkyl.

[0175] In some embodiments, each instance of R2is independently OH . Insome embodiments, each instance of R2is independently OH

[0176] In some embodiments, at least one instance of R2is OH , and at least one instance ofR1is optionally substituted Ce 12 alkenyl. In some embodiments, at least one instance of R2isOH , and at least one instance of R1is optionally substituted C« alkenyl.

[0177] In some embodiments, at least one instance of R2is OH , and at least one instance ofR1is unsubstituted Ce 12 alkenyl. In some embodiments, at least one instance of R2is OH , and at least one instance of R1is unsubstituted C« alkenyl.

[0178] In some embodiments, at least one instance of R2is OH , and at least one instance of R1is unsubstituted linear Ce 12 alkenyl. In some embodiments, at least one instance of R2isOH ,andat least one instance of R1is unsubstituted linear C« alkenyl.

[0179] In some embodiments, at least one instance of R2is

[0180] In some embodiments, each instance of R2is independently OH ,ai| each instance of R1is independently optionally substituted Ce 12 alkenyl. In some embodiments, each instance of R2isindependently OH , and each instance of R1is independently optionally substituted C« alkenyl.

[0181] In some embodiments, each instance of R2is independently OH and each instance ofR1is independently unsubstituted Ce 12 alkenyl. In some embodiments, each instance of R2isindependently OH , and each instance of R1is independently unsubstituted C« alkenyl.

[0182] In some embodiments, each instance of R2is independently OH and each instance ofR1is independently unsubstituted linear Ce 12 alkenyl. In some embodiments, each instance of R2isindependently OH , and each instance of R1is independently unsubstituted linear C« alkenyl.

[0183] In some embodiments, each instance of R2is independently OH

[0184] In some embodiments, at least one instance of R2is OH , and at least one instance ofR1is optionally substituted Ce 12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. Insome embodiments, at least one instance of R2is OH , and at least one instance of R1is optionally substituted C9 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0185] In some embodiments, at least one instance of R2is OH , and at least one instance of R1is unsubstituted Ce 12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. In someembodiments, at least one instance of R2is OH , and at least one instance of R1is unsubstituted C9 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0186] In some embodiments, at least one instance of R2is OH , and at least one instance of R1is unsubstituted linear Ce 12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. In someembodiments, at least one instance of R2is OH , and at least one instance of R1is unsubstituted linear C9 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0187] In some embodiments, at least one instance of R2is

[0188] In some embodiments, each instance of R2is independently OH , and each instance ofR1is independently optionally substituted Ce 12 heteroalkyl, wherein the heteroalkyl contains 1 oxygenR1atom. In some embodiments, each instance of R2is independently OH , and each instance ofR1is independently optionally substituted C9 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0189] In some embodiments, each instance of R2is independently OH , and each instance ofR1is independently unsubstituted Ce 12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.In some embodiments, each instance of R2is independently OH ,andeach instance of R1is independently unsubstituted C9 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0190] In some embodiments, each instance of R2is independently OH , and each instance ofR1is independently unsubstituted linear Ce 12 heteroalkyl, wherein the heteroalkyl contains 1 oxygenR1atom. In some embodiments, each instance of R2is independently OH , and each instance ofR1is independently unsubstituted linear C9 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0191] In some embodiments, each instance of R2is independentlyR3

[0192] As generally described herein, each instance of R3is independently. , of R3is independently of Formula (R3-a).

[0194] In some embodiments, at least one instance of R3is of Formula (R3-a-l):(R3-a-l). In some embodiments, each instance of R3is independently of Formula (R3-a-l).

[0195] In some embodiments, at least one instance of R3is of Formula (R3-a-l), wherein R1is optionally substituted alkyl. In some embodiments, at least one instance of R3is of Formula (R3-a-l), wherein R1is unsubstituted Cm alkyl. In some embodiments, at least one instance of R3is of Formula (R3-a-l), wherein R1is unsubstituted linear C3-12 alkyl. In some embodiments, at least one instance of R3is of Formula (R3-a-l), wherein R1is / z-hcxyl or n-decyl. In some embodiments, at least one instance of R3is. In some embodiments, at least one instance

[0196] In some embodiments, at least one instance of R3is of Formula (R3-a-l), wherein R1is optionally substituted alkenyl. In some embodiments, at least one instance of R3is of Formula (R3-a- 1), wherein R1is unsubstituted Cm alkenyl. In some embodiments, at least one instance of R3is of Formula (R3-a-l), wherein R1is unsubstituted linear C3-12 alkenyl. In some embodiments, at least one instance

[0197] In some embodiments, at least one instance of R3is of Formula (R3-a-l), wherein R1is optionally substituted heteroalkyl. In some embodiments, at least one instance of R3is of Formula (R3-a-l), wherein R1is unsubstituted Cm heteroalkyl. In some embodiments, at least one instance of R3is of Formula (R3-a-l), wherein R1is unsubstituted branched C3-12 heteroalkyl, wherein theheteroalkyl contains 1 oxygen atom. In some embodiments, at least one instance of R3is

[0198] In some embodiments, each instance of R3is independently of Formula (R3-a-l), wherein R1is optionally substituted alkyl. In some embodiments, each instance of R3is independently of Formula (R3-a-l), wherein R1is unsubstituted Ci-12 alkyl. In some embodiments, each instance of R3is independently of Formula (R3-a-l), wherein R1is unsubstituted linear C3-12 alkyl. In some embodiments, each instance of R3is independently of Formula (R3-a-l), wherein R1is n-hexyl or n- decyl. In some embodiments, each instance of R3is independently

[0199] In some embodiments, each instance of R3is independently of Formula (R3-a-l), wherein R1is optionally substituted alkenyl. In some embodiments, each instance of R3is independently of Formula (R3-a-l), wherein R1is unsubstituted Cm alkenyl. In some embodiments, each instance of R3is independently of Formula (R3-a-l), wherein R1is unsubstituted linear C3-12 alkenyl. In some embodiments, each instance of R3is independently

[0200] In some embodiments, each instance of R3is independently of Formula (R3-a-l), wherein R1is optionally substituted heteroalkyl. In some embodiments, each instance of R3is independently of Formula (R3-a-l), wherein R1is unsubstituted Cm heteroalkyl. In some embodiments, each instance of R3is independently of Formula (R3-a-l), wherein R1is unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. In some embodiments, each instance of R3is independently

[0201] In some embodiments, at least one instance of R3is of Formula (R3-a), wherein R2isOH . In some embodiments, at least one instance of R3is of Formula (R3-a-2):some embodiments, each instance of R3is independently of Formula (R3-a-2).

[0202] In some embodiments, at least one instance of R3is of Formula (R3-a-2), wherein each instance of R1is independently optionally substituted alkyl. In some embodiments, at least one instance of R3is of Formula (R3-a-2), wherein each instance of R1is independently unsubstituted Cm alkyl. In some embodiments, at least one instance of R3is of Formula (R3-a-2), wherein each instance of R1is independently unsubstituted linear C3-12 alkyl. In some embodiments, at least one instance of R3is of Formula (R3-a-2), wherein each instance of R1is independently / z-hcxyl or n-decyl. In someinstance of R1is independently optionally substituted alkenyl. In some embodiments, at least one instance of R3is of Formula (R3-a-2), wherein each instance of R1is independently unsubstituted Cm alkenyl. In some embodiments, at least one instance of R3is of Formula (R3-a-2), wherein each instance of R1is independently unsubstituted linear C3-12 alkenyl. In some embodiments, at least one

[0204] In some embodiments, at least one instance of R3is of Formula (R3-a-2), wherein each instance of R1is independently optionally substituted heteroalkyl. In some embodiments, at least one instance of R3is of Formula (R3-a-2), wherein each instance of R1is independently unsubstituted Ci-12 heteroalkyl. In some embodiments, at least one instance of R3is of Formula (R3-a-2), wherein each instance of R1is independently unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0205] In some embodiments, each instance of R3is independently of Formula (R3-a-2), wherein each instance of R1is independently optionally substituted alkyl. In some embodiments, each instance of R3is independently of Formula (R3-a-2), wherein each instance of R1is independentlyunsubstituted Ci-12 alkyl. In some embodiments, each instance of R3is independently of Formula (R3- a-2), wherein each instance of R1is independently unsubstituted linear C3-12 alkyl. In some embodiments, each instance of R3is independently of Formula (R3-a-2), wherein each instance of R1is independently / z-hcxyl or n-decyl. In some embodiments, each instance of R3is independentlysome embodiments, each instance of R3is independently

[0206] In some embodiments, each instance of R3is independently of Formula (R3-a-2), wherein each instance of R1is independently optionally substituted alkenyl. In some embodiments, each instance of R3is independently of Formula (R3-a-2), wherein each instance of R1is independently unsubstituted Ci-12 alkenyl. In some embodiments, each instance of R3is independently of Formula (R3-a-2), wherein each instance of R1is independently unsubstituted linear C3-12 alkenyl. In some embodiments, each instance of R3is independently

[0207] In some embodiments, each instance of R3is independently of Formula (R3-a-2), wherein each instance of R1is independently optionally substituted heteroalkyl. In some embodiments, each instance of R3is independently of Formula (R3-a-2), wherein each instance of R1is independently unsubstituted Ci-12 heteroalkyl. In some embodiments, each instance of R3is independently of Formula (R3-a-2), wherein each instance of R1is independently unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.R4

[0208] As generally described herein, each instance of R4is independently

[0209] In some embodiments, at least one instance of R4is of Formula (R4-a):some embodiments, each instance ofR4is independently of Formula (R4-a).

[0210] In some embodiments, at least one instance of R4is of Formula (R4-a), wherein each instance of R2is independently hydrogen. In some embodiments, at least one instance of R4is of Formula (R4-some embodiments, each instance of R4is independently of Formula (R4-a-l).

[0211] In some embodiments, at least one instance of R4is of Formula (R4-a-l), wherein each instance of R1is independently optionally substituted alkyl. In some embodiments, at least one instance of R4is of Formula (R4-a-l), wherein each instance of R1is independently unsubstituted Cm alkyl. In some embodiments, at least one instance of R4is of Formula (R4-a-l), wherein each instance of R1is independently unsubstituted linear C3-12 alkyl. In some embodiments, at least one instance of R4is of Formula (R4-a-l), wherein each instance of R1is independently / z-hcxyl or n-decyl.

[0212] In some embodiments, at least one instance of R4is of Formula (R4-a-l), wherein each instance of R1is independently optionally substituted alkenyl. In some embodiments, at least one instance of R4is of Formula (R4-a-l), wherein each instance of R1is independently unsubstituted Cm alkenyl. In some embodiments, at least one instance of R4is of Formula (R4-a-l), wherein each instance of R1is independently unsubstituted linear C3-12 alkenyl. In some embodiments, at least one instance of R4is of Formula (R4-a-l), wherein each instance of R1is independently 7-octenyl.

[0213] In some embodiments, at least one instance of R4is of Formula (R4-a-l), wherein each instance of R1is independently optionally substituted heteroalkyl. In some embodiments, at least one instance of R4is of Formula (R4-a-l), wherein each instance of R1is independently unsubstituted Ci-12 heteroalkyl. In some embodiments, at least one instance of R4is of Formula (R4-a-l), wherein each instance of R1is independently unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0214] In some embodiments, each instance of R4is independently of Formula (R4-a-l), wherein each instance of R1is independently optionally substituted alkyl. In some embodiments, each instance of R4is independently of Formula (R4-a-l), wherein each instance of R1is independentlyunsubstituted Cm alkyl. In some embodiments, each instance of R4is independently of Formula (R4- a-1), wherein each instance of R1is independently unsubstituted linear C3-12 alkyl. In some embodiments, each instance of R4is independently of Formula (R4-a-l), wherein each instance of R1is independently / z-hcxyl or n-decyl.

[0215] In some embodiments, each instance of R4is independently of Formula (R4-a-l), wherein each instance of R1is independently optionally substituted alkenyl. In some embodiments, each instance of R4is independently of Formula (R4-a-l), wherein each instance of R1is independently unsubstituted Ci-12 alkenyl. In some embodiments, each instance of R4is independently of Formula (R4-a-l), wherein each instance of R1is independently unsubstituted linear C3-12 alkenyl. In some embodiments, each instance of R4is independently of Formula (R4-a-l), wherein each instance of R1is independently 7-octenyl.

[0216] In some embodiments, each instance of R4is independently of Formula (R4-a-l), wherein each instance of R1is independently optionally substituted heteroalkyl. In some embodiments, each instance of R4is independently of Formula (R4-a-l), wherein each instance of R1is independently unsubstituted Ci-12 heteroalkyl. In some embodiments, each instance of R4is independently of Formula (R4-a-l), wherein each instance of R1is independently unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0217] In some embodiments, at least one instance of R4is of Formula (R4-a), wherein each instanceof R2is independently OH . In some embodiments, at least one instance of R4is of Formulasome embodiments, each instance of R4is independently of Formula (R4-a-2).

[0218] In some embodiments, at least one instance of R4is of Formula (R4-a-2), wherein each instance of R1is independently optionally substituted alkyl. In some embodiments, at least one instance of R4is of Formula (R4-a-2), wherein each instance of R1is independently unsubstituted Cm alkyl. In some embodiments, at least one instance of R4is of Formula (R4-a-2), wherein each instance of R1is independently unsubstituted linear C3-12 alkyl. In some embodiments, at least one instance of R4is of Formula (R4-a-2), wherein each instance of R1is independently / z-hcxyl or n-decyl.

[0219] In some embodiments, at least one instance of R4is of Formula (R4-a-2), wherein each instance of R1is independently optionally substituted alkenyl. In some embodiments, at least one instance of R4is of Formula (R4-a-2), wherein each instance of R1is independently unsubstituted Ci-12 alkenyl. In some embodiments, at least one instance of R4is of Formula (R4-a-2), wherein each instance of R1is independently unsubstituted linear C3-12 alkenyl. In some embodiments, at least one instance of R4is of Formula (R4-a-2), wherein each instance of R1is independently 7-octenyl.

[0220] In some embodiments, at least one instance of R4is of Formula (R4-a-2), wherein each instance of R1is independently optionally substituted heteroalkyl. In some embodiments, at least one instance of R4is of Formula (R4-a-2), wherein each instance of R1is independently unsubstituted Ci-12 heteroalkyl. In some embodiments, at least one instance of R4is of Formula (R4-a-2), wherein each instance of R1is independently unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0221] In some embodiments, each instance of R4is independently of Formula (R4-a-2), wherein each instance of R1is independently optionally substituted alkyl. In some embodiments, each instance of R4is independently of Formula (R4-a-2), wherein each instance of R1is independently unsubstituted Ci-12 alkyl. In some embodiments, each instance of R4is independently of Formula (R4- a-2), wherein each instance of R1is independently unsubstituted linear C3-12 alkyl. In some embodiments, each instance of R4is independently of Formula (R4-a-2), wherein each instance of R1is independently / z-hcxyl or n-decyl.

[0222] In some embodiments, each instance of R4is independently of Formula (R4-a-2), wherein each instance of R1is independently optionally substituted alkenyl. In some embodiments, each instance of R4is independently of Formula (R4-a-2), wherein each instance of R1is independently unsubstituted Ci-12 alkenyl. In some embodiments, each instance of R4is independently of Formula (R4-a-2), wherein each instance of R1is independently unsubstituted linear C3-12 alkenyl. In some embodiments, each instance of R4is independently of Formula (R4-a-2), wherein each instance of R1is independently 7-octenyl.

[0223] In some embodiments, each instance of R4is independently of Formula (R4-a-2), wherein each instance of R1is independently optionally substituted heteroalkyl. In some embodiments, each instance of R4is independently of Formula (R4-a-2), wherein each instance of R1is independently unsubstituted Ci-12 heteroalkyl. In some embodiments, each instance of R4is independently of Formula (R4-a-2), wherein each instance of R1is independently unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. x, y, and z

[0224] As generally described herein: each x is independently 0 or 1 ; each y is independently 0 or 1 ; andeach z is independently 0 or 1 ; provided that within each instance ofeach x is 0, each y is 0, and each z is 0; each x is 1, each y is 0, and each z is 0; each x is 1, each y is 1, and each z is 0; or each x is 1 , each y is 1 , and each z is 1.

[0225] In some embodiments, at least one x is 0. In some embodiments, at least one x is 1. In some embodiments, each x is independently 0. In some embodiments, each x is independently 1.

[0226] In some embodiments, at least one y is 0. In some embodiments, at least one y is 1. In some embodiments, each y is independently 0. In some embodiments, each y is independently 1.

[0227] In some embodiments, at least one z is 0. In some embodiments, at least one z is 1. In some embodiments, each z is independently 0. In some embodiments, each z is independently 1.

[0228] In some embodiments, at least one x is 0, at least one y is 0, and at least one z is 0. In some embodiments, at least one x is 1, at least one y is 0, and at least one z is 0. In some embodiments, at least one x is 1, at least one y is 1, and at least one z is 0. In some embodiments, at least one x is 1, at least one y is 1, and at least one z is 1. In some embodiments, each x is 0, each y is 0, and each z is 0. In some embodiments, each x is 1, each y is 0, and each z is 0. In some embodiments, each x is 1, each y is 1, and each z is 0. In some embodiments, each x is 1, each y is 1, and each z is 1.

[0229] In some embodiments, the compound of Formula (I) or Formula (I') comprises at least one instance of Formula(II), wherein R1, R2, R3, and R4are as defined herein.

[0230] In some embodiments, within at least one instance of Formula (II), each x is 0. In some embodiments, within at least one instance of Formula (II), each x is 1. In some embodiments, within at least one instance of Formula (II), each y is 0. In some embodiments, within at least one instance of Formula (II), each y is 1. In some embodiments, within at least one instance of Formula (II), each z is 0. In some embodiments, within at least one instance of Formula (II), each z is 1.

[0231] In some embodiments, within at least one instance of Formula (II), x is 0, y is 0, and z is 0; x is 1, y is 0, and z is 0; x is 1, y is 1, and z is 0; or x is 1, y is 1, and z is 1. In some embodiments, within at least one instance of Formula (II), x is 0, y is 0, and z is 0. In some embodiments, within at least one instance of Formula (II), x is 1, y is 0, and z is 0. In some embodiments, within at least oneinstance of Formula (II), x is 1, y is 1, and z is 0. In some embodiments, within at least one instance of Formula (II), x is 1, y is 1, and z is 1.

[0232] In some embodiments, within at least one instance of Formula (II), each x is 0, each y is 0, and each z is 0; each x is 1, each y is 0, and each z is 0; each x is 1, each y is 1, and each z is 0; or each x is 1, each y is 1, and each z is 1. In some embodiments, within at least one instance of Formula (II), each x is 0, each y is 0, and each z is 0. In some embodiments, within at least one instance of Formula (II), each x is 1, each y is 0, and each z is 0. In some embodiments, within at least one instance of Formula (II), each x is 1, each y is 1, and each z is 0. In some embodiments, within at least one instance of Formula (II), each x is 1, each y is 1, and each z is 1.

[0233] In some embodiments, within each instance of Formula (II), each x is 0. In some embodiments, within each instance of Formula (II), each x is 1. In some embodiments, within each instance of Formula (II), each y is 0. In some embodiments, within each instance of Formula (II), each y is 1. In some embodiments, within each instance of Formula (II), each z is 0. In some embodiments, within each instance of Formula (II), each z is 1.

[0234] In some embodiments, within each instance of Formula (II), x is 0, y is 0, and z is 0; x is 1, y is 0, and z is 0; x is 1, y is 1, and z is 0; or x is 1, y is 1, and z is 1. In some embodiments, within each instance of Formula (II), x is 0, y is 0, and z is 0. In some embodiments, within each instance of Formula (II), x is 1, y is 0, and z is 0. In some embodiments, within each instance of Formula (II), x is 1, y is 1, and z is 0. In some embodiments, within each instance of Formula (II), x is 1, y is 1, and z is 1.

[0235] In some embodiments, within each instance of Formula (II), each x is 0, each y is 0, and each z is 0; each x is 1, each y is 0, and each z is 0; each x is 1, each y is 1, and each z is 0; or each x is 1, each y is 1, and each z is 1. In some embodiments, within each instance of Formula (II), each x is 0, each y is 0, and each z is 0. In some embodiments, within each instance of Formula (II), each x is 1, each y is 0, and each z is 0. In some embodiments, within each instance of Formula (II), each x is 1, each y is 1, and each z is 0. In some embodiments, within each instance of Formula (II), each x is 1, each y is 1 , and each z is 1.some embodiments,

[0239] As generally described herein, n is 1, 2, 3, 4, 5, or 6; and p is 0, 1, 2, 3, 4, or 5; wherein the sum of n and p equals the number of attachment points in Q.

[0240] In some embodiments, n is 1, 2, 3, 4, 5, or 6. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.

[0241] In some embodiments, p is 0, 1, 2, 3, 4, or 5. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

[0242] In some embodiments, the sum of n and p equals the number of attachment points in Q. In some embodiments, the sum of n and p is 1, 2, 3, 4, 5, 6, 7, 8, 9 ,10, or 11. In some embodiments, thesum of n and p is 2. In some embodiments, the sum of n and p is 4. In some embodiments, the sum of n and p is 6.

[0243] In some embodiments, n and p are the same.

[0244] In some embodiments, n and p are both 1, 2, 3, 4, or 5. In some embodiments, n and p are both 1. In some embodiments, n and p are both 2. In some embodiments, n and p are both 3.

[0245] In some embodiments, n and p are different.

[0246] In some embodiments, n is 1, 2, 3, 4, 5, or 6; and p is 0. In some embodiments, n is 2, and p is 0. In some embodiments, n is 4, and p is 0. In some embodiments, n is 6, and p is 0.Subgeneric Embodiments

[0247] In some embodiments, the compound of Formula (I) or Formula (I') comprises at least one instance of Formula(II).

[0248] In some embodiments, within at least one instance of Formula (II)each x is 0, each y is 0, and each z is 0; each x is 1, each y is 0, and each z is 0; each x is 1, each y is 1, and each z is 0; or each x is 1, each y is 1, and each z is 1; wherein R1, R2, R3, and R4are as defined herein. In some embodiments, within at least one instance of Formula (II), each x is 0. In some embodiments, within at least one instance of Formula (II), each x is 1. In some embodiments, within at least one instance of Formula (II), each y is 0. In some embodiments, within at least one instance of Formula (II), each y is 1. In some embodiments, within at least one instance of Formula (II), each z is 0. In some embodiments, within at least one instance of Formula (II), each z is 1. In some embodiments, within at least one instance of Formula (II), each x is 0, each y is 0, and each z is 0. In some embodiments, within at least one instance of Formula (II), each x is 1, each y is 0, and each z is 0. In some embodiments, within at least one instance of Formula (II), each x is 1, each y is 1, and each z is 0. In some embodiments, within at least one instance of Formula (II), each x is 1, each y is 1, and each z is

[0249] In some embodiments, at least one instance of Formula (II) is of Formula(Il-a). In some embodiments, at least one instance of Formula (II) is of Formula (Ioptionally substituted alkyl. In some embodiments, at least one instance of Formula (II) is of Formula(Il-a), wherein R1is unsubstituted Ci-12 alkyl. In some embodiments, at least one instance of Formula (II) is of Formula (Il-a), wherein R1is unsubstituted linear C3-12 alkyl. In some embodiments, at least one instance of Formula (II) is of Formula (Il-a), wherein R1is n-hexyl or n-decyl. In someembodiments, at least one instance of Formula (II) is OH . In some embodiments,at least one instance of Formula (II) is OH

[0250] In some embodiments, at least one instance of Formula (II) is of Formula (Il-a), wherein R1is optionally substituted alkenyl. In some embodiments, at least one instance of Formula (II) is of Formula (Il-a), wherein R1is unsubstituted Cm alkenyl. In some embodiments, at least one instance of Formula (II) is of Formula (Il-a), wherein R1is unsubstituted linear C3-12 alkenyl. In someembodiments, at least one instance of Formula (II) is OH

[0251] In some embodiments, at least one instance of Formula (II) is of Formula (Il-a), wherein R1is optionally substituted heteroalkyl. In some embodiments, at least one instance of Formula (II) is of Formula (Il-a), wherein R1is unsubstituted Cm heteroalkyl. In some embodiments, at least one instance of Formula (II) is of Formula (Il-a), wherein R1is unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. In some embodiments, at least one instance ofFormula (

[0252] In some embodiments, each instance of Formula (II) is independently of Formula (Il-a). In some embodiments, each instance of Formula (II) is independently of Formula (Il-a), wherein R1is optionally substituted alkyl. In some embodiments, each instance of Formula (II) is independently of Formula (Il-a), wherein R1is unsubstituted Ci-12 alkyl. In some embodiments, each instance of Formula (II) is independently of Formula (Il-a), wherein R1is unsubstituted linear C3-12 alkyl. In some embodiments, each instance of Formula (II) is independently of Formula (Il-a), wherein R1is / z-hcxyl or / 7-dccyl. In some embodiments, each instance of Formula (II) is independently

[0253] In some embodiments, each instance of Formula (II) is independently of Formula (Il-a), wherein R1is optionally substituted alkenyl. In some embodiments, each instance of Formula (II) is independently of Formula (Il-a), wherein R1is unsubstituted Ci-12 alkenyl. In some embodiments, each instance of Formula (II) is independently of Formula (Il-a), wherein R1is unsubstituted linear C312 alkenyl. In some embodiments, each instance of Formula (II) is independently

[0254] In some embodiments, each instance of Formula (II) is independently of Formula (Il-a), wherein R1is optionally substituted heteroalkyl. In some embodiments, each instance of Formula (II) is independently of Formula (Il-a), wherein R1is unsubstituted Cm heteroalkyl. In some embodiments, each instance of Formula (II) is independently of Formula (Il-a), wherein R1is unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. In some embodiments, each instance of Formula (II) is independently

[0255] In some embodiments, at least one instance of Formula (II) is of Formula (Il-b):(Il-b). In some embodiments, each instance of Formula (II) is independently of Formula (Il-b).

[0256] In some embodiments, at least one instance of Formula (II) is of Formula (Il-b), wherein R2is hydrogen. In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-1):(II-b-1). In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-1).

[0257] In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-1), wherein R1is optionally substituted alkyl. In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-1), wherein R1is unsubstituted Cm alkyl. In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-1), wherein R1is unsubstituted linear C3-12 alkyl. In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-1), wherein R1is / z-hcxyl or / 7-dccyl. In some embodiments, at least one instance of Formula (Il-b) is

[0258] In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-1), wherein R1is optionally substituted alkenyl. In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-1), wherein R1is unsubstituted Cm alkenyl. In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-1), wherein R1is unsubstituted linear C3-12 alkenyl. Insome embodiments, at least one instance of Formula (Il-b) is

[0259] In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-1), wherein R1is optionally substituted heteroalkyl. In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-1), wherein R1is unsubstituted Cm heteroalkyl. In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-1), wherein R1is unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. In some embodiments, at least one instance of Formula (

[0260] In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-1), wherein R1is optionally substituted alkyl. In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-1), wherein R1is unsubstituted Ci-12 alkyl. In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-1), wherein R1is unsubstituted linear C3-12 alkyl. In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-1), wherein R1is n-hexyl or n-decyl. In some embodiments, each instance of Formula (Il-b) is

[0261] In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-1), wherein R1is optionally substituted alkenyl. In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-1), wherein R1is unsubstituted Cm alkenyl. In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-1), wherein R1is unsubstituted linear C3-12 alkenyl. In some embodiments, each instance of Formula (Il-b) is independently

[0262] In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-1), wherein R1is optionally substituted heteroalkyl. In some embodiments, each instance of Formula (II- b) is independently of Formula (II-b-1), wherein R1is unsubstituted Ci-12 heteroalkyl. In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-1), wherein R1is unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom. In someembodiments, each instance of Formula (Il-b) is independently

[0263] In some embodiments, at least one instance of Formula (II) is of Formula (Il-b), wherein R2isOH . In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-2):some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-2).

[0264] In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-2), wherein each instance of R1is independently optionally substituted alkyl. In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-2), wherein each instance of R1is independently unsubstituted Cm alkyl. In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-2), wherein each instance of R1is independently unsubstituted linear C3-12 alkyl. In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-2), wherein each instance of R1is independently / z-hcxyl or n-decyl. In some embodiments, at least one instance of Formula (Il-b)

[0265] In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-2), wherein each instance of R1is independently optionally substituted alkenyl. In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-2), wherein each instance of R1is independently unsubstituted Cm alkenyl. In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-2), wherein each instance of R1is independently unsubstituted linear C3-12 alkenyl. Insome embodiments, at least one instance of Formula (Il-b) is

[0266] In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-2), wherein each instance of R1is independently optionally substituted heteroalkyl. In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-2), wherein each instance of R1is independently unsubstituted Ci-12 heteroalkyl. In some embodiments, at least one instance of Formula (Il-b) is of Formula (II-b-2), wherein each instance of R1is independently unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0267] In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-2), wherein each instance of R1is independently optionally substituted alkyl. In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-2), wherein each instance of R1is independently unsubstituted Ci-12 alkyl. In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-2), wherein each instance of R1is independently unsubstituted linear C3-12 alkyl. In some embodiments, each instance of Formula (Il-b) is independently of Formula (Il-b- 2), wherein each instance of R1is independently / z-hcxyl or n-decyl. In some embodiments, eachembodiments, each instance of Formula (Il-b) is independently

[0268] In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-2), wherein each instance of R1is independently optionally substituted alkenyl. In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-2), wherein each instance of R1is independently unsubstituted Ci-12 alkenyl. In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-2), wherein each instance of R1is independently unsubstituted linearC3-12 alkenyl. In some embodiments, each instance of Formula (Il-b) is independently

[0269] In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-2), wherein each instance of R1is independently optionally substituted heteroalkyl. In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-2), wherein each instance of R1is independently unsubstituted Ci-12 heteroalkyl. In some embodiments, each instance of Formula (Il-b) is independently of Formula (II-b-2), wherein each instance of R1is independently unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0270] In some embodiments, at least one instance of Formula (II) is of Formula (II-c):some embodiments, each instance ofFormula (II) is independently of Formula (II-c).

[0271] In some embodiments, at least one instance of Formula (II) is of Formula (II-c), wherein each instance of R2is independently hydrogen. In some embodiments, at least one instance of Formula (II- c) is of Formulasome embodiments, each instance of Formula (II-c) is independently of Formula (II-c-1).

[0272] In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-1), wherein each instance of R1is independently optionally substituted alkyl. In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-1), wherein each instance of R1is independently unsubstituted Cm alkyl. In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-1), wherein each instance of R1is independently unsubstituted linear C3-12 alkyl. In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-1), wherein each instance of R1is independently / z-hcxyl or n-decyl.

[0273] In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-1), wherein each instance of R1is independently optionally substituted alkenyl. In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-1), wherein each instance of R1is independentlyunsubstituted Ci-12 alkenyl. In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-1), wherein each instance of R1is independently unsubstituted linear C3-12 alkenyl. In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-1), wherein each instance of R1is independently 7-octenyl.

[0274] In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-1), wherein each instance of R1is independently optionally substituted heteroalkyl. In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-1), wherein each instance of R1is independently unsubstituted Ci-12 heteroalkyl. In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-1), wherein each instance of R1is independently unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0275] In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c-1), wherein each instance of R1is independently optionally substituted alkyl. In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c-1), wherein each instance of R1is independently unsubstituted Ci-12 alkyl. In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c-1), wherein each instance of R1is independently unsubstituted linear C3-12 alkyl. In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c- 1), wherein each instance of R1is independently / z-hcxyl or n-decyl.

[0276] In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c-1), wherein each instance of R1is independently optionally substituted alkenyl. In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c-1), wherein each instance of R1is independently unsubstituted Ci-12 alkenyl. In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c-1), wherein each instance of R1is independently unsubstituted linear C3-12 alkenyl. In some embodiments, each instance of Formula (II-c) is independently of Formula (II- c-1), wherein each instance of R1is independently 7-octenyl.

[0277] In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c-1), wherein each instance of R1is independently optionally substituted heteroalkyl. In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c-1), wherein each instance of R1is independently unsubstituted Ci-12 heteroalkyl. In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c-1), wherein each instance of R1is independently unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0278] In some embodiments, at least one instance of Formula (II) is of Formula (II-c), wherein eachinstance of R2is independently OH . in some embodiments, at least one instance of Formula(II-c) is of Formulasome embodiments, each instance of Formula (II-c) is independently of Formula (II-c-2).

[0279] In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-2), wherein each instance of R1is independently optionally substituted alkyl. In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-2), wherein each instance of R1is independently unsubstituted Cm alkyl. In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-2), wherein each instance of R1is independently unsubstituted linear C3-12 alkyl. In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-2), wherein each instance of R1is independently / z-hcxyl or n-decyl.

[0280] In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-2), wherein each instance of R1is independently optionally substituted alkenyl. In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-2), wherein each instance of R1is independently unsubstituted Cm alkenyl. In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-2), wherein each instance of R1is independently unsubstituted linear C3-12 alkenyl. In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-2), wherein each instance of R1is independently 7-octenyl.

[0281] In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-2), wherein each instance of R1is independently optionally substituted heteroalkyl. In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-2), wherein each instance of R1is independently unsubstituted Ci-12 heteroalkyl. In some embodiments, at least one instance of Formula (II-c) is of Formula (II-c-2), wherein each instance of R1is independently unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0282] In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c-2), wherein each instance of R1is independently optionally substituted alkyl. In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c-2), wherein each instance of R1is independently unsubstituted Ci-12 alkyl. In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c-2), wherein each instance of R1is independently unsubstituted linear C3-12 alkyl. In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c- 2), wherein each instance of R1is independently / z-hcxyl or n-decyl.

[0283] In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c-2), wherein each instance of R1is independently optionally substituted alkenyl. In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c-2), wherein each instance of R1is independently unsubstituted C1-12 alkenyl. In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c-2), wherein each instance of R1is independently unsubstituted linear C3-12 alkenyl. In some embodiments, each instance of Formula (II-c) is independently of Formula (II- c-2), wherein each instance of R1is independently 7-octenyl.

[0284] In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c-2), wherein each instance of R1is independently optionally substituted heteroalkyl. In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c-2), wherein each instance of R1is independently unsubstituted C1-12 heteroalkyl. In some embodiments, each instance of Formula (II-c) is independently of Formula (II-c-2), wherein each instance of R1is independently unsubstituted branched C3-12 heteroalkyl, wherein the heteroalkyl contains 1 oxygen atom.

[0285] In some embodiments, at least one instance of Formula (II) is of Formula (II-d):some embodiments, each instance of Formula (II) is independently of Formula (II-d).

[0286] In some embodiments, at least one instance of Formula (II) is of Formula (II-d), wherein each instance of R2is independently hydrogen. In some embodiments, each instance of Formula (II) is independently of Formula (II-d), wherein each instance of R2is independently hydrogen.

[0287] In some embodiments, at least one instance of Formula (II) is of Formula (II-d), wherein eachinstance of R2is independently OH . In some embodiments, each instance of Formula (II) isindependently of Formula (II-d), wherein each instance of R2is independently OH

[0288] In some embodiments, the compound of Formula (I) or Formula (F) is of Formula (III):or a pharmaceutically acceptable salt thereof.

[0289] In some embodiments, the compound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, and n and p are both 1. In some embodiments, the compound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, and n and p are both 2. In some embodiments, the compound of Formula (I) is of Formula (III), or a pharmaceutically acceptable saltthereof, and n and p are both 3. In some embodiments, the compound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, and n is 2, and p is 0. In some embodiments, the compound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, and n is 4, and p is 0. In some embodiments, the compound of Formula (I) is of Formula (III), or a pharmaceutically acceptable salt thereof, and n is 6, and p is 0.

[0290] In some embodiments, the compound of Formula (III) is of Formulae (III-a-1) to (III-a-5):or a pharmaceutically acceptable salt thereof.

[0291] In some embodiments, the compound of Formula (III) is of Formulae (III-a-2) or (III-a-5), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III) is of Formula (III-a-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III) is of Formula (III-a-5), or a pharmaceutically acceptable salt thereof.

[0292] In some embodiments, the compound of Formula (III) is of Formulae (III-b-1) or (III-b-2):or a pharmaceutically acceptable salt thereof.

[0293] In some embodiments, the compound of Formula (III) is of Formula (III-b-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III) is of Formula (III-b-2), or a pharmaceutically acceptable salt thereof.

[0294] In some embodiments, the compound of Formula (III) is of Formulae (III-c-1) to (III-c-9):or a pharmaceutically acceptable salt thereof.

[0295] In some embodiments, the compound of Formula (III) is of Formulae (III-c-5) or (III-c-9), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III) is ofFormula (III-c-5), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III) is of Formula (III-c-9), or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, the compound of Formula (III) is of Formulae (III-d-1) to (III-d-5):or a pharmaceutically acceptable salt thereof.

[0297] In some embodiments, the compound of Formula (III) is of Formulae (III-d-2) or (III-d-5), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III) is of Formula (III-d-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III) is of Formula (III-d-5), or a pharmaceutically acceptable salt thereof.

[0298] In some embodiments, the compound of Formula (III) is of Formulae (III-e-1) to (III-e-5):or a pharmaceutically acceptable salt thereof.

[0299] In some embodiments, the compound of Formula (III) is of Formulae (III-e-2) or (III-e-5), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III) is of Formula (III-e-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III) is of Formula (III-e-5), or a pharmaceutically acceptable salt thereof.

[0300] In some embodiments, the compound of Formula (III) is of Formulae (III-f-1) to (III-f-20):or a pharmaceutically acceptable salt thereof.

[0301] In some embodiments, the compound of Formula (III) is of Formulae (III-a-2), (III-a-3), (III- b-1), (III-c-4), (III-c-5), (III-d-2), (III-d-3), (III-e-2), (III-e-3), (III-f-8), (III-f-9), (III-f-10), (III-f-11), or (III -f- 12), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III) is of Formulae (III-a-2), (III-b-1), (III-c-5), (III-d-2), or (III-e-2), or a pharmaceutically acceptable salt thereof.

[0302] In some embodiments, the compound of Formula (III) is of Formulae (III-a-5), (III-b-2), (III- c-9), (III-d-5), (III-e-5), or (III-f-20), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (III) is of Formulae (III-a-5), (III-b-2), (III-c-9), (III-d-5), or (III-e-5), or a pharmaceutically acceptable salt thereof.

[0303] In some embodiments, the compound of Formula (I) or Formula (F) is of Formula (IV):or a pharmaceutically acceptable salt thereof.

[0304] In some embodiments, the compound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, and n and p are both 1. In some embodiments, the compound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, and n and p are both 2. In some embodiments, the compound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, and n and p are both 3. In some embodiments, the compound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, and n is 2, and p is 0. In some embodiments, the compound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, and n is 4, and p is 0. In some embodiments, the compound of Formula (I) is of Formula (IV), or a pharmaceutically acceptable salt thereof, and n is 6, and p is 0.

[0305] In some embodiments, the compound of Formula (IV) is of Formulae (IV-a-1) to (IV-a-5):or a pharmaceutically acceptable salt thereof.

[0306] In some embodiments, the compound of Formula (IV) is of Formulae (IV-a-2) or (IV-a-5), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) is of Formula (IV-a-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) is of Formula (IV-a-5), or a pharmaceutically acceptable salt thereof.

[0307] In some embodiments, the compound of Formula (IV) is of Formulae (IV-b-1) or (IV-b-2):or a pharmaceutically acceptable salt thereof.

[0308] In some embodiments, the compound of Formula (IV) is of Formula (IV-b-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) is ofFormula (IV-b-2), or a pharmaceutically acceptable salt thereof.

[0309] In some embodiments, the compound of Formula (IV) is of Formulae (IV-c-1) to (IV-c-9):or a pharmaceutically acceptable salt thereof.

[0310] In some embodiments, the compound of Formula (IV) is of Formulae (IV-c-5) or (IV-c-9), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) is of Formula (IV-c-5), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) is of Formula (IV-c-9), or a pharmaceutically acceptable salt thereof.

[0311] In some embodiments, the compound of Formula (IV) is of Formulae (IV-d-1) to (IV-d-5):or a pharmaceutically acceptable salt thereof.

[0312] In some embodiments, the compound of Formula (IV) is of Formulae (IV-d-2) or (IV-d-5), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) is of Formula (IV-d-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) is of Formula (IV-d-5), or a pharmaceutically acceptable salt thereof.

[0313] In some embodiments, the compound of Formula (IV) is of Formulae (IV-e-1) to (IV-e-5):or a pharmaceutically acceptable salt thereof.

[0314] In some embodiments, the compound of Formula (IV) is of Formulae (IV-e-2) or (IV-e-5), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) is of Formula (IV-e-2), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) is of Formula (IV-e-5), or a pharmaceutically acceptable salt thereof.

[0315] In some embodiments, the compound of Formula (IV) is of Formulae (IV-f-1) to (IV-f-20):or a pharmaceutically acceptable salt thereof.

[0316] In some embodiments, the compound of Formula (IV) is of Formulae (IV-a-2), (IV-a-3), (IV- b-1), (IV-c-4), (IV-c-5), (IV-d-2), (IV-d-3), (IV-e-2), (IV-e-3), (IV-f-8), (IV-f-9), (IV-f-10), (IV-f-11), or (IV-f-12), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) is of Formulae (IV-a-2), (IV-b-1), (IV-c-5), (IV-d-2), or (IV-e-2), or a pharmaceutically acceptable salt thereof.

[0317] In some embodiments, the compound of Formula (IV) is of Formulae (IV-a-5), (IV-b-2), (IV- c-9), (IV-d-5), (IV-e-5), or (IV-f-20), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IV) is of Formulae (IV-a-5), (IV-b-2), (IV-c-9), (IV-d-5), or (IV-e-5), or a pharmaceutically acceptable salt thereof.

[0318] In some embodiments, the compound of Formula (I) or Formula (F) is of Formula (V):or a pharmaceutically acceptable salt thereof.

[0319] In some embodiments, the compound of Formula (I) is of formula:or a pharmaceutically acceptable salt thereof.

[0320] In some embodiments, the compound of Formula (I) is of formula:or a pharmaceutically acceptable salt thereof.

[0321] As described herein, compounds of the present disclosure may be identified by the nomenclature CWGX-LY-Z, wherein “CW” refers to the initiator core (Cl, C2, C3, C4, C5, C6, as shown in FIG. 1), “GX” refers to the dendrimer generation (GO, Gl, G2, as shown in FIG. 1), “LY” refers to the lipid (L8, LI 2, LB, UNL10, as shown in FIG. 1), and Z refers to the lipid conjugation percentage (0%, 50%, 100%, as shown in FIG. 1). As a non-limiting example, the compound “C1G1-L8-50” refers to the generation 1 dendrimer prepared from initiator core Cl, using lipid L8, with 50% lipid conjugation:

[0322] In some embodiments, a provided compound (a compound described herein, a compound of the present disclosure) is a compound of any of the formulae herein (e.g., Formula (I), Formula (I')), or a pharmaceutically acceptable salt thereof. In some embodiments, a provided compound is a compound of any of the formulae herein (e.g., Formula (I), Formula (I')), or a salt thereof. In some embodiments, a provided compound is a compound of any of the formulae herein (e.g., Formula (I), Formula (I')).Compositions and Kits

[0323] In another aspect, the present disclosure provides a composition comprising: a compound of Formula (I), or a pharmaceutically acceptable salt thereof; a helper lipid; a sterol; and a PEGylated lipid. In some embodiments, the composition further comprises a nucleic acid.

[0324] In another aspect, the present disclosure provides a composition comprising: a compound of Formula (I'), or a pharmaceutically acceptable salt thereof; a helper lipid; a sterol; and a PEGylated lipid. In some embodiments, the composition further comprises a nucleic acid.

[0325] In another aspect, the present disclosure provides a composition comprising: a compound of Formula (I), or a pharmaceutically acceptable salt thereof; a helper lipid; a sterol; a PEGylated lipid; and a nucleic acid.

[0326] In another aspect, the present disclosure provides a composition comprising: a compound of Formula (I'), or a pharmaceutically acceptable salt thereof; a helper lipid; a sterol; a PEGylated lipid; and a nucleic acid.

[0327] In some embodiments, the composition encapsulates the nucleic acid. In some embodiments, the composition further comprises a pharmaceutically acceptable excipient.

[0328] In some embodiments, the provided compound is provided in an effective amount in the pharmaceutical composition. In some embodiments, the effective amount is an amount effective for delivering a nucleic acid (e.g., RNA (e.g., mRNA)) to a subject or a cell, tissue, or biological sample. In some embodiments, the effective amount is an amount effective for delivering RNA (e.g., mRNA) to a subject or a cell, tissue, or biological sample. In some embodiments, the effective amount is an amount effective for delivering mRNA to a subject or a cell, tissue, or biological sample.

[0329] In some embodiments, the composition is formulated as a particle. In some embodiments, the composition is formulated as a nanoparticle or microparticle. In some embodiments, the particle is a microparticle (z.e., particle having a characteristic dimension of less than about 1 millimeter and at least about 1 micrometer, where the characteristic dimension of the particle is the smallest cross- sectional dimension of the particle). In some embodiments, the particle is a nanoparticle (z.e., a particle having a characteristic dimension of less than about 1 micrometer and at least about 1 nanometer, where the characteristic dimension of the particle is the smallest cross-sectional dimension of the particle). In some embodiments, the composition is formulated as a lipid nanoparticle.

[0330] The particles described herein may include additional materials such as polymers (e.g., synthetic polymers (e.g., PEG, PLGA) and natural polymers (e.g., phospholipids)). In some embodiments, the additional materials are approved by a regulatory agency, such as the U.S. FDA, for human and veterinary use.

[0331] The particles may be prepared using any method known in the art, such as precipitation, milling, spray drying, single and double emulsion solvent evaporation, solvent extraction, phase separation, and simple and complex coacervation. The conditions used in preparing the particles may be altered to yield particles of a desired size or property (e.g., hydrophobicity, hydrophilicity, external morphology, “stickiness”, shape, polydispersity, etc.). The method of preparing the particle and the conditions (e.g., solvent, temperature, concentration, and air flow rate, etc.) used may also depend on the agent being complexed, encapsulated, or mixed, and / or the composition of the matrix.

[0332] Methods developed for making particles for delivery of agents that are included in the particles are described in the literature. See, e.g., Doubrow, M., Ed., “Microcapsules and Nanoparticles in Medicine and Pharmacy,” CRC Press, Boca Raton, 1992; Mathiowitz and Langer, J.Controlled Release 5:13-22, 1987; Mathiowitz et al., Reactive Polymers 6:275-283, 1987; Mathiowitz et al., J. Appl. Polymer Sci. 35:755-774, 1988, which are incorporated by reference herein.

[0333] If the particles prepared by any of the above methods have a size range outside of the desired range, the particles can be sized, for example, using a sieve. The particles may also be coated. In some embodiments, the particles are coated with a targeting agent. In some embodiments, the particles are coated with a surface-altering agent. In some embodiments, the particles are coated to achieve desirable surface properties (e.g., a particular charge).

[0334] In some embodiments, the composition comprises between about 1 mol % and about 90 mol %, between about 1 mol % and about 80 mol %, between about 1 mol % and about 75 mol %, between about 1 mol % and about 70 mol %, between about 1 mol % and about 65 mol %, between about 1 mol % and about 60 mol %, between about 1 mol % and about 55 mol %, between about 1 mol % and about 50 mol %, between about 10 mol % and about 90 mol %, between about 10 mol % and about 80 mol %, between about 10 mol % and about 75 mol %, between about 10 mol % and about 70 mol %, between about 10 mol % and about 65 mol %, between about 10 mol % and about 60 mol %, between about 10 mol % and about 55 mol %, between about 10 mol % and about 50 mol %, between about 20 mol % and about 80 mol %, between about 20 mol % and about 75 mol %, between about 20 mol % and about 70 mol %, between about 20 mol % and about 65 mol %, between about 20 mol % and about 60 mol %, between about 20 mol % and about 55 mol %, between about 20 mol % and about 50 mol %, between about 25 mol % and about 80 mol %, between about 25 mol % and about 75 mol %, between about 25 mol % and about 70 mol %, between about 25 mol % and about 65 mol %, between about 25 mol % and about 60 mol %, between about 25 mol % and about 55 mol %, between about 25 mol % and about 50 mol %, between about 30 mol % and about 75 mol %, between about 30 mol % and about 70 mol %, between about 30 mol % and about 65 mol %, between about 30 mol % and about 60 mol %, between about 30 mol % and about 55 mol %, between about 30 mol % and about 50 mol %, between about 35 mol % and about 70 mol %, between about 35 mol % and about 65 mol %, between about 35 mol % and about 60 mol %, between about 35 mol % and about 55 mol %, between about 35 mol % and about 50 mol %, between about 40 mol % and about 65 mol %, between about 40 mol % and about 60 mol %, between about 40 mol % and about 55 mol %, between about 40 mol % and about 50 mol %, between about 45 mol % and about 65 mol %, between about 45 mol % and about 60 mol %, between about 45 mol % and about 55 mol %, between about 45 mol % and about 50 mol %, between about 50 mol % and about 65 mol %, between about 50 mol % and about 60 mol %, between about 50 mol % and about 55 mol %, between about 37.5 mol % and about62.5 mol %, between about 37.5 mol % and about 60 mol %, between about 37.5 mol % and about57.5 mol %, between about 37.5 mol % and about 55 mol %, between about 37.5 mol % and about52.5 mol %, between about 40 mol % and about 62.5 mol %, between about 40 mol % and about 57.5 mol %, between about 40 mol % and about 52.5 mol %, between about 42.5 mol % and about 62.5 mol %, between about 42.5 mol % and about 60 mol %, between about 42.5 mol % and about 57.5mol %, between about 42.5 mol % and about 55 mol %, between about 42.5 mol % and about 52.5 mol %, between about 45 mol % and about 62.5 mol %, between about 45 mol % and about 57.5 mol %, between about 45 mol % and about 52.5 mol %, between about 47.5 mol % and about 62.5 mol %, between about 47.5 mol % and about 60 mol %, between about 47.5 mol % and about 57.5 mol %, between about 47.5 mol % and about 55 mol %, between about 47.5 mol % and about 52.5 mol %, between about 45 mol % and about 54 mol %, between about 45 mol % and about 53 mol %, between about 45 mol % and about 52 mol %, between about 45 mol % and about 51 mol %, between about 46 mol % and about 54 mol %, between about 46 mol % and about 53 mol %, between about 46 mol % and about 52 mol %, between about 46 mol % and about 51 mol %, between about 47 mol % and about 53 mol %, between about 47 mol % and about 52 mol %, between about 47 mol % and about 51 mol %, between about 48 mol % and about 52 mol %, between about 48 mol % and about 51 mol %, between about 49 mol % and about 51 mol %, between about 49 mol % and about 50.75 mol %, between about 49 mol % and about 50.5 mol %, between about 49 mol % and about 50.25 mol %, between about 49.25 mol % and about 50.75 mol %, between about 49.25 mol % and about 50.5 mol %, between about 49.25 mol % and about 50.25 mol %, between about 49.5 mol % and about 50.75 mol %, between about 49.5 mol % and about 50.5 mol %, between about 49.5 mol % and about 50.25 mol %, between about 49.75 mol % and about 50.75 mol %, between about 49.75 mol % and about 50.5 mol %, or between about 49.75 mol % and about 50.25 mol % of the compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof.

[0335] In some embodiments, the composition comprises between about 10 mol % and about 90 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 20 mol % and about 80 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 25 mol % and about 75 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 37.5 mol % and about 62.5 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 42.5 mol % and about 57.5 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 45 mol % and about 55 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 45 mol % and about 52.5 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 47.5 mol % and about 55 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 47.5 mol % and about 52.5 mol % of the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. In some embodiments, the composition comprises between about 49 mol % and about 51 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 49.25 mol % and about 50.75 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 49.5 mol % and about 50.5 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 49.75 mol % and about 50.25 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0336] In some embodiments, the composition comprises about 30 mol %, about 35 mol %, about 40 mol %, about 45 mol %, about 47.5 mol %, about 49 mol %, about 49.5 mol %, about 50 mol %, about 50.5 mol %, about 51 mol %, about 52.5 mol %, about 55 mol %, about 60 mol %, about 65 mol %, or about 70 mol % of the compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof.

[0337] In some embodiments, the composition comprises about 45 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 47.5 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 49 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 49.5 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 50 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 50.5 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 51 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 52.5 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 55 mol % of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0338] In some embodiments, the composition comprises between about 10 mol % and about 90 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 20 mol % and about 80 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 25 mol % and about 75 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 37.5 mol % and about 62.5 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 42.5 mol %and about 57.5 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 45 mol % and about 55 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 45 mol % and about 52.5 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 47.5 mol % and about 55 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 47.5 mol % and about 52.5 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 49 mol % and about 51 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 49.25 mol % and about 50.75 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 49.5 mol % and about 50.5 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises between about 49.75 mol % and about 50.25 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof.

[0339] In some embodiments, the composition comprises about 45 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 47.5 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 49 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 49.5 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 50 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 50.5 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 51 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 52.5 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 55 mol % of the compound of Formula (I'), or a pharmaceutically acceptable salt thereof.

[0340] In some embodiments, the composition comprises a hydrodynamic diameter of between about 1 nm and about 1000 nm, between about 1 nm and about 750 nm, between about 1 nm and about 500 nm, between about 10 nm and about 1000 nm, between about 10 nm and about 750 nm, between about 10 nm and about 500 nm, between about 50 nm and about 1000 nm, between about 50 nm and about 750 nm, between about 50 nm and about 500 nm, between about 75 nm and about 1000 nm, between about 75 nm and about 750 nm, between about 75 nm and about 500 nm, between about 100 nm and about 1000 nm, between about 100 nm and about 750 nm, between about 100 nm and about500 nm, between about 100 nm and about 450 nm, between about 100 nm and about 400 nm, between about 100 nm and about 350 nm, between about 100 nm and about 325 nm, between about 100 nm and about 300 nm, between about 100 nm and about 275 nm, between about 100 nm and about 250 nm, between about 100 nm and about 225 nm, between about 100 nm and about 200 nm, between about 100 nm and about 175 nm, between about 100 nm and about 150 nm, between about 100 nm and about 125 nm, between about 125 nm and about 325 nm, between about 125 nm and about 300 nm, between about 125 nm and about 275 nm, between about 125 nm and about 250 nm, between about 125 nm and about 225 nm, between about 125 nm and about 200 nm, between about 125 nm and about 175 nm, between about 125 nm and about 150 nm, between about 150 nm and about 325 nm, between about 150 nm and about 300 nm, between about 150 nm and about 275 nm, between about 150 nm and about 250 nm, between about 150 nm and about 225 nm, between about 150 nm and about 200 nm, between about 150 nm and about 175 nm, between about 175 nm and about 325 nm, between about 175 nm and about 300 nm, between about 175 nm and about 275 nm, between about 175 nm and about 250 nm, between about 175 nm and about 225 nm, between about 175 nm and about 200 nm, between about 200 nm and about 325 nm, between about 200 nm and about 300 nm, between about 200 nm and about 275 nm, between about 200 nm and about 250 nm, between about 200 nm and about 225 nm, between about 225 nm and about 325 nm, between about 225 nm and about 300 nm, between about 225 nm and about 275 nm, between about 225 nm and about 250 nm, between about 250 nm and about 325 nm, between about 250 nm and about 300 nm, between about 250 nm and about 275 nm, between about 275 nm and about 325 nm, between about 275 nm and about 300 nm, or between about 300 nm and about 325 nm.

[0341] In some embodiments, the composition comprises a hydrodynamic diameter of between about 100 nm and about 400 nm. In some embodiments, the composition comprises a hydrodynamic diameter of between about 100 nm and about 300 nm. In some embodiments, the composition comprises a hydrodynamic diameter of between about 100 nm and about 200 nm. In some embodiments, the composition comprises a hydrodynamic diameter of between about 200 nm and about 300 nm.

[0342] In some embodiments, the hydrodynamic diameter is about 100 nm. In some embodiments, the hydrodynamic diameter is about 125 nm. In some embodiments, the hydrodynamic diameter is about 150 nm. In some embodiments, the hydrodynamic diameter is about 175 nm. In some embodiments, the hydrodynamic diameter is about 200 nm. In some embodiments, the hydrodynamic diameter is about 225 nm. In some embodiments, the hydrodynamic diameter is about 250 nm. In some embodiments, the hydrodynamic diameter is about 275 nm. In some embodiments, the hydrodynamic diameter is about 300 nm.

[0343] In some embodiments, the composition comprises a polydispersity index (PDI) of less than about 0.50, less than about 0.45, less than about 0.40, less than about 0.35, less than about 0.30, lessthan about 0.25, less than about 0.20, or less than about 0.15. In some embodiments, the PDI is less than about 0.3.

[0344] In some embodiments, the PDI is between about 0.10 and 0.50, between about 0.10 and 0.40, between about 0.10 and 0.35, between about 0.10 and 0.30, between about 0.10 and 0.25, between about 0.10 and 0.20, between about 0.10 and 0.15, between about 0.15 and about 0.40, between about 0.15 and about 0.35, between about 0.15 and about 0.30, between about 0.15 and about 0.25, between about 0.15 and about 0.20, between about 0.20 and about 0.40, between about 0.20 and about 0.35, between about 0.20 and about 0.30, between about 0.20 and about 0.25, between about 0.25 and about 0.40, between about 0.25 and about 0.35, between about 0.25 and about 0.30, between about 0.30 and about 0.40, between about 0.30 and about 0.35, or between about 0.35 and about 0.40.

[0345] In some embodiments, the PDI is between about 0.10 and 0.30. In some embodiments, the PDI is between about 0.10 and 0.20. In some embodiments, the PDI is between about 0.20 and about 0.30. In some embodiments, the PDI is between about 0.10 and 0.20. In some embodiments, the PDI is between about 0.15 and about 0.25. In some embodiments, the PDI is between about 0.15 and about 0.30. In some embodiments, the PDI is between about 0.10 and about 0.25.

[0346] In some embodiments, the PDI is about 0.30. In some embodiments, the PDI is about 0.25. In some embodiments, the PDI is about 0.20. In some embodiments, the PDI is about 0.15. In some embodiments, the PDI is about 0.10.

[0347] In some embodiments, the composition comprises a zeta potential of between about 100 mV and about -100 mV, between about 75 mV and about -75 mV, between about 50 mV and about -50 mV, between about 25 mV and about -25 mV, between about 20 mV and about -20 mV, between about 15 mV and about -15 mV, between about -10 mV to about 10 mV, between about 5 mV and about -5 mV, between about 100 mV and about 0 mV, between about 75 mV and about 0 mV, between about 50 mV and about 0 mV, between about 25 mV and about 0 mV, between about 20 mV and about 0 mV, between about 15 mV and about 0 mV, between about 10 mV and about 0 mV, between about 5 mV and about 0 mV, between about 0 mV and about -100 mV, between about 0 mV and about -75 mV, between about 0 mV and about -50 mV, between about 0 mV and about -25 mV, between about 0 mV and about -20 mV, between about 0 mV and about -15 mV, between about 0 mV and about -10 mV, or between about 0 mV and about -5 mV.

[0348] In some embodiments, the composition comprises a zeta potential of between about 25 mV and about -25 mV, between about 20 mV and about -20 mV, between about 0 mV and about -100 mV, between about 0 mV and about -75 mV, between about 0 mV and about -50 mV, between about 0 mV and about -25 mV, between about 0 mV and about -20 mV, between about 0 mV and about -15 mV, between about 0 mV and about -10 mV, or between about 0 mV and about -5 mV.

[0349] In some embodiments, the composition comprises a zeta potential of between about 20 mV and about -20 mV. In some embodiments, the composition comprises a zeta potential of between about 0 mV and about -20 mV. In some embodiments, the composition comprises a zeta potential ofbetween about 0 mV and about -15 mV. In some embodiments, the composition comprises a zeta potential of between about 0 mV and about -10 mV. In some embodiments, the composition comprises a zeta potential of between about 0 mV and about -5 mV.

[0350] In some embodiments, the composition comprises a zeta potential of about 0 mV. In some embodiments, the composition comprises a zeta potential of about -5 mV. In some embodiments, the composition comprises a zeta potential of about -10 mV. In some embodiments, the composition comprises a zeta potential of about -15 mV. In some embodiments, the composition comprises a zeta potential of about -20 mV.

[0351] In some embodiments, the composition comprises an apparent pKa of between about 0.0 and about 14.0, between about 1.0 and about 13.0, between about 2.0 and about 12.0, between about 3.0 and about 11.0, between about 4.0 and about 10.0, between about 5.0 and about 10.0, between about 6.0 and about 10.0, between about 6.5 and about 10.0, between about 7.0 and about 10.0, between about 7.5 and about 10.0, between about 8.0 and about 10.0, between about 8.5 and about 10.0, between about 9.0 and about 10.0, between about 9.5 and about 10.0, between about 6.0 and about 9.0, between about 6.5 and about 9.0, between about 7.0 and about 9.0, between about 7.5 and about9.0, between about 8.0 and about 9.0, between about 8.5 and about 9.0, between about 6.0 and about8.5, between about 6.5 and about 8.5, between about 7.0 and about 8.5, between about 7.5 and about8.5, between about 8.0 and about 8.5, between about 6.0 and about 8.0, between about 6.5 and about8.0, between about 7.0 and about 8.0, between about 7.5 and about 8.0, between about 6.0 and about7.5, between about 6.5 and about 7.5, between about 7.0 and about 7.5, between about 6.0 and about7.0, between about 6.5 and about 7.0, or between about 6.0 and about 6.5.

[0352] In some embodiments, the composition comprises an apparent pKa of between about 5.0 and about 10.0, between about 5.0 and about 9.0, between about 6.0 and about 9.0, between about 6.5 and about 9.0, between about 7.0 and about 9.0, between about 7.5 and about 9.0, between about 6.5 and about 8.5, between about 7.0 and about 8.5, between about 7.5 and about 8.5, between about 6.5 and about 8.0, or between about 7.0 and about 8.0.

[0353] In some embodiments, the composition comprises an apparent pKa of between about 6.5 and about 9.0. In some embodiments, the composition comprises an apparent pKa of between about 7.0 and about 9.0. In some embodiments, the composition comprises an apparent pKa of between about 7.5 and about 9.0. In some embodiments, the composition comprises an apparent pKa of between about 6.5 and about 8.5. In some embodiments, the composition comprises an apparent pKa of between about 7.0 and about 8.5. In some embodiments, the composition comprises an apparent pKa of between about 7.5 and about 8.5. In some embodiments, the composition comprises an apparent pKa of between about 6.5 and about 8.0.

[0354] In some embodiments, the composition comprises an apparent pKa of about 7.0. In some embodiments, the composition comprises an apparent pKa of about 7.5. In some embodiments, thecomposition comprises an apparent pKa of about 8.0. In some embodiments, the composition comprises an apparent pKa of about 8.5.

[0355] In some embodiments, the composition comprises an apparent pKa of between about 6.5 and about 8.0 and exhibits liver tropism. In some embodiments, the composition comprises an apparent pKa of between about 7.0 and about 8.0 and exhibits liver tropism. In some embodiments, the composition comprises an apparent pKa of about 7.0 and exhibits liver tropism. In some embodiments, the composition comprises an apparent pKa of about 7.5 and exhibits liver tropism. In some embodiments, the composition comprises an apparent pKa of about 8.0 and exhibits liver tropism.

[0356] In some embodiments, the composition comprises an apparent pKa of between about 7.0 and about 9.0 and exhibits spleen tropism. In some embodiments, the composition comprises an apparent pKa of between about 7.5 and about 9.0 and exhibits spleen tropism. In some embodiments, the composition comprises an apparent pKa of between about 7.5 and about 8.5 and exhibits spleen tropism. In some embodiments, the composition comprises an apparent pKa of about 7.5 and exhibits spleen tropism. In some embodiments, the composition comprises an apparent pKa of about 8.0 and exhibits spleen tropism. In some embodiments, the composition comprises an apparent pKa of about 8.5 and exhibits spleen tropism.

[0357] In some embodiments, the composition comprises an apparent pKa of between about 6.5 and about 8.0, p is 0, and no instance of R2is hydrogen. In some embodiments, the composition comprises an apparent pKa of between about 7.0 and about 8.0, p is 0, and no instance of R2is hydrogen. In some embodiments, the composition comprises an apparent pKa of about 7.0, p is 0, and no instance of R2is hydrogen. In some embodiments, the composition comprises an apparent pKa of about 7.5, p is 0, and no instance of R2is hydrogen. In some embodiments, the composition comprises an apparent pKa of about 8.0, p is 0, and no instance of R2is hydrogen.

[0358] In some embodiments, the composition comprises an apparent pKa of between about 7.0 and about 9.0, and p is not 0 or at least one instance of R2is hydrogen. In some embodiments, the composition comprises an apparent pKa of between about 7.5 and about 9.0, and p is not 0 or at least one instance of R2is hydrogen. In some embodiments, the composition comprises an apparent pKa of between about 7.5 and about 8.5, and p is not 0 or at least one instance of R2is hydrogen. In some embodiments, the composition comprises an apparent pKa of about 7.5, and p is not 0 or at least one instance of R2is hydrogen. In some embodiments, the composition comprises an apparent pKa of about 8.0, and p is not 0 or at least one instance of R2is hydrogen. In some embodiments, the composition comprises an apparent pKa of about 8.5, and p is not 0 or at least one instance of R2is hydrogen.

[0359] 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 (z.e., the “active ingredient”) into association with a carrier or excipient, and / or one or moreother accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0360] 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.

[0361] 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.

[0362] 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.

[0363] 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 dry 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.

[0364] 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, cross-linked 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.

[0365] 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 (aluminumsilicate) 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, methylcellulose), 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 (Myrj® 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, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0366] 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).

[0367] 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, hydroxy ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly (vinyl-pyrrolidone), 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.

[0368] 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.

[0369] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxy anisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0370] 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.

[0371] 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.

[0372] 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.

[0373] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0374] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0375] 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®.

[0376] 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.

[0377] Exemplary 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.

[0378] 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. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0379] 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, corn, 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.

[0380] 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.

[0381] 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 someembodiments, 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 preparations of the compositions disclosed herein are in the form of a liquid or suspension that is diluted prior to administration.

[0382] 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.

[0383] In order to prolong the effect of a drug, 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.

[0384] 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.

[0385] 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.

[0386] 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. 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 theyrelease 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 polethylene glycols and the like.

[0387] 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.

[0388] 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.

[0389] 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.

[0390] 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 administrableformulations 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.

[0391] 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- propelling solvent / 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.

[0392] 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).

[0393] 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.

[0394] 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.

[0395] 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.

[0396] 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 opthalmically- 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.

[0397] 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.

[0398] Compounds 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 within 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 the specific 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.

[0399] The compounds and 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 compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.

[0400] The exact amount of a compound 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 multiple 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 a subject 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 anydose of multiple doses) described herein includes independently between 0.1 pg 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 compound 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.

[0401] 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.

[0402] A compound or 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 compounds or 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 cellular engineering 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 different effects. 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.

[0403] The compound or 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 prophylactically 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.

[0404] 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 antiproliferative 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 an 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 (HD AC 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, all- trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the compounds described herein or pharmaceutical compositions 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 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.

[0405] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.

[0406] Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits are useful for cellular engineering in a subject or cell.

[0407] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for cellular engineering in a subject or cell. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

[0408] In some embodiments, a provided composition (a composition described herein, a composition of the present disclosure) is a composition comprising a compound of any of theformulae herein (e.g., Formula (I), Formula (I')), or a pharmaceutically acceptable salt thereof. In some embodiments, a provided composition is a composition comprising a compound of any of the formulae herein (e.g., Formula (I), Formula (I')), or a salt thereof. In some embodiments, a provided composition is a composition comprising a compound of any of the formulae herein e.g., Formula (I), Formula (I')).Helper Lipid

[0409] In some embodiments, the helper lipid is a phospholipid. In some embodiments, the helper lipid is a phosphoethanolamine (e.g., 1 ,2-distearoyl-sn-glycero-3-phosphorylethanolamine (DSPE), 1 ,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)) or a phosphatidylcholine (e.g., 1,2- distearoyl-sn-glycero-3-phosphocholine (distearoylphosphatidylcholine, DSPC)).

[0410] In some embodiments, the helper lipid is a phosphoethanolamine. In some embodiments, the helper lipid is l,2-distearoyl-sn-glycero-3-phosphorylethanolamine (DSPE) or 1 ,2-dioleoyl-sn- glycero-3 -phosphoethanolamine (DOPE) .

[0411] In some embodiments, the helper lipid is a phosphatidylcholine. In some embodiments, the helper lipid is l,2-distearoyl-sn-glycero-3-phosphocholine (distearoylphosphatidylcholine, DSPC).

[0412] In some embodiments, the composition comprises between about 1 mol % and about 50 mol %, between about 1 mol % and about 40 mol %, between about 1 mol % and about 30 mol %, between about 1 mol % and about 25 mol %, between about 1 mol % and about 20 mol %, between about 1 mol % and about 15 mol %, between about 1 mol % and about 14 mol %, between about 1 mol % and about 13 mol %, between about 1 mol % and about 12 mol %, between about 1 mol % and about 11 mol %, between about 1 mol % and about 10.5 mol %, between about 1 mol % and about 10 mol %, between about 5 mol % and about 20 mol %, between about 5 mol % and about 15 mol %, between about 5 mol % and about 14 mol %, between about 5 mol % and about 13 mol %, between about 5 mol % and about 12 mol %, between about 5 mol % and about 11 mol %, between about 5 mol % and about 10 mol %, between about 6 mol % and about 15 mol %, between about 6 mol % and about 14 mol %, between about 6 mol % and about 13 mol %, between about 6 mol % and about 12 mol %, between about 6 mol % and about 11 mol %, between about 6 mol % and about 10 mol %, between about 7 mol % and about 15 mol %, between about 7 mol % and about 14 mol %, between about 7 mol % and about 13 mol %, between about 7 mol % and about 12 mol %, between about 7 mol % and about 11 mol %, between about 7 mol % and about 10 mol %, between about 7.5 mol % and about 12.5 mol %, between about 7.5 mol % and about 12 mol %, between about 7.5 mol % and about 11.5 mol %, between about 7.5 mol % and about 11 mol %, between about 7.5 mol % and about 10.75 mol %, between about 7.5 mol % and about 10.5 mol %, between about 7.5 mol % and about 10.25 mol %, between about 7.5 mol % and about 10 mol %, between about 8 mol % and about 15 mol %, between about 8 mol % and about 14 mol %, between about 8 mol % and about 13 mol %, between about 8 mol % and about 12 mol %, between about 8 mol % and about 11 mol %, betweenabout 8 mol % and about 10 mol %, between about 8.5 mol % and about 12.5 mol %, between about8.5 mol % and about 12 mol %, between about 8.5 mol % and about 11.5 mol %, between about 8.5 mol % and about 11 mol %, between about 8.5 mol % and about 10.75 mol %, between about 8.5 mol % and about 10.5 mol %, between about 8.5 mol % and about 10.25 mol %, between about 8.5 mol % and about 10 mol %, between about 9 mol % and about 15 mol %, between about 9 mol % and about 14 mol %, between about 9 mol % and about 13 mol %, between about 9 mol % and about 12.5 mol %, between about 9 mol % and about 12 mol %, between about 9 mol % and about 11.5 mol %, between about 9 mol % and about 11 mol %, between about 9 mol % and about 10.75 mol %, between about 9 mol % and about 10.5 mol %, between about 9 mol % and about 10.25 mol %, between about 9 mol % and about 10 mol %, between about 9.25 mol % and about 12.5 mol %, between about 9.25 mol % and about 12 mol %, between about 9.25 mol % and about 11.5 mol %, between about 9.25 mol % and about 11 mol %, between about 9.25 mol % and about 10.75 mol %, between about 9.25 mol % and about 10.5 mol %, between about 9.25 mol % and about 10.25 mol %, between about 9.25 mol % and about 10 mol %, between about 9.5 mol % and about 12.5 mol %, between about 9.5 mol % and about 12 mol %, between about 9.5 mol % and about 11.5 mol %, between about 9.5 mol % and about 11 mol %, between about 9.5 mol % and about 10.75 mol %, between about 9.5 mol % and about 10.5 mol %, between about 9.5 mol % and about 10.25 mol %, between about 9.5 mol % and about 10 mol %, between about 9.75 mol % and about 12.5 mol %, between about 9.75 mol % and about 12 mol %, between about 9.75 mol % and about 11.5 mol %, between about 9.75 mol % and about 11 mol %, between about 9.75 mol % and about 10.75 mol %, between about 9.75 mol % and about 10.5 mol %, between about 9.75 mol % and about 10.25 mol %, or between about 9.75 mol % and about 10 mol % of the helper lipid.

[0413] In some embodiments, the composition comprises between about 1 mol % and about 20 mol % of the helper lipid. In some embodiments, the composition comprises between about 5 mol % and about 15 mol % of the helper lipid. In some embodiments, the composition comprises between about7.5 mol % and about 12.5 mol % of the helper lipid. In some embodiments, the composition comprises between about 8 mol % and about 12 mol % of the helper lipid. In some embodiments, the composition comprises between about 8.5 mol % and about 11.5 mol % of the helper lipid. In some embodiments, the composition comprises between about 9 mol % and about 11 mol % of the helper lipid. In some embodiments, the composition comprises between about 9.25 mol % and about 10.75 mol % of the helper lipid. In some embodiments, the composition comprises between about 9.5 mol % and about 10.5 mol % of the helper lipid. In some embodiments, the composition comprises between about 9.75 mol % and about 10.75 mol % of the helper lipid.

[0414] In some embodiments, the composition comprises about 5 mol %, about 6 mol %, about 7 mol %, about 7.5 mol %, about 8 mol %, about 9 mol %, about 9.25 mol %, about 9.5 mol %, about 9.75 mol %, about 10 mol %, about 10.25 mol %, about 10.5 mol %, about 10.75 mol %, about 11mol %, about 12 mol %, about 12.5 mol %, about 13 mol %, about 14 mol %, or about 15 mol % of the helper lipid.

[0415] In some embodiments, the composition comprises about 8 mol % of the helper lipid. In some embodiments, the composition comprises about 9 mol % of the helper lipid. In some embodiments, the composition comprises about 9.25 mol % of the helper lipid. In some embodiments, the composition comprises about 9.5 mol % of the helper lipid. In some embodiments, the composition comprises about 9.75 mol % of the helper lipid. In some embodiments, the composition comprises about 10 mol % of the helper lipid. In some embodiments, the composition comprises about 10.25 mol % of the helper lipid. In some embodiments, the composition comprises about 10.5 mol % of the helper lipid. In some embodiments, the composition comprises about 10.75 mol % of the helper lipid. In some embodiments, the composition comprises about 11 mol % of the helper lipid. In some embodiments, the composition comprises about 12 mol % of the helper lipid.

[0416] In some embodiments, the composition comprises between about 1 mol % and about 50 mol %, between about 1 mol % and about 40 mol %, between about 1 mol % and about 30 mol %, between about 1 mol % and about 25 mol %, between about 1 mol % and about 20 mol %, between about 1 mol % and about 15 mol %, between about 1 mol % and about 14 mol %, between about 1 mol % and about 13 mol %, between about 1 mol % and about 12 mol %, between about 1 mol % and about 11 mol %, between about 1 mol % and about 10.5 mol %, between about 1 mol % and about 10 mol %, between about 5 mol % and about 20 mol %, between about 5 mol % and about 15 mol %, between about 5 mol % and about 14 mol %, between about 5 mol % and about 13 mol %, between about 5 mol % and about 12 mol %, between about 5 mol % and about 11 mol %, between about 5 mol % and about 10 mol %, between about 6 mol % and about 15 mol %, between about 6 mol % and about 14 mol %, between about 6 mol % and about 13 mol %, between about 6 mol % and about 12 mol %, between about 6 mol % and about 11 mol %, between about 6 mol % and about 10 mol %, between about 7 mol % and about 15 mol %, between about 7 mol % and about 14 mol %, between about 7 mol % and about 13 mol %, between about 7 mol % and about 12 mol %, between about 7 mol % and about 11 mol %, between about 7 mol % and about 10 mol %, between about 7.5 mol % and about 12.5 mol %, between about 7.5 mol % and about 12 mol %, between about 7.5 mol % and about 11.5 mol %, between about 7.5 mol % and about 11 mol %, between about 7.5 mol % and about 10.75 mol %, between about 7.5 mol % and about 10.5 mol %, between about 7.5 mol % and about 10.25 mol %, between about 7.5 mol % and about 10 mol %, between about 8 mol % and about 15 mol %, between about 8 mol % and about 14 mol %, between about 8 mol % and about 13 mol %, between about 8 mol % and about 12 mol %, between about 8 mol % and about 11 mol %, between about 8 mol % and about 10 mol %, between about 8.5 mol % and about 12.5 mol %, between about 8.5 mol % and about 12 mol %, between about 8.5 mol % and about 11.5 mol %, between about 8.5 mol % and about 11 mol %, between about 8.5 mol % and about 10.75 mol %, between about 8.5 mol % and about 10.5 mol %, between about 8.5 mol % and about 10.25 mol %, between about 8.5 mol %and about 10 mol %, between about 9 mol % and about 15 mol %, between about 9 mol % and about 14 mol %, between about 9 mol % and about 13 mol %, between about 9 mol % and about 12.5 mol %, between about 9 mol % and about 12 mol %, between about 9 mol % and about 11.5 mol %, between about 9 mol % and about 11 mol %, between about 9 mol % and about 10.75 mol %, between about 9 mol % and about 10.5 mol %, between about 9 mol % and about 10.25 mol %, between about 9 mol % and about 10 mol %, between about 9.25 mol % and about 12.5 mol %, between about 9.25 mol % and about 12 mol %, between about 9.25 mol % and about 11.5 mol %, between about 9.25 mol % and about 11 mol %, between about 9.25 mol % and about 10.75 mol %, between about 9.25 mol % and about 10.5 mol %, between about 9.25 mol % and about 10.25 mol %, between about 9.25 mol % and about 10 mol %, between about 9.5 mol % and about 12.5 mol %, between about 9.5 mol % and about 12 mol %, between about 9.5 mol % and about 11.5 mol %, between about 9.5 mol % and about 11 mol %, between about 9.5 mol % and about 10.75 mol %, between about 9.5 mol % and about 10.5 mol %, between about 9.5 mol % and about 10.25 mol %, between about 9.5 mol % and about 10 mol %, between about 9.75 mol % and about 12.5 mol %, between about 9.75 mol % and about 12 mol %, between about 9.75 mol % and about 11.5 mol %, between about 9.75 mol % and about 11 mol %, between about 9.75 mol % and about 10.75 mol %, between about 9.75 mol % and about 10.5 mol %, between about 9.75 mol % and about 10.25 mol %, or between about 9.75 mol % and about 10 mol % of DSPC.

[0417] In some embodiments, the composition comprises between about 1 mol % and about 20 mol % of DSPC. In some embodiments, the composition comprises between about 5 mol % and about 15 mol % of DSPC. In some embodiments, the composition comprises between about 7.5 mol % and about 12.5 mol % of DSPC. In some embodiments, the composition comprises between about 8 mol % and about 12 mol % of DSPC. In some embodiments, the composition comprises between about 8.5 mol % and about 11.5 mol % of DSPC. In some embodiments, the composition comprises between about 9 mol % and about 11 mol % of DSPC. In some embodiments, the composition comprises between about 9.25 mol % and about 10.75 mol % of DSPC. In some embodiments, the composition comprises between about 9.5 mol % and about 10.5 mol % of DSPC. In some embodiments, the composition comprises between about 9.75 mol % and about 10.75 mol % of DSPC.

[0418] In some embodiments, the composition comprises about 5 mol %, about 6 mol %, about 7 mol %, about 7.5 mol %, about 8 mol %, about 9 mol %, about 9.25 mol %, about 9.5 mol %, about 9.75 mol %, about 10 mol %, about 10.25 mol %, about 10.5 mol %, about 10.75 mol %, about 11 mol %, about 12 mol %, about 12.5 mol %, about 13 mol %, about 14 mol %, or about 15 mol % of DSPC.

[0419] In some embodiments, the composition comprises about 8 mol % of DSPC. In some embodiments, the composition comprises about 9 mol % of DSPC. In some embodiments, the composition comprises about 9.25 mol % of DSPC. In some embodiments, the composition comprisesabout 9.5 mol % of DSPC. In some embodiments, the composition comprises about 9.75 mol % of DSPC. In some embodiments, the composition comprises about 10 mol % of DSPC. In some embodiments, the composition comprises about 10.25 mol % of DSPC. In some embodiments, the composition comprises about 10.5 mol % of DSPC. In some embodiments, the composition comprises about 10.75 mol % of DSPC. In some embodiments, the composition comprises about 11 mol % of DSPC. In some embodiments, the composition comprises about 12 mol % of DSPC.Sterol

[0420] In some embodiments, the sterol is cholesterol, sitosterol, campesterol, stigmasterol, brassicasterol (including dihydrobrassicasterol), desmosterol, chalinosterol, poriferasterol, clionasterol, ergosterol, coprosterol, codisterol, isofucosterol, fucosterol, clerosterol, nervisterol, lathosterol, stellasterol, spinasterol, chondrillasterol, peposterol, avenasterol, isoavenasterol, fecosterol, pollinastasterol, or a derivative thereof.

[0421] In some embodiments, the sterol is cholesterol, or a derivative thereof. In some embodiments, the sterol is cholesterol.

[0422] In some embodiments, the composition comprises between about 1 mol % and about 75 mol %, between about 5 mol % and about 70 mol %, between about 10 mol % and about 65 mol %, between about 20 mol % and about 60 mol %, between about 25 mol % and about 55 mol %, between about 30 mol % and about 50 mol %, between about 1 mol % and about 50 mol %, between about 1 mol % and about 45 mol %, between about 1 mol % and about 40 mol %, between about 10 mol % and about 75 mol %, between about 10 mol % and about 50 mol %, between about 10 mol % and about 45 mol %, between about 10 mol % and about 40 mol %, between about 15 mol % and about 75 mol %, between about 15 mol % and about 50 mol %, between about 10 mol % and about 45 mol %, between about 10 mol % and about 40 mol %, between about 20 mol % and about 75 mol %, between about 20 mol % and about 50 mol %, between about 20 mol % and about 45 mol %, between about 20 mol % and about 40 mol %, between about 25 mol % and about 75 mol %, between about 25 mol % and about 50 mol %, between about 25 mol % and about 45 mol %, between about 25 mol % and about 40 mol %, between about 30 mol % and about 75 mol %, between about 30 mol % and about 45 mol %, between about 30 mol % and about 40 mol %, between about 35 mol % and about 75 mol %, between about 35 mol % and about 45 mol %, between about 35 mol % and about 44 mol %, between about 35 mol % and about 43 mol %, between about 35 mol % and about 42 mol %, between about 35 mol % and about 41 mol %, between about 35 mol % and about 40 mol %, between about 35 mol % and about 39 mol %, between about 35 mol % and about 38 mol %, between about 36 mol % and about 45 mol %, between about 36 mol % and about 44 mol %, between about 36 mol % and about 43 mol %, between about 36 mol % and about 42 mol %, between about 36 mol % and about 41 mol %, between about 36 mol % and about 40 mol %, between about 36 mol % and about 39 mol %, between about 36 mol % and about 38 mol %, between about 37 mol % and about 45 mol %, between about 37mol % and about 44 mol %, between about 37 mol % and about 43 mol %, between about 37 mol % and about 42 mol %, between about 37 mol % and about 41 mol %, between about 37 mol % and about 40 mol %, between about 37 mol % and about 39 mol %, between about 37 mol % and about 38 mol %, between about 38 mol % and about 45 mol %, between about 38 mol % and about 44 mol %, between about 38 mol % and about 43 mol %, between about 38 mol % and about 42 mol %, between about 38 mol % and about 41 mol %, between about 38 mol % and about 40 mol %, between about 38 mol % and about 39 mol %, between about 37.5 mol % and about 45 mol %, between about 37.5 mol % and about 42.5 mol %, between about 37.5 mol % and about 40 mol %, between about 37.5 mol % and about 39 mol %, between about 37.5 mol % and about 38.5 mol %, between about 30 mol % and about 38.5 mol %, between about 32.5 mol % and about 38.5 mol %, between about 35 mol % and about 38.5 mol %, between about 35.5 mol % and about 40 mol %, between about 36.5 mol % and about 40 mol %, between about 35.5 mol % and about 39.5 mol %, between about 36.5 mol % and about 39.5 mol %, between about 35.5 mol % and about 39 mol %, between about 36.5 mol % and about 39 mol %, between about 35.5 mol % and about 38.5 mol %, between about 36.5 mol % and about 38.5 mol %, between about 37.25 mol % and about 38.75 mol %, between about 37.25 mol % and about 38.5 mol %, between about 37.25 mol % and about 38.25 mol %, between about 37.5 mol % and about 38.75 mol %, between about 37.5 mol % and about 38.25 mol %, between about 37.75 mol % and about 38.75 mol %, between about 37.75 mol % and about 38.5 mol %, or between about 37.75 mol % and about 38.25 mol % of the sterol.

[0423] In some embodiments, the composition comprises between about 1 mol % and about 75 mol % of the sterol. In some embodiments, the composition comprises between about 1 mol % and about 50 mol % of the sterol. In some embodiments, the composition comprises between about 25 mol % and about 50 mol % of the sterol. In some embodiments, the composition comprises between about 35 mol % and about 45 mol % of the sterol. In some embodiments, the composition comprises between about 35 mol % and about 42.5 mol % of the sterol. In some embodiments, the composition comprises between about 37.5 mol % and about 40 mol % of the sterol. In some embodiments, the composition comprises between about 37 mol % and about 39 mol % of the sterol.

[0424] In some embodiments, the composition comprises about 25 mol %, about 30 mol %, about 35 mol %, about 36 mol %, about 36.5 mol %, about 37 mol %, about 37.5 mol %, about 38 mol %, about 38.5 mol %, about 39 mol %, about 39.5 mol %, about 40 mol %, about 41 mol %, about 42 mol %, about 43 mol %, about 44 mol %, about 45 mol %, about 50 mol %, or about 55 mol % of the sterol. In some embodiments, the composition comprises about 35 mol %, about 36 mol %, about 36.5 mol %, about 37 mol %, about 37.5 mol %, about 38 mol %, about 38.5 mol %, about 39 mol %, about 39.5 mol %, about 40 mol %, or about 41 mol % of the sterol. In some embodiments, the composition comprises about 38 mol % of the sterol.

[0425] In some embodiments, the composition comprises between about 1 mol % and about 75 mol %, between about 5 mol % and about 70 mol %, between about 10 mol % and about 65 mol %,between about 20 mol % and about 60 mol %, between about 25 mol % and about 55 mol %, between about 30 mol % and about 50 mol %, between about 1 mol % and about 50 mol %, between about 1 mol % and about 45 mol %, between about 1 mol % and about 40 mol %, between about 10 mol % and about 75 mol %, between about 10 mol % and about 50 mol %, between about 10 mol % and about 45 mol %, between about 10 mol % and about 40 mol %, between about 15 mol % and about 75 mol %, between about 15 mol % and about 50 mol %, between about 10 mol % and about 45 mol %, between about 10 mol % and about 40 mol %, between about 20 mol % and about 75 mol %, between about 20 mol % and about 50 mol %, between about 20 mol % and about 45 mol %, between about 20 mol % and about 40 mol %, between about 25 mol % and about 75 mol %, between about 25 mol % and about 50 mol %, between about 25 mol % and about 45 mol %, between about 25 mol % and about 40 mol %, between about 30 mol % and about 75 mol %, between about 30 mol % and about 45 mol %, between about 30 mol % and about 40 mol %, between about 35 mol % and about 75 mol %, between about 35 mol % and about 45 mol %, between about 35 mol % and about 44 mol %, between about 35 mol % and about 43 mol %, between about 35 mol % and about 42 mol %, between about 35 mol % and about 41 mol %, between about 35 mol % and about 40 mol %, between about 35 mol % and about 39 mol %, between about 35 mol % and about 38 mol %, between about 36 mol % and about 45 mol %, between about 36 mol % and about 44 mol %, between about 36 mol % and about 43 mol %, between about 36 mol % and about 42 mol %, between about 36 mol % and about 41 mol %, between about 36 mol % and about 40 mol %, between about 36 mol % and about 39 mol %, between about 36 mol % and about 38 mol %, between about 37 mol % and about 45 mol %, between about 37 mol % and about 44 mol %, between about 37 mol % and about 43 mol %, between about 37 mol % and about 42 mol %, between about 37 mol % and about 41 mol %, between about 37 mol % and about 40 mol %, between about 37 mol % and about 39 mol %, between about 37 mol % and about 38 mol %, between about 38 mol % and about 45 mol %, between about 38 mol % and about 44 mol %, between about 38 mol % and about 43 mol %, between about 38 mol % and about 42 mol %, between about 38 mol % and about 41 mol %, between about 38 mol % and about 40 mol %, between about 38 mol % and about 39 mol %, between about 37.5 mol % and about 45 mol %, between about 37.5 mol % and about 42.5 mol %, between about 37.5 mol % and about 40 mol %, between about 37.5 mol % and about 39 mol %, between about 37.5 mol % and about 38.5 mol %, between about 30 mol % and about 38.5 mol %, between about 32.5 mol % and about 38.5 mol %, between about 35 mol % and about 38.5 mol %, between about 35.5 mol % and about 40 mol %, between about 36.5 mol % and about 40 mol %, between about 35.5 mol % and about 39.5 mol %, between about 36.5 mol % and about 39.5 mol %, between about 35.5 mol % and about 39 mol %, between about 36.5 mol % and about 39 mol %, between about 35.5 mol % and about 38.5 mol %, between about 36.5 mol % and about 38.5 mol %, between about 37.25 mol % and about 38.75 mol %, between about 37.25 mol % and about 38.5 mol %, between about 37.25 mol % and about 38.25 mol %, between about 37.5 mol % and about 38.75 mol %, between about 37.5 mol % and about 38.25 mol %, between about 37.75mol % and about 38.75 mol %, between about 37.75 mol % and about 38.5 mol %, or between about 37.75 mol % and about 38.25 mol % of cholesterol.

[0426] In some embodiments, the composition comprises between about 1 mol % and about 75 mol % of cholesterol. In some embodiments, the composition comprises between about 1 mol % and about 50 mol % of cholesterol. In some embodiments, the composition comprises between about 25 mol % and about 50 mol % of cholesterol. In some embodiments, the composition comprises between about 35 mol % and about 45 mol % of cholesterol. In some embodiments, the composition comprises between about 35 mol % and about 42.5 mol % of cholesterol. In some embodiments, the composition comprises between about 37.5 mol % and about 40 mol % of cholesterol. In some embodiments, the composition comprises between about 37 mol % and about 39 mol % of cholesterol.

[0427] In some embodiments, the composition comprises about 25 mol %, about 30 mol %, about 35 mol %, about 36 mol %, about 36.5 mol %, about 37 mol %, about 37.5 mol %, about 38 mol %, about 38.5 mol %, about 39 mol %, about 39.5 mol %, about 40 mol %, about 41 mol %, about 42 mol %, about 43 mol %, about 44 mol %, about 45 mol %, about 50 mol %, or about 55 mol % of cholesterol. In some embodiments, the composition comprises about 35 mol %, about 36 mol %, about 36.5 mol %, about 37 mol %, about 37.5 mol %, about 38 mol %, about 38.5 mol %, about 39 mol %, about 39.5 mol %, about 40 mol %, or about 41 mol % of cholesterol. In some embodiments, the composition comprises about 38 mol % of cholesterol.PEGylated Lipid

[0428] In some embodiments, the PEG component of the PEGylated lipid has a molecular weight of between about 100 Da and about 5000 Da, between about 500 Da and about 5000 Da, between about 500 Da and about 4000 Da, between about 500 Da and about 3000 Da, between about 500 Da and about 2000 Da, between about 500 Da and about 1000 Da, between about 1000 Da and about 5000 Da, between about 1000 Da and about 4000 Da, between about 1000 Da and about 3000 Da, between about 1000 Da and about 2000 Da, between about 1500 Da and about 5000 Da, between about 1500 Da and about 4000 Da, between about 1500 Da and about 3000 Da, or between about 1500 Da and about 2500 Da.

[0429] In some embodiments, the PEG component of the PEGylated lipid has a molecular weight of about 350 Da, about 550 Da, about 750 Da, about 1000 Da, about 2000 Da, about 3000 Da, or about 5000 Da. In some embodiments, the PEG component of the PEGylated lipid has a molecular weight of about 750 Da, about 1000 Da, about 2000 Da, about 3000 Da, or about 5000 Da. In some embodiments, the PEG component of the PEGylated lipid has a molecular weight of about 1000 Da, about 2000 Da, or about 3000 Da. In some embodiments, the PEG component of the PEGylated lipid has a molecular weight of about 2000 Da.

[0430] In some embodiments, the PEGylated lipid is stearoyl-substituted (Cis), palmitoyl-substituted (Cie), or myristoyl-substituted (Cu). In some embodiments, the PEGylated lipid is myristoylsubstituted (C14).

[0431] In some embodiments, the PEGylated lipid is selected from the group consisting of 1,2- distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-5000] (C18PEG5000), l,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-5000] (CiePEG5000), 1 ,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-5000] (CuPEGSOOO), l,2-distearoyl-sn-glycero-3- phosphoethanolamine-N-[methoxy(polyethylene glycol)-3000] (CisPEG3000), 1 ,2-dipalmitoyl-sn- glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-3000] (CiePEG3000), 1,2- dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-3000] (C14PEG3000), 1 ,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)- 2000] (C18PEG2000), 1 ,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (CiePEG2000), 1 ,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-2000] (C14PEG2OOO), l,2-distearoyl-sn-glycero-3- phosphoethanolamine-N-[methoxy(polyethylene glycol)-1000] (CisPEGlOOO), 1 ,2-dipalmitoyl-sn- glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-1000] (CiePEGlOOO), 1,2- dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-1000] (C14PEGIOOO), 1 ,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)- 750] (C18PEG750), 1 ,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-750] (CiePEG750), 1 ,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-750] (CuPEG750), 1 ,2-distearoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DSG-PEG2000), and l,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG2000).

[0432] In some embodiments, the PEGylated lipid is l,2-distearoyl-rac-glycero-3- methoxypolyethylene glycol-2000 (DSG-PEG2000) or l,2-dimyristoyl-rac-glycero-3- methoxypoly ethylene glycol-2000 (DMG-PEG2000). In some embodiments, the PEGylated lipid is 1 ,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG2000).

[0433] In some embodiments, the composition comprises between about 0.5 mol % and about 50 mol %, between about 0.5 mol % and about 25 mol %, between about 0.5 mol % and about 10 mol %, between about 0.5 mol % and about 9 mol %, between about 0.5 mol % and about 8 mol %, between about 0.5 mol % and about 7 mol %, between about 0.5 mol % and about 6 mol %, between about 0.5 mol % and about 5 mol %, between about 0.5 mol % and about 4.5 mol %, between about 0.5 mol % and about 4 mol %, between about 0.5 mol % and about 3.5 mol %, between about 0.5 mol % and about 3 mol %, between about 0.5 mol % and about 2.75 mol %, between about 0.5 mol % and about 2.5 mol %, between about 0.5 mol % and about 2.25 mol %, between about 0.5 mol % and about 2 mol %, between about 1 mol % and about 10 mol %, between about 1 mol % and about 9 mol %,between about 1 mol % and about 8 mol %, between about 1 mol % and about 7 mol %, between about 1 mol % and about 6 mol %, between about 1 mol % and about 5 mol %, between about 1 mol % and about 4.5 mol %, between about 1 mol % and about 4 mol %, between about 1 mol % and about 3.5 mol %, between about 1 mol % and about 3 mol %, between about 1 mol % and about 2.75 mol %, between about 1 mol % and about 2.5 mol %, between about 1 mol % and about 2.25 mol %, between about 1 mol % and about 2 mol %, between about 1.25 mol % and about 10 mol %, between about 1.25 mol % and about 9 mol %, between about 1.25 mol % and about 8 mol %, between about 1.25 mol % and about 7 mol %, between about 1.25 mol % and about 6 mol %, between about 1.25 mol % and about 5 mol %, between about 1.25 mol % and about 4.5 mol %, between about 1.25 mol % and about 4 mol %, between about 1.25 mol % and about 3.5 mol %, between about 1.25 mol % and about 3 mol %, between about 1.25 mol % and about 2.75 mol %, between about 1.25 mol % and about 2.5 mol %, between about 1.25 mol % and about 2.25 mol %, between about 1.25 mol % and about 2 mol %, between about 1.5 mol % and about 10 mol %, between about 1.5 mol % and about 9 mol %, between about 1.5 mol % and about 8 mol %, between about 1.5 mol % and about 7 mol %, between about 1.5 mol % and about 6 mol %, between about 1.5 mol % and about 5 mol %, between about 1.5 mol % and about 4.5 mol %, between about 1.5 mol % and about 4 mol %, between about 1.5 mol % and about 3.5 mol %, between about 1.5 mol % and about 3 mol %, between about 1.5 mol % and about 2.75 mol %, between about 1.5 mol % and about 2.5 mol %, between about 1.5 mol % and about 2.25 mol %, between about 1.5 mol % and about 2 mol %, between about 1.75 mol % and about 10 mol %, between about 1.75 mol % and about 9 mol %, between about 1.75 mol % and about 8 mol %, between about 1.75 mol % and about 7 mol %, between about 1.75 mol % and about 6 mol %, between about 1.75 mol % and about 5 mol %, between about 1.75 mol % and about 4.5 mol %, between about 1.75 mol % and about 4 mol %, between about 1.75 mol % and about 3.5 mol %, between about 1.75 mol % and about 3 mol %, between about 1.75 mol % and about 2.75 mol %, between about 1.75 mol % and about 2.5 mol %, between about 1.75 mol % and about 2.25 mol %, or between about 1.75 mol % and about 2 mol % of the PEGylated lipid.

[0434] In some embodiments, the composition comprises between about 0.5 mol % and about 10 mol % of the PEGylated lipid. In some embodiments, the composition comprises between about 0.5 mol % and about 5 mol % of the PEGylated lipid. In some embodiments, the composition comprises between about 0.5 mol % and about 4 mol % of the PEGylated lipid. In some embodiments, the composition comprises between about 0.5 mol % and about 3 mol % of the PEGylated lipid. In some embodiments, the composition comprises between about 1 mol % and about 5 mol % of the PEGylated lipid. In some embodiments, the composition comprises between about 1 mol % and about 3 mol % of the PEGylated lipid. In some embodiments, the composition comprises between about 1.25 mol % and about 2.75 mol % of the PEGylated lipid. In some embodiments, the composition comprises between about 1.5 mol % and about 2.5 mol % of the PEGylated lipid. In someIllembodiments, the composition comprises or between about 1.75 mol % and about 2.25 mol % of the PEGylated lipid.

[0435] In some embodiments, the composition comprises about 1 mol % of the PEGylated lipid. In some embodiments, the composition comprises about 1.25 mol % of the PEGylated lipid. In some embodiments, the composition comprises about 1.5 mol % of the PEGylated lipid. In some embodiments, the composition comprises about 1.75 mol % of the PEGylated lipid. In some embodiments, the composition comprises about 2 mol % of the PEGylated lipid. In some embodiments, the composition comprises about 2.25 mol % of the PEGylated lipid. In some embodiments, the composition comprises about 2.5 mol % of the PEGylated lipid. In some embodiments, the composition comprises about 2.75 mol % of the PEGylated lipid. In some embodiments, the composition comprises about 3 mol % of the PEGylated lipid.

[0436] In some embodiments, the composition comprises between about 0.5 mol % and about 50 mol %, between about 0.5 mol % and about 25 mol %, between about 0.5 mol % and about 10 mol %, between about 0.5 mol % and about 9 mol %, between about 0.5 mol % and about 8 mol %, between about 0.5 mol % and about 7 mol %, between about 0.5 mol % and about 6 mol %, between about 0.5 mol % and about 5 mol %, between about 0.5 mol % and about 4.5 mol %, between about 0.5 mol % and about 4 mol %, between about 0.5 mol % and about 3.5 mol %, between about 0.5 mol % and about 3 mol %, between about 0.5 mol % and about 2.75 mol %, between about 0.5 mol % and about2.5 mol %, between about 0.5 mol % and about 2.25 mol %, between about 0.5 mol % and about 2 mol %, between about 1 mol % and about 10 mol %, between about 1 mol % and about 9 mol %, between about 1 mol % and about 8 mol %, between about 1 mol % and about 7 mol %, between about 1 mol % and about 6 mol %, between about 1 mol % and about 5 mol %, between about 1 mol % and about 4.5 mol %, between about 1 mol % and about 4 mol %, between about 1 mol % and about 3.5 mol %, between about 1 mol % and about 3 mol %, between about 1 mol % and about 2.75 mol %, between about 1 mol % and about 2.5 mol %, between about 1 mol % and about 2.25 mol %, between about 1 mol % and about 2 mol %, between about 1.25 mol % and about 10 mol %, between about 1.25 mol % and about 9 mol %, between about 1.25 mol % and about 8 mol %, between about 1.25 mol % and about 7 mol %, between about 1.25 mol % and about 6 mol %, between about 1.25 mol % and about 5 mol %, between about 1.25 mol % and about 4.5 mol %, between about 1.25 mol % and about 4 mol %, between about 1.25 mol % and about 3.5 mol %, between about 1.25 mol % and about 3 mol %, between about 1.25 mol % and about 2.75 mol %, between about 1.25 mol % and about 2.5 mol %, between about 1.25 mol % and about 2.25 mol %, between about 1.25 mol % and about 2 mol %, between about 1.5 mol % and about 10 mol %, between about 1.5 mol % and about 9 mol %, between about 1.5 mol % and about 8 mol %, between about 1.5 mol % and about 7 mol %, between about 1.5 mol % and about 6 mol %, between about 1.5 mol % and about 5 mol %, between about 1.5 mol % and about 4.5 mol %, between about 1.5 mol % and about 4 mol %, between about1.5 mol % and about 3.5 mol %, between about 1.5 mol % and about 3 mol %, between about 1.5 mol% and about 2.75 mol %, between about 1.5 mol % and about 2.5 mol %, between about 1.5 mol % and about 2.25 mol %, between about 1.5 mol % and about 2 mol %, between about 1.75 mol % and about 10 mol %, between about 1.75 mol % and about 9 mol %, between about 1.75 mol % and about 8 mol %, between about 1.75 mol % and about 7 mol %, between about 1.75 mol % and about 6 mol %, between about 1.75 mol % and about 5 mol %, between about 1.75 mol % and about 4.5 mol %, between about 1.75 mol % and about 4 mol %, between about 1.75 mol % and about 3.5 mol %, between about 1.75 mol % and about 3 mol %, between about 1.75 mol % and about 2.75 mol %, between about 1.75 mol % and about 2.5 mol %, between about 1.75 mol % and about 2.25 mol %, or between about 1.75 mol % and about 2 mol % of DMG-PEG2000.

[0437] In some embodiments, the composition comprises between about 0.5 mol % and about 10 mol % of DMG-PEG2000. In some embodiments, the composition comprises between about 0.5 mol % and about 5 mol % of DMG-PEG2000. In some embodiments, the composition comprises between about 0.5 mol % and about 4 mol % of DMG-PEG2000. In some embodiments, the composition comprises between about 0.5 mol % and about 3 mol % of DMG-PEG2000. In some embodiments, the composition comprises between about 1 mol % and about 5 mol % of DMG-PEG2000. In some embodiments, the composition comprises between about 1 mol % and about 3 mol % of DMG- PEG2000. In some embodiments, the composition comprises between about 1.25 mol % and about 2.75 mol % of DMG-PEG2000. In some embodiments, the composition comprises between about 1.5 mol % and about 2.5 mol % of DMG-PEG2000. In some embodiments, the composition comprises or between about 1.75 mol % and about 2.25 mol % of DMG-PEG2000.

[0438] In some embodiments, the composition comprises about 1 mol % of DMG-PEG2000. In some embodiments, the composition comprises about 1.25 mol % of DMG-PEG2000. In some embodiments, the composition comprises about 1.5 mol % of DMG-PEG2000. In some embodiments, the composition comprises about 1.75 mol % of DMG-PEG2000. In some embodiments, the composition comprises about 2 mol % of DMG-PEG2000. In some embodiments, the composition comprises about 2.25 mol % of DMG-PEG2000. In some embodiments, the composition comprises about 2.5 mol % of DMG-PEG2000. In some embodiments, the composition comprises about 2.75 mol % of DMG-PEG2000. In some embodiments, the composition comprises about 3 mol % of DMG-PEG2000.Nucleic Acid

[0439] In some embodiments, the composition further comprises a nucleic acid (z.e., a polynucleotide).

[0440] In some embodiments, the nucleic acid is plasmid DNA (pDNA), single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), genomic DNA (gDNA), complementary DNA (cDNA), antisense DNA, chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA(mtDNA or mDNA), kinetoplast DNA (kDNA), provirus, lysogen, repetitive DNA, satellite DNA, or viral DNA.

[0441] In some embodiments, the nucleic acid is RNA. In some embodiments, the nucleic acid is single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), small interfering RNA (siRNA), precursor messenger RNA (pre-mRNA), small hairpin RNA or short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer RNA (tRNA), antisense RNA (asRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or IncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, or viral satellite RNA. In some embodiments, the nucleic acid is small interfering RNA (siRNA) or messenger RNA (mRNA). In some embodiments, the nucleic acid is messenger RNA (mRNA). In some embodiments, the nucleic acid is an RNA that carries out RNA interference (RNAi). The phenomenon of RNAi is discussed in greater detail, for example, in the following references: Elbashir et al., 2001, Genes Dev., 15:188; Fire et al., 1998, Nature, 391:806; Tabara et al., 1999, Cell, 99:123; Hammond et al., Nature, 2000, 404:293; Zamore et al., 2000, Cell, 101:25; Chakraborty, 2007, Curr. Drug Targets, 8:469; and Morris and Rossi, 2006, Gene Ther., 13:553. In some embodiments, upon delivery of an RNA into a subject, tissue, or cell, the RNA is able to interfere with the expression of a specific gene in the subject, tissue, or cell. In some embodiments, the nucleic acid is a pDNA, siRNA, mRNA, or a combination thereof.

[0442] In some embodiments, the RNA is coding RNA or non-coding RNA. In some embodiments, the coding RNA is messenger RNA (mRNA). In some embodiments, the RNA is precursor messenger RNA. In some embodiments, the non-coding RNA is double-stranded RNA, short hairpin RNA, microRNA, guide RNA, transfer RNA, antisense RNA, long non-coding RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA, ribosomal RNA, Piwi-interacting RNA, small nucleolar RNA, or spliced leader RNA. In some embodiments, the non-coding RNA is small interfering RNA. In some embodiments, the RNA is single-stranded RNA, heterogeneous nuclear RNA, satellite RNA, viral RNA, or viral satellite RNA. In some embodiments, the nucleic acid is ribozyme or flexizyme.

[0443] In some embodiments, the nucleic acid may be provided as an antisense agent or RNAi. See, e.g., Fire et al., Nature 391:806-811, 1998. Antisense therapy is meant to include, e.g., administration or in situ provision of single- or double-stranded polynucleotides, or derivatives thereof, which specifically hybridize, e.g., bind, under cellular conditions, with cellular mRNA and / or genomic DNA, or mutants thereof, so as to inhibit the expression of the encoded protein, e.g., by inhibiting transcription and / or translation. See, e.g., Crooke, “Molecular mechanisms of action of antisense drugs,” Biochim. Biophys. Acta 1489(1):31-44, 1999; Crooke, “Evaluating the mechanism of action of anti-proliferative antisense drugs,” Antisense Nucleic Acid Drug Dev. 10(2): 123-126, discussion 127,2000; Methods in Enzymology volumes 313-314, 1999. The binding may be by conventional base pair complementarity, or, for example, in the case of binding to DNA duplexes, through specific interactions in the major groove of the double helix (i.e., triple helix formation). See, e.g., Chan et al., J. Mol. Med. 75(4):267-282, 1997.

[0444] In some embodiments, pDNA, siRNA, dsRNA, shRNA, miRNA, mRNA, tRNA, asRNA, and / or RNAi can be designed and / or predicted using one or more of a large number of available algorithms. To give but a few examples, the following resources can be utilized to design and / or predict polynucleotides: algorithms found at Alnylum Online; Dharmacon Online; OligoEngine Online; Molecula Online; Ambion Online; BioPredsi Online; RNAi Web Online; Chang Bioscience Online; Invitrogen Online; LentiWeb Online GenScript Online; Protocol Online; Reynolds et al., 2004, Nat. Biotechnol., 22:326; Naito et al., 2006, Nucleic Acids Res., 34:W448; Li et al., 2007, RNA, 13:1765; Yiu et al., 2005, Bioinformatics, 21:144; and Jia et al., 2006, BMC Bioinformatics, 7: 271.

[0445] The nucleic acid included in a composition may be of any size or sequence, and may be single- or double-stranded. In some embodiments, the nucleic acid includes at least about 30, at least about 100, at least about 300, at least about 1,000, at least about 3,000, or at least about 10,000 base pairs. In some embodiments, the nucleic acid includes less than about 10,000, less than about 3,000, less than about 1,000, less than about 300, less than about 100, or less than about 30 base pairs. Combinations of the above ranges e.g., at least about 100 and less than about 1,000) are also within the scope of the invention. The nucleic acid may be provided by any means known in the art. In some embodiments, the nucleic acid is engineered using recombinant techniques. See, e.g., Ausubel et al., Current Protocols in Molecular Biology (John Wiley & Sons, Inc., New York, 1999); Molecular Cloning: A Laboratory Manual, 2nd Ed., Ed. by Sambrook, Fritsch, and Maniatis (Cold Spring Harbor Laboratory Press: 1989). The nucleic acid may also be obtained from natural sources and purified from contaminating components found normally in nature. The nucleic acid may also be chemically synthesized in a laboratory. In some embodiments, the nucleic acid is synthesized using standard solid phase chemistry. The nucleic acid may be isolated and / or purified. In some embodiments, the nucleic acid is substantially free of impurities. In some embodiments, the nucleic acid is 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 99% free of impurities.

[0446] The nucleic acid may be modified by physical, chemical, and / or biological means. The modifications include methylation, phosphorylation, and end-capping, etc. In some embodiments, the modifications lead to increased stability of the nucleic acid.

[0447] Wherever a nucleic acid is employed in the composition, a derivative of the nucleic acid may also be used. These derivatives include products resulted from modifications of the nucleic acid in the base moieties, sugar moieties, and / or phosphate moieties of the nucleic acid. Modified base moieties include, but are not limited to, 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3- methyl adenosine, 5-methylcytidine, C5 -bromouridine, C5 -fluorouridine, C5 -iodouridine,C5-propynyl-uridine, C5-propynyl-cytidine, C5 -methylcytidine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, 0(6)-methylguanine, and 2-thiocytidine. Modified sugar moieties include, but are not limited to, 2'-fluororibosc, ribose, 2'-dcoxyribosc, 3 / -azido-2 / ,3 / -dideoxyribose, 2 / ,3 / -dideoxyribose, arabinose (the 2'-cpimcr of ribose), acyclic sugars, and hexoses. The nucleosides may be strung together by linkages other than the phosphodiester linkage found in naturally occurring DNA and RNA. Modified linkages include, but are not limited to, phosphorothioate and 5'-N-phosphoramiditc linkages. Combinations of the various modifications may be used in a single nucleic acid. These modified nucleic acids may be provided by any means known in the art; however, as will be appreciated by those of skill in the art, the modified nucleic acid may be prepared using synthetic chemistry in vitro.

[0448] The nucleic acid described herein may be in any form, such as a circular plasmid, a linearized plasmid, a cosmid, a viral genome, a modified viral genome, and an artificial chromosome.

[0449] The nucleic acid described herein may be of any sequence. In some embodiments, the nucleic acid encodes a protein or peptide. The encoded protein may be an enzyme, structural protein, receptor, soluble receptor, ion channel, active (e.g., pharmaceutically active) protein, cytokine, interleukin, antibody, antibody fragment, antigen, coagulation factor, albumin, growth factor, hormone, and insulin, etc. The nucleic acid may also comprise regulatory regions to control the expression of a gene. These regulatory regions may include, but are not limited to, promoters, enhancer elements, repressor elements, TATA boxes, ribosomal binding sites, and stop sites for transcription, etc. In some embodiments, the nucleic acid is not intended to encode a protein. For example, the nucleic acid may be used to fix an error in the genome of the cell being transfected.

[0450] In some embodiments, the nucleic acid is immunomodulatory, e.g., immunostimulatory, or immunosuppressive.

[0451] In some embodiments, the nucleic acid described herein comprises a sequence encoding an antigenic peptide or protein. A composition containing the nucleic acid can be delivered to a subject to induce an immunologic response sufficient to decrease the chance of a subsequent infection and / or lessen the symptoms associated with such an infection. The nucleic acid of these vaccines may be combined with interleukins, interferon, cytokines, and / or adjuvants described herein.

[0452] The antigenic protein or peptides encoded by the nucleic acid may be derived from bacterial organisms, such as Streptococccus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyrogenes, Corynebacterium diphtheriae, Listeria monocytogenes, Bacillus anthracis, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Neisseria meningitidis, Neisseria gonorrhoeae, Streptococcus mutans, Pseudomonas aeruginosa, Salmonella typhi, Haemophilus parainfluenzae, Bordetella pertussis, Francisella tularensis, Yersinia pestis, Vibrio cholerae, Legionella pneumophila, Mycobacterium tuberculosis, Mycobacterium leprae, Treponema pallidum, Leptospirosis interrogans, Borrelia burgdorferi, and Camphylobacter jejuni; from viruses, such assmallpox virus, influenza A virus, influenza B virus, respiratory syncytial virus, parainfluenza virus, measles virus, HIV virus, varicella-zoster virus, herpes simplex 1 virus, herpes simplex 2 virus, cytomegalovirus, Epstein-Barr virus, rotavirus, rhino virus, adenovirus, papillomavirus, poliovirus, mumps virus, rabies virus, rubella virus, coxsackieviruses, equine encephalitis virus, Japanese encephalitis virus, yellow fever virus, Rift Valley fever virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, and hepatitis E virus; and from fungal, protozoan, or parasitic organisms, such as Cryptococcus neoformans, Histoplasma capsulatum, Candida albicans, Candida tropicalis, Nocardia asteroides, Rickettsia ricketsii, Rickettsia typhi, Mycoplasma pneumoniae, Chlamydial psittaci, Chlamydial trachomatis, Plasmodium falciparum, Trypanosoma brucei, Entamoeba histolytica, Toxoplasma gondii, Trichomonas vaginalis, and Schistosoma mansoni.

[0453] In some embodiments, the mRNA is luciferase (FLuc) mRNA.

[0454] In some embodiments, the ratio of the total lipids to the nucleic acid is between about 100:1 w / w and about 1:1 w / w, between about 80:1 w / w and about 20:1 w / w, between about 75:1 w / w and about 25:1 w / w, between about 60:1 w / w and about 20:1 w / w, between about 55:1 w / w and about 25:1 w / w, between about 50:1 w / w and about 30:1 w / w, between about 45:1 w / w and about 35:1 w / w, between about 42.5:1 w / w and about 37.5:1 w / w, between about 41:1 w / w and about 39:1 w / w, between about 60:1 w / w and about 40:1 w / w, between about 50:1 w / w and about 40:1 w / w, between about 40:1 w / w and about 30:1 w / w, between about 50:1 w / w and about 20:1 w / w, or between about 70: 1 w / w and about 30: 1 w / w, wherein the total lipids consist of the compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, the helper lipid, the sterol, and the PEGylated lipid.

[0455] In some embodiments, the ratio of the total lipids to the nucleic acid is between about 80:1 w / w and about 20:1 w / w, wherein the total lipids consist of the compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, the helper lipid, the sterol, and the PEGylated lipid. In some embodiments, the ratio of the total lipids to the nucleic acid is between about 60:1 w / w and about 20: 1 w / w, wherein the total lipids consist of the compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, the helper lipid, the sterol, and the PEGylated lipid. In some embodiments, the ratio of the total lipids to the nucleic acid is between about 50:1 w / w and about 30:1 w / w, wherein the total lipids consist of the compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, the helper lipid, the sterol, and the PEGylated lipid. In some embodiments, the ratio of the total lipids to the nucleic acid is between about 45:1 w / w and about 35:1 w / w, wherein the total lipids consist of the compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, the helper lipid, the sterol, and the PEGylated lipid. In some embodiments, the ratio of the total lipids to the nucleic acid is between about 42.5:1 w / w and about 37.5:1 w / w, wherein the total lipids consist of the compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, the helper lipid, the sterol, and the PEGylated lipid. In some embodiments, the ratio of the total lipids to the nucleic acid is between about 41:1 w / w and about 39:1w / w, wherein the total lipids consist of the compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, the helper lipid, the sterol, and the PEGylated lipid.

[0456] In some embodiments, the ratio of the total lipids to the nucleic acid is about 100:1 w / w, about 90:1 w / w, about 80:1 w / w, about 70:1 w / w, about 60:1 w / w, about 50:1 w / w, about 45:1 w / w, about 42.5:1 w / w, about 40:1 w / w, about 37.5:1 w / w, about 35:1 w / w, about 30:1 w / w, about 20:1 w / w, about 10:1 w / w, about 5:1 w / w, or about 1:1 w / w, wherein the total lipids consist of the compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, the helper lipid, the sterol, and the PEGylated lipid.

[0457] In some embodiments, the ratio of the total lipids to the nucleic acid is about 50:1 w / w, wherein the total lipids consist of the compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, the helper lipid, the sterol, and the PEGylated lipid. In some embodiments, the ratio of the total lipids to the nucleic acid is about 45:1 w / w, wherein the total lipids consist of the compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, the helper lipid, the sterol, and the PEGylated lipid. In some embodiments, the ratio of the total lipids to the nucleic acid is about 42.5:1 w / w, wherein the total lipids consist of the compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, the helper lipid, the sterol, and the PEGylated lipid. In some embodiments, the ratio of the total lipids to the nucleic acid is about 40:1 w / w, wherein the total lipids consist of the compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, the helper lipid, the sterol, and the PEGylated lipid. In some embodiments, the ratio of the total lipids to the nucleic acid is about 37.5:1 w / w, wherein the total lipids consist of the compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, the helper lipid, the sterol, and the PEGylated lipid. In some embodiments, the ratio of the total lipids to the nucleic acid is about 35:1 w / w, wherein the total lipids consist of the compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, the helper lipid, the sterol, and the PEGylated lipid. In some embodiments, the ratio of the total lipids to the nucleic acid is about 30:1 w / w, wherein the total lipids consist of the compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, the helper lipid, the sterol, and the PEGylated lipid.Subgeneric Embodiments

[0458] In some embodiments, the composition comprises a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and DSPC. In some embodiments, the composition comprises a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and cholesterol. In some embodiments, the composition comprises a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and DMG-PEG2000.

[0459] In some embodiments, the composition comprises a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, DSPC, and cholesterol. In some embodiments, the composition comprises a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptablesalt thereof, DSPC, and DMG-PEG2000. In some embodiments, the composition comprises a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, cholesterol, and DMG-PEG2000.

[0460] In some embodiments, the composition comprises a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, DSPC, cholesterol, and DMG-PEG2000.

[0461] In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and between about 5 mol % and about 15 mol % of DSPC. In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and between about 7.5 mol % and about 12.5 mol % of DSPC. In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and between about 9 mol % and about 11 mol % of DSPC.

[0462] In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and between about 30 mol % and about 50 mol % of cholesterol. In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and between about 35 mol % and about 45 mol % of cholesterol. In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and between about 37 mol % and about 39 mol % of cholesterol.

[0463] In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and between about 0.5 mol % and about 5 mol % of DMG-PEG2000. In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and between about 1 mol % and about 3 mol % of DMG-PEG2000. In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and between about 1.5 mol % and about 2.5 mol % of DMG-PEG2000.

[0464] In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, between about 5 mol % and about 15 mol % of DSPC, and between about 30 mol % and about 50 mol % of cholesterol. In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, between about 5 mol % and about 15 mol % of DSPC, and between about 0.5 mol % and about 5 mol % of DMG-PEG2000. In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceuticallyacceptable salt thereof, between about 30 mol % and about 50 mol % of cholesterol, and between about 0.5 mol % and about 5 mol % of DMG-PEG2000,

[0465] In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, between about 5 mol % and about 15 mol % of DSPC, between about 30 mol % and about 50 mol % of cholesterol, and between about 0.5 mol % and about 5 mol % of DMG-PEG2000.

[0466] In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, between about 7.5 mol % and about 12.5 mol % of DSPC, and between about 35 mol % and about 45 mol % of cholesterol. In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, between about 7.5 mol % and about 12.5 mol % of DSPC, and between about 1 mol % and about 3 mol % of DMG-PEG2000. In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, between about 35 mol % and about 45 mol % of cholesterol, and between about 1 mol % and about 3 mol % of DMG-PEG2000.

[0467] In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, between about 7.5 mol % and about 12.5 mol % of DSPC, between about 35 mol % and about 45 mol % of cholesterol, and between about 1 mol % and about 3 mol % of DMG-PEG2000.

[0468] In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, between about 9 mol % and about 11 mol % of DSPC, and between about 37 mol % and about 39 mol % of cholesterol. In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, between about 9 mol % and about 11 mol % of DSPC, and between about 1.5 mol % and about 2.5 mol % of DMG-PEG2000. In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, between about 37 mol % and about 39 mol % of cholesterol, and between about 1.5 mol % and about 2.5 mol % of DMG-PEG2000.

[0469] In some embodiments, the composition comprises between about 40 mol % and about 60 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, between about 9 mol % and about 11 mol % of DSPC, between about 37 mol % and about 39 mol % of cholesterol, and between about 1.5 mol % and about 2.5 mol % of DMG-PEG2000.

[0470] In some embodiments, the composition comprises between about 45 mol % and about 55 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and between about 5 mol % and about 15 mol % of DSPC. In some embodiments, the compositioncomprises between about 45 mol % and about 55 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and between about 7.5 mol % and about 12.5 mol % of DSPC. In some embodiments, the composition comprises between about 45 mol % and about 55 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and between about 9 mol % and about 11 mol % of DSPC.

[0471] In some embodiments, the composition comprises between about 45 mol % and about 55 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and between about 30 mol % and about 50 mol % of cholesterol. In some embodiments, the composition comprises between about 45 mol % and about 55 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and between about 35 mol % and about 45 mol % of cholesterol. In some embodiments, the composition comprises between about 45 mol % and about 55 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and between about 37 mol % and about 39 mol % of cholesterol.

[0472] In some embodiments, the composition comprises between about 45 mol % and about 55 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and between about 0.5 mol % and about 5 mol % of DMG-PEG2000. In some embodiments, the composition comprises between about 45 mol % and about 55 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and between about 1 mol % and about 3 mol % of DMG-PEG2000. In some embodiments, the composition comprises between about 45 mol % and about 55 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, and between about 1.5 mol % and about 2.5 mol % of DMG-PEG2000.

[0473] In some embodiments, the composition comprises between about 45 mol % and about 55 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, between about 5 mol % and about 15 mol % of DSPC, and between about 30 mol % and about 50 mol % of cholesterol. In some embodiments, the composition comprises between about 45 mol % and about 55 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, between about 5 mol % and about 15 mol % of DSPC, and between about 0.5 mol % and about 5 mol % of DMG-PEG2000. In some embodiments, the composition comprises between about 45 mol % and about 55 mol % of a compound of Formula (I) or Formula (I'), or a pharmaceutically acceptable salt thereof, between about 30 mol % an...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I) :or a pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted heteroalkyl;each instance of R2is independently hydrogen or OHn is 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, or 5; wherein the sum of n and p equals the number of attachment points in Q;each x is independently 0 or 1 ; each y is independently 0 or 1 ; and each z is independently 0 or 1 ; provided that within each instance ofeach x is 0, each y is 0, and each z is 0; each x is 1, each y is 0, and each z is 0; each x is 1, each y is 1, and each z is 0; or each x is 1 , each y is 1 , and each z is 1.

2. A compound of Formula (I'):or a pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted heteroalkyl;each instance of R2is independently hydrogen or OH each instance of R3is independentlyeach instance of R4is independentlyn is 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, or 5; wherein the sum of n and p equals the number of attachment points in Q; each x is independently 0 or 1 ; each y is independently 0 or 1 ; and each z is independently 0 or 1 ; provided that within each instance ofeach x is 0, each y is 0, and each z is 0; each x is 1, each y is 0, and each z is 0; each x is 1, each y is 1, and each z is 0; or each x is 1 , each y is 1 , and each z is 1 ; provided that the compound of Formula (I') is not of formula:

3. The compound, or pharmaceutically acceptable salt thereof, of claim 1 or 2, wherein each instance of R1is independently optionally substituted alkyl.

4. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-3, wherein each instance of R1is independently optionally substituted Ce-io alkyl.

5. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-4, wherein each instance of R1is independently unsubstituted Ce-io alkyl.

6. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-5, wherein each instance of R1is independently unsubstituted linear Ce-io alkyl.

7. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-6, wherein each instance of R1is independently n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl.

8. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-7, wherein each instance of R1is independently / z-hcxyl or n-decyl.

9. The compound, or pharmaceutically acceptable salt thereof, of claim 1 or 2, wherein each instance of R1is independently optionally substituted alkenyl.

10. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1, 2, and 9, wherein each instance of R1is independently optionally substituted Ce-io alkenyl.

11. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1, 2, 9, and10, wherein each instance of R1is independently unsubstituted Ce-io alkenyl.

12. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1, 2, and 9-11, wherein each instance of R1is independently unsubstituted linear Ce-io alkenyl.

13. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1, 2, and 9-12, wherein each instance of R1is independently 7-octenyl.

14. The compound, or pharmaceutically acceptable salt thereof, of claim 1 or 2, wherein each instance of R1is independently optionally substituted heteroalkyl.

15. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1, 2, and 14 wherein each instance of R1is independently optionally substituted Ce-io heteroalkyl.

16. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1, 2, 14, and15, wherein each instance of R1is independently17. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-16, wherein at least one instance of R2is hydrogen.

18. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-17, wherein each instance of R2is hydrogen.

19. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-16,wherein at least one instance of R2is OH .

20. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-16 and 19,wherein each instance of R2is independently OH .

21. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-20, wherein at least one instance of R3is of Formula (R3-a-l):(R3-a-l), or at least one instance of R3is of Formula (22. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-21, wherein each instance of R3is of Formula (R3-a-l):(R3-a-l), or each instance of R3is of Formula (23. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-22, wherein at least one instance of R4is of Formula (R4-a-l):

24. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-23,wherein each instance of R4is of Formula (R4-a-l):

25. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-24,26. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-25, wherein n and p are the same.

27. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-26, wherein n is 1 and p is 1.

28. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-26, wherein n is 2 and p is 2.

29. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-26, wherein n is 3 and p is 3.

30. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-25, wherein p is 0.

31. The compound of any one of claims 1-16 or 25-30, wherein the compound is of Formula (III):or a pharmaceutically acceptable salt thereof.

32. The compound of any one of claims 1-16 and 25-31, wherein the compound is of Formulae (III-a-2), (III-a-3), (III-b-1), (III-c-4), (III-c-5), (III-d-2), (III-d-3), (III-e-2), (III-e-3), (III-f-8), (Ill-f- 9), (III-f-10), (III-f-11), or (III-f-12):or a pharmaceutically acceptable salt thereof.

33. The compound of claim 32, wherein the compound is of Formulae (III-a-2), (III-b-1), (III-c- 5), (III-d-2), or (III-e-2), or a pharmaceutically acceptable salt thereof.

34. The compound of any one of claims 1-16 and 25-31, wherein the compound is of Formulae (ni-a-5), (III-b-2), (III-c-9), (III-d-5), (III-e-5), or (III-f-20):or a pharmaceutically acceptable salt thereof.

35. The compound of claim 34, wherein the compound is of Formulae (III-a-5), (III-b-2), (III-c- 9), (III-d-5) , or (III-e-5), or a pharmaceutically acceptable salt thereof.

36. The compound of any one of claims 1-27, wherein the compound is of Formula (IV):or a pharmaceutically acceptable salt thereof.

37. The compound of any one of claims 1-27 and 36, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

38. The compound of claim 37, wherein the compound is of Formulae (IV-a-2), (IV-b-1), (IV-c- 5), (IV-d-2), or (IV-e-2), or a pharmaceutically acceptable salt thereof.

39. The compound of any one of claims 1-27 and 36, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

40. The compound of claim 39, wherein the compound is of Formulae (IV-a-5), (IV-b-2), (IV-c- 9), (IV-d-5), or (IV-e-5), or a pharmaceutically acceptable salt thereof.

41. The compound of any one of claims 1-40, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

42. The compound of any one of claims 1-40, wherein the compound is of formula:or a pharmaceutically acceptable salt thereof.

43. A composition comprising: the compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof; a helper lipid; a sterol; and a PEGylated lipid.

44. The composition of claim 43, wherein the helper lipid is distearoylphosphatidylcholine (DSPC).

45. The composition of claim 43 or 44, wherein the PEGylated lipid is a PEG-2000.

46. The composition of any one of claims 43-45, the composition further comprising a nucleic acid.

47. The composition of claim 46, wherein the nucleic acid is RNA.

48. The composition of claim 46 or 47, wherein the nucleic acid is mRNA.

49. The composition of claim 48, wherein the mRNA encodes for luciferase.

50. The composition of any one of claims 43-49, comprising a hydrodynamic diameter of between about 100 nm and about 400 nm.

51. The composition of claim 50, wherein the hydrodynamic diameter is about 200 nm.

52. The composition of any one of claims 43-51, comprising a polydispersity index (PDI) of less than about 0.5.

53. The composition of claim 52, wherein the PDI is less than about 0.3.

54. The composition of any one of claims 43-53, comprising a zeta potential of between about 25 mV and about -25 mV.

55. The composition of claim 54, wherein the zeta potential is between about -10 mV to about 10 mV.

56. The composition of any one of claims 43-55, comprising an apparent pKa of between about 5.0 and about 9.0.

57. The composition of claim 56, wherein the apparent pKa is between about 7.0 and about 8.0 or between about 7.5 and about 8.5.

58. The composition of any one of claims 43-57, wherein the composition exhibits liver tropism.

59. The composition of any one of claims 43-57, wherein the composition exhibits spleen tropism.

60. A method of treating or preventing a disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of the composition of any one of claims 43-59.

61. The method of claim 60, wherein the disease is a proliferative disease.

62. The method of claim 61, wherein the proliferative disease is cancer.

63. The method of claim 62, wherein the cancer comprises a solid tumor.

64. The method of claim 62 or 63, wherein the cancer is brain tumor (glioblastoma), pancreatic cancer, or ovarian cancer.

65. A method of cellular engineering, the method comprising administering to a subject in need thereof or contacting a cell, tissue, or biological sample with the composition of any one of claims 43- 59.

66. The method of claim 65, comprising engineering an immune cell.

67. The method of claim 66, wherein the immune cell is a granulocyte, monocyte, macrophage, or a dendritic cell.

68. The method of claim 66, wherein the immune cell is a myeloid derived suppressor cell (MDSC).

69. The method of claim 66, wherein the immune cell is a tumor-infiltrating monocyte (TIM).

70. The method of any one of claims 66-69, wherein the engineering comprises transfecting the immune cell.

71. The method of any one of claims 60-70, wherein the administration is by injection.

72. A method of preparing a compound of Formula (I):or a pharmaceutically acceptable salt thereof, the method comprising treating an amine of formula:0, 1, 2, or 3 times with methyl acrylate followed by ethylene diamine, to produce a compound ofFormula (VI):or a pharmaceutically acceptable salt thereof; and treating the compound of Formula (VI) with an epoxide of formula:to produce the compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted heteroalkyl;each instance of R2is independently hydrogen or OH each instance of R3is independentlyn is 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, or 5; wherein the sum of n and p equals the number of attachment points in Q; each x is independently 0 or 1 ; each y is independently 0 or 1 ; and each z is independently 0 or 1 ; provided that within each instance ofeach x is 0, each y is 0, and each z is 0; each x is 1, each y is 0, and each z is 0; each x is 1, each y is 1, and each z is 0; or each x is 1 , each y is 1 , and each z is 1.

73. A compound made by the method of claim 72.

74. A method of preparing a compound of Formula (I'):or a pharmaceutically acceptable salt thereof, the method comprising treating an amine of formula:0, 1, 2, or 3 times with methyl acrylate followed by ethylene diamine, to produce a compound of Formula (VI):or a pharmaceutically acceptable salt thereof; and treating the compound of Formula (VI) with an epoxide of formula:to produce the compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein: each instance of R1is independently optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted heteroalkyl;each instance of R2is independently hydrogen or OHn is 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, or 5; wherein the sum of n and p equals the number of attachment points in Q; each x is independently 0 or 1 ; each y is independently 0 or 1 ; and each z is independently 0 or 1 ; provided that within each instance ofeach x is 0, each y is 0, and each z is 0; each x is 1, each y is 0, and each z is 0; each x is 1, each y is 1, and each z is 0; or each x is 1 , each y is 1 , and each z is 1 ; provided that the compound of Formula (I') is not of formula:

75. A compound made by the method of claim 74.

76. A kit comprising: the composition of any one of claims 43-59; and instructions for its use.

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