Compositions and methods for targeting tumor-associated macrophages

Abstract

The present disclosure relates to compositions targeting tumor-associated macrophages. The compositions disclosed herein preferably comprise a glucan backbone, a tumor-associated macrophage targeting moiety, a targeting moiety linker, a payload, and optionally a payload linker. The present disclosure also provides methods of making such compositions. The present disclosure also provides methods of treatment using such compositions.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 447,626, filed February 22, 2023, entitled “Compositions and methods for targeting tumor-associated macrophages,” the contents of which are incorporated herein by reference in their entirety. Background Technology

[0003] Soft tissue sarcoma (STS) is a rare but deadly cancer in children and adults. The American Cancer Society estimates that approximately 13,000 new cases of STS are diagnosed in the United States each year, with an estimated 5,130 deaths, and a 5-year survival rate of only 16% for metastatic disease. Conventional treatments, including surgery, chemotherapy, and radiation therapy, have limited success rates for STS. For example, the median overall survival for metastatic UPS (undifferentiated pleomorphic sarcoma), a highly aggressive adult sarcoma, is only 15.5 months. The 5-year survival rate for metastatic cases of Ewing's sarcoma / primitive neuroectodermal tumor (PNET), an aggressive adolescent-associated sarcoma, is 15%. Treatment of solid tumors has recently improved with the advent of a broad range of targeted therapies, such as small molecules and biologics. Small molecules have excellent penetration into solid tumors, but many of them work by inhibiting signal transduction pathways, resulting in growth inhibition rather than direct tumor cytotoxicity. Cancer cells can develop resistance to small molecules if the entire tumor is not killed. Biologics, such as antibodies and antibody-drug conjugates (ADCs), have shown potent efficacy against certain malignancies and exhibit good stability in the bloodstream. However, antibodies have limited penetration into solid tumors, and tumor cells can develop resistance to ADCs through various cellular modifications (Collins et al., "Acquired Resistance to Antibody-Drug Conjugates," Cancers (Basel), 2019, 11(3):394). Therefore, new approaches are needed to overcome the limitations of current technology and further improve the treatment outcomes of STS. Furthermore, STS encompasses more than 50 different histological and molecular subtypes, each exhibiting variable clinical behavior (Katz et al., "More Than 50 Subtypes of Soft Tissue Sarcoma: Paving the Path for Histology-Driven Treatments," Am Soc Clin Oncol Educ Book, 2018, 38, 925-938). Partly due to this variability, current STS treatment options have limited efficacy, and there is no sustainable and effective single or combination therapy for all STS subtypes.

[0004] Various molecular targeting methods have been used to target CD206. +Cells, particularly macrophages, are sought after for delivering diagnostic and therapeutic agents to sites where these cells accumulate. One example of such molecules is found in US2017 / 0209584, entitled “Compositions for Targeting Macrophages and Other CD206 High Expressing Cells and Methods of Treating and Diagnosis.” While molecules disclosed in this and other references can target CD206 of interest… + Cells, but these molecules have many drawbacks. Summary of the Invention

[0005] In one aspect, a composition is provided comprising i) a tumor-associated macrophage-targeting moiety; ii) a dextran backbone, wherein the dextran backbone comprises a plurality of backbone monomers; and iii) a component comprising pyrrolobenzodiazepine. (PBD) active component of a dimer, wherein the active component is coupled to the dextran backbone; and iv) a targeting connector that links the targeting portion to the dextran backbone, wherein the targeting connector comprises a urethane group and a chain portion, and wherein the urethane group is connected to the backbone monomer and the chain portion is connected to the urethane group and the tumor-associated macrophage targeting portion.

[0006] A method for delivering a drug to tumor-associated macrophages is also provided, the method comprising contacting the macrophages with the composition described herein.

[0007] A method for treating a subject with cancer, granulomatous disease, or non-malignant tumor is also provided, the method comprising administering to the subject a therapeutically effective amount of the composition described herein. Attached Figure Description

[0008] Figure 1 This is a morphological image of mouse M1 cells.

[0009] Figure 2 This is a morphological image of mouse M2 cells.

[0010] Figure 3 This is a graph showing the viability results of mouse M1, M2, and 3T3 cells after treatment with the compound of formula (A-1).

[0011] Figure 4 The figure shows the viability results of mouse M1, M2, and 3T3 cells after treatment with the compound of formula (A-1).

[0012] Figure 5This is a graph showing the viability results of mouse M1, M2 and 3T3 cells after treatment with the compound of formula (A-2).

[0013] Figure 6 This is a graph showing the viability results of mouse M1, M2 and 3T3 cells after treatment with the compound of formula (A-2).

[0014] Figure 7A and 7B The figure shows the weight loss in mice treated with an increased concentration of formula (A-1).

[0015] Figure 8 This is a graph showing the food intake of mice given an increased concentration of formula (A-1).

[0016] Figure 9A-9L This is a graph depicting the hematological parameters between groups of mice administered an increased concentration of formula (A-1).

[0017] Figure 10A-10T This is a graph depicting the differences in serum components between groups of mice treated with increased concentrations of formula (A-1).

[0018] Figure 11 The reduced tumor burden in mice treated with formula (A-1) in the PDX myxofibrosarcoma model was depicted. Detailed Implementation

[0019] This disclosure relates to compositions targeting tumor-associated macrophages. The compositions disclosed herein comprise a dextran backbone, a tumor-associated macrophage targeting portion, a targeting portion adapter, a payload, and optionally a payload adapter. This disclosure also provides methods for preparing and using such compositions.

[0020] Chemical definition

[0021] Unless otherwise stated, as used herein, "alkyl" means and includes having a specified number of carbon atoms (i.e., C1-C1). 10 This refers to a saturated straight-chain (i.e., unbranched) or branched monovalent hydrocarbon chain, or a combination thereof, having one to ten carbon atoms. Specific alkyl groups have 1 to 20 carbon atoms (“C1-C2”). 20 Alkyl groups, having 1 to 10 carbon atoms ("C1-C1") 10 Alkyl groups, having 6 to 10 carbon atoms ("C6-C") 10Alkyl groups are groups having 1 to 6 carbon atoms (“C1-C6 alkyl”), 2 to 6 carbon atoms (“C2-C6 alkyl”), or 1 to 4 carbon atoms (“C1-C4 alkyl”). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc.

[0022] As used herein, "alkylene" refers to residues that are identical to alkyl but have a divalent oxidation state. Specific alkylene groups have 1 to 20 carbon atoms ("C1-C2"). 20 Alkylenes ("C1-C1") have 1 to 10 carbon atoms. 10 Alkylenes ("C6-C10") have 6 to 10 carbon atoms. 10 Alkylenes are groups having 1 to 6 carbon atoms ("C1-C6 alkylenes"), 1 to 5 carbon atoms ("C1-C5 alkylenes"), 1 to 4 carbon atoms ("C1-C4 alkylenes"), or 1 to 3 carbon atoms ("C1-C3 alkylenes"). Examples of alkylenes include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), butylene (-CH2(CH2)2CH2-), isobutylene (-CH2CH(CH3)CH2-), pentylene (-CH2(CH2)3CH2-), hexylene (-CH2(CH2)4CH2-), heptylene (-CH2(CH2)5CH2-), octylene (-CH2(CH2)6CH2-), etc.

[0023] "Halogen" or "halogen" refers to elements in Group 17 with atomic numbers 9 to 85. Preferred halogenated groups include fluorine, chlorine, bromine, and iodine groups. When a residue is substituted with more than one halogen, it can be designated by using a prefix corresponding to the number of halogen moieties attached, such as dihaloaryl, dihaloalkyl, trihaloaryl, etc., which refer to aryl and alkyl groups substituted with two ("di") or three ("tri") halogenated groups, which may be, but are not necessarily, the same halogen; thus, 4-chloro-3-fluorophenyl falls within the range of dihaloaryl. An alkyl group in which every hydrogen atom is replaced by a halogenated group is called a "perhaloalkyl". A preferred perhaloalkyl is trifluoromethyl (-CF3). Similarly, "perhaloalkoxy" refers to an alkoxy group in a hydrocarbon in which each H atom is halogenated to form the alkyl moieties of the alkoxy group. An example of a perhaloalkoxy is trifluoromethoxy (-OCF3).

[0024] "Carbamate" refers to the group -OC(=O)-NH-. Unless otherwise specified, it should be understood that the nitrogen atom of the carbamate group is unsubstituted (i.e., it carries a hydrogen atom).

[0025] "Oxytochemical" refers to a partial = O.

[0026] Unless otherwise specified, "aryl" by itself or as part of another term means a substituted or unsubstituted monovalent carbocyclic aromatic hydrocarbon group having the number of carbon atoms (typically 6-20) derived by removing a hydrogen atom from a single carbon atom of the parent aromatic ring system. Some aryl groups are represented as "Ar" in exemplary structures. Typical aryl groups include, but are not limited to, groups derived from benzene, substituted benzenes, naphthalenes, anthracene, biphenyls, etc. An exemplary aryl group is phenyl.

[0027] Unless otherwise indicated, “aleneyl” itself or as part of another term is an aryl group as defined above, which has two covalent bonds (i.e., it is divalent) and can be in the ortho, meta, or para orientation.

[0028] Unless otherwise specified, "heterocyclic group" itself, or as part of another term, refers to a monocyclic or non-aromatic monocyclic or bicyclic ring system having 3 to 9 carbon atoms (also called ring members) and one to four heteroatom ring members independently selected from N, O, P, or S, and derived by removing a hydrogen atom from a ring atom of the parent ring system, whether monovalently substituted or unsubstituted. One or more N, C, or S atoms in the heterocycle may be oxidized. The ring including the heteroatom may be aromatic or non-aromatic.

[0029] Unless otherwise stated, heterocyclic groups attach to their side groups at any heteroatom or carbon atom to produce a stable structure. Therefore, heteroaryl groups can be bonded to the aromatic carbons of their aromatic ring system, referred to as C-linked heteroaryl groups, or to non-double-bonded nitrogen atoms (i.e., not =N-) in their aromatic ring system, referred to as N-linked heteroaryl groups. Thus, nitrogen-containing heterocyclic groups can be C-linked or N-linked, and include pyrrole moieties such as pyrrole-1-yl (N-linked) and pyrrole-3-yl (C-linked), and imidazole moieties such as imidazole-1-yl and imidazole-3-yl (both N-linked), as well as imidazole-2-yl, imidazole-4-yl, and imidazole-5-yl moieties (all C-linked).

[0030] When explicitly given, the size of a heterocyclic or heteroaryl ring system is indicated by the total number of atoms in the ring. For example, the name 5- or 6-membered heteroaryl indicates the total number of aromatic atoms in the heteroaryl ring system (i.e., 5 or 6), but does not imply the number of aromatic heteroatoms or aromatic carbons in the ring system. Fused heteroaryls are explicitly stated or implied by the context itself, and are generally indicated by the number of aromatic atoms in each aromatic ring fused together to form a fused heteroaryl ring system. For example, a 5,6-membered heteroaryl is an aromatic 5-membered ring fused to an aromatic 6-membered ring, where one or both rings have aromatic heteroatoms or where heteroatoms are shared between the two rings.

[0031] Unless otherwise stated, "optionally substituted" means that the group may be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) substituents listed for that group, wherein the substituents may be the same or different. In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two substituents. In another embodiment, the optionally substituted group has three substituents. In another embodiment, the optionally substituted group has four substituents. In some embodiments, the optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, the optionally substituted group is unsubstituted.

[0032] Composition

[0033] The compositions disclosed herein comprise various components, including a dextran backbone, a tumor-associated macrophage targeting moiety, a targeting moiety linker, and a payload (e.g., pyrrolobenzodiazepine). The disclosed composition comprises a combination of tumor-associated macrophages (TAMs) and optional payload adapters. The arrangement of these components provides a composition targeting TAMs. The disclosed composition can utilize TAMs as recipient cells to pick up, process, and deliver payloads to the tumor environment. For example, sarcomas are characterized by abundant tumor-associated macrophages (TAMs) (Fujiwara et al., 2021). Immunohistochemistry of anti-CD206 on human sarcoma microarrays, including 59 samples covering 19 sarcoma subtypes, has shown that this TAM receptor is highly and relatively homogeneously expressed in virtually all samples. The disclosed composition can be used by cells present in tumor-associated macrophages (e.g., CD206 receptors). + Internalization. The ability to be internalized by cells present in tumor-associated macrophages allows the disclosed compositions to effectively deliver payloads (e.g., pyrrolobenzodiazepines). This application describes improved compositions and methods for treating cancer, including delivering an agent (e.g., pyrrolobenzodiazepine) to the disease site where such cells accumulate. This method delivers the drug to tumor-associated macrophages. The compositions disclosed herein are larger than typical small molecules but smaller than antibody-drug conjugates, allowing for excellent penetration to the target site and minimal leakage into normal tissue, thereby limiting potential toxicity. Furthermore, while rapidly dividing, mutated, and heterogeneous cancer cells often develop resistance to conventional therapies, terminally differentiated macrophages are not subject to selection pressures to develop resistance to the treatments disclosed herein.

[0034] The disclosed compositions can also target specific receptors present on or near tumors, such as CD205 (DEC205), CD206, CD207 (langerin), CD209 (DC-SIGN), CD280 (ENDO180), and CD301 (MGL), thereby allowing targeted delivery of payloads to tumors.

[0035] dextran backbone

[0036] The compounds described herein comprise a dextran backbone, which is a linear, branched, or cyclic oligosaccharide or polysaccharide comprising multiple glucose monomers. In some embodiments, the multiple glucose monomers are primarily linked by C-1→C-6 glycosidic bonds. Other bonds, such as α-1,3 or α-1,4 bonds, may also be present. In some embodiments, the multiple glucose monomers are linked by α-1,6 and α-1,3 glycosidic bonds. In some embodiments, the multiple glucose monomers are linked by a mixture of α-1,6 and α-1,4 glycosidic bonds. The dextran backbone can also be defined as a polymer of glucose, wherein the positions of the glycosidic bonds are varied. The dextran backbone may comprise α or β isomers of glucose, or a mixture of α and β isomers. Examples of dextran backbones include dextran as a linear or branched compound and cyclodextrin as a cyclic dextran. It should be understood that in some embodiments, monomers labeled, for example, a, b, or c, are interspersed within the construct. It should also be understood that in some implementations, the constructs described herein may be segmented or distributed, for example, randomized.

[0037] The mass and molecular weight of the dextran backbone can vary, depending in part on the number of glucose monomers. In some embodiments, the molecular weight of the dextran backbone can range from 1 to 30 kilodaltons (kDa). Preferred embodiments include dextran backbones of approximately 1 kDa, 3 kDa, 6 kDa, 10 kDa, 20 kDa, or 30 kDa. In some embodiments, the molecular weight of the dextran backbone can range from 1,000 to 30,000 g / mol. In some embodiments, the dextran backbone may contain a number of glucose monomers ranging from 5 to 167. The dextran backbone can be linear, branched, cyclic, or a combination thereof. For example, dextran is an example of a linear or branched dextran backbone. Cyclodextrin is another example of a dextran backbone. The backbone described herein can be substituted or unsubstituted. For example, the substituted cyclodextrin is a cyclodextrin derivative that is hydrophobic, hydrophilic, ionized, non-ionized, or any other variant thereof.

[0038] In some embodiments, the dextran backbone comprises multiple backbone monomers, wherein the multiple backbone monomers include multiple D-glucose monomers at α-1,6 glycosidic bonds or β-1,4 glycosidic bonds. In some embodiments, the multiple D-glucose monomers are n, where n = 16 to 111. In some embodiments, n = 50 to 65. In some embodiments, the dextran backbone is a linear dextran molecule. In some embodiments, the dextran backbone is a cyclodextrin molecule containing 6 to 16 D-glucose monomers.

[0039] Targeted portion

[0040] The compositions disclosed herein comprise a targeting portion (e.g., a tumor-associated macrophage targeting portion) coupled to the dextran backbone. In some embodiments, the targeting portion binds to a receptor, said receptor including, but not limited to, CD205 (DEC205), CD206, CD207 (Langerin), CD209 (DC-SIGN), CD280 (ENDO180), or CD301 (MGL). In some embodiments, the targeting portion is the CD205 targeting portion. In some embodiments, the targeting portion is the CD206 targeting portion. In some embodiments, the targeting portion is the CD207 targeting portion. In some embodiments, the targeting portion is the CD209 targeting portion. In some embodiments, the targeting portion is the CD280 targeting portion. In some embodiments, the targeting portion is the CD301 targeting portion. In some embodiments, the target receptor is on tumor-associated macrophages. In some embodiments, the target receptor is on cancer cells or tumor cells. In some embodiments, the targeting portion comprises mannose, galactose, collagen, fucose, sulfated N-acetylgalactosamine, N-acetylglucosamine, luteinizing hormone, thyroid-stimulating hormone, phospholipase A2 or a fragment thereof, or chondroitin sulfate. In some embodiments, the targeting portion comprises mannose, including its D- and L-isomers. In some embodiments, the targeting portion comprises furanose. In some embodiments, the targeting portion comprises pyranose. In some embodiments, the targeting portion is D-mannose. It should be understood that the tumor-associated macrophage targeting portion may be referred to as the targeting portion.

[0041] In some embodiments, the targeting moiety is attached to approximately 10% to approximately 50% of the glucose residues, or approximately 20% to approximately 45% of the glucose residues, or approximately 25% to approximately 40% of the glucose residues in the dextran backbone. (It should be noted that, with respect to the collection or group of compositions described herein, the MW mentioned herein, as well as the number and degree of conjugation of the receptor substrate, leash, and therapeutic moiety attached to the dextran backbone, refer to the average amount of a given number of carrier molecules, as synthetic techniques will cause some fluctuations.)

[0042] Target connector to main chain ratio

[0043] The density of the target moiety relative to the main chain subunits is expressed using the ratio of the target moiety to the main chain subunits of a linear, branched, or cyclic polysaccharide backbone. For example, the degree of substitution (ds) is used to convey the density of the target moiety on the dextran backbone. The target moiety to dextran backbone ratio refers to the number of target moieties that replace one or more main chain subunits. For example, a ratio of 1:7 or 1:7 means that there is one target moiety for every seven glucose subunits in the dextran backbone. ds describes the average number of substituents or substitution sites per base. For example, a ds of 0.9 means that one main chain subunit is replaced by an average of 0.9 target moieties. In some embodiments, the target moiety to main chain subunit ratio is from about 1:5 to about 1:25. In some embodiments, the target moiety to main chain subunit ratio is from at least 1:50 (e.g., at least 1:33, at least 1:35, at least 1:40, or at least 1:45) to about 1:5. In some embodiments, the ratio of the targeting portion to the main chain subunit is from about 1:6 to about 1:19. In some embodiments, ds is from about 0.1 to about 7. In some embodiments, ds is from about 0.5 to 5. In some embodiments, in combination with the above embodiments, the targeting portion comprises mannose.

[0044] Target connector

[0045] A target adaptor is a cleavable or non-cleavable adaptor that links the dextran backbone to a target region. A cleavable adaptor can be cleaved by an enzyme (e.g., a protease), temperature changes, pH changes, chemical stimuli, or any combination thereof. A cleavable adaptor may contain a protease cleavage site. In some embodiments, the cleavable adaptor can be cleaved by lysosomal proteases or endosomal proteases.

[0046] The targeting linker may comprise a urethane group. In some embodiments, the targeting linker comprises a urethane group and a chain portion, wherein the urethane group is linked to the main chain monomer and the chain portion connects the urethane group and the targeting portion. In some embodiments, the chain portion of the targeting linker comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) units selected from the group consisting of: optionally substituted alkylene chains, optionally substituted CO-alkylene chains, peptide chains, polymer chains, and heteroatoms selected from the group consisting of O atoms, S atoms, and optionally substituted N atoms. In some embodiments, the chain portion comprises C1-C 12Alkylene chain. In some embodiments, the chain portion comprises a C3-C7 alkylene chain. In some embodiments, the chain portion comprises a C6 alkylene chain. In some embodiments, the chain portion is a C6 alkylene chain. In some embodiments, the alkylene chain is substituted by one or more substituents selected from the group consisting of: oxo, OH, NH2, SH, C1-C 12 Alkyl, C1-C 12 Haloalkyl, O(C1-C) 12 Alkyl), O(C1-C) 12 Halogenated alkyl groups), NH (C1-C 12 alkyl), NH (C1-C) 12 Halogenated alkyl), N(C1-C) 12 Alkyl)2, N(C1-C 12 (halogenated alkyl)2, S(C1-C 12 Alkyl), S(C1-C 12 Halogenated alkyl groups), C(O)OH, C(O)O(C1-C 12 Alkyl), C(O)O(C1-C 12 Halogenated alkyl groups), C(O)NH(C1-C 12 Alkyl), C(O)NH(C1-C 12 Halogenated alkyl groups), C(O)N(C1-C 12 Alkyl)2, C(O)N(C1-C 12 (halogenated alkyl)2, C(O)S(C1-C 12 Alkyl) and C(O)S(C1-C 12 (Halogenated alkyl). In some embodiments, the alkylene chain is unsubstituted.

[0047] In some embodiments, one or more targeting portions are attached to the dextran backbone via a connector. The connector may attach to approximately 1% to approximately 50% of the backbone portion. In some embodiments, the targeting connector comprises C 1-12 alkylene chains and urethane groups, wherein the urethane groups are attached to the main chain monomer and C 1-12 The alkylene chain connects the urethane group and the target portion.

[0048] Active components

[0049] The active ingredient is a molecule or compound that can be used for therapeutic purposes. The active ingredient is also referred to as the payload. The active ingredient may be or contain a cytotoxic agent or a cell growth inhibitor. In some embodiments, the payload facilitates targeted delivery of the composition described herein to macrophages or cancer cells. In some embodiments, the payload is a hydrophobic payload (e.g., topoisomerase inhibitor I, topoisomerase inhibitor II, or temozolomide). In some embodiments, the payload is a hydrophilic payload. In some embodiments, the payload is a therapeutic agent. In some embodiments, the therapeutic agent is selected from, but is not limited to, lomustine, epirubicin, topotecan, irinotecan, pemetrexed, docetaxel, oxaliplatin, hexamethylmelamine, pentorubicin, and sarcin.

[0050] In some embodiments, the active component comprises pyrrolobenzodiazepine (PBD) toxin or a pharmaceutically acceptable salt thereof. In some embodiments, PBD is a dimer. In some embodiments, the active ingredient comprises a PBD dimer of formula (I) or a pharmaceutically acceptable salt thereof:

[0051]

[0052] in:

[0053] A is C6-C 10 Alpha-aryl and X-selection freedom The group formed

[0054] Where R N Selected from the group consisting of H and C1-C4 alkyl groups; and the asterisk indicates the group with Q. 2 Attachment point;

[0055] Q 1 and Q 2 Each is independently selected from single bonds, -Z-(CH2). n - or -CH=CH-, where Z is selected from the group consisting of free single bonds, O, S and NH, and the subscript n is from 1 to 3;

[0056] R 12 C6-C 10 aryl groups, which are optionally selected by one or more choices -OR 12a and -COOR 12b The group consists of substituents, where R is substituted. 12a and R 12bEach is independently H or C1-C6 alkyl;

[0057] R 6 R 7 and R 9 Each independently chooses H and R. b -OR b 、-SR b -NR b R c The group consisting of -NO2, -SnMe3 and halogenated compounds;

[0058] Where R b and R c Each is independently selected from C1-C6 alkyl groups, 4- to 10-membered heterocyclic groups, and C5-C6 alkyl groups. 20 A group consisting of aryl groups, each of which is optionally substituted;

[0059] R 10 and R 11 Each can independently choose H and -OR. 11a and-SO Z The group consists of M, where R 11a It is H or C1-C6 alkyl, the subscript Z is 2 or 3, and M is a pharmaceutically acceptable cation; or

[0060] R 10 and R 11 A nitrogen-carbon double bond is formed between the nitrogen atom and the carbon atom to which they are attached;

[0061] R” represents C3-C 12 Alkylenes, whose chains are optionally selected from one or more elements of O, S, and NR. N2 The heteroatom of the group is interrupted, where R N2 It is H or C1-C4 alkyl, and / or is C5-C 10 Aromatic group interruption;

[0062] Y and Y' each independently choose from the groups composed of O, S, and NH; and

[0063] R 6’ R 7’ R 9’ R 10’ and R 11’ Selected independently from R 6 R 7 and R 9 R 10 and R 11 Same group.

[0064] In some implementation schemes, in combination with the above or below implementation schemes, A is C6-C. 10Alpha-aryl and X is Where R N H and an asterisk indicate Q 2 The attachment point. In some implementations, in combination with the above or below implementations, Q 1 It is a single key. In some implementations, in combination with the above or below implementations, Q 2 It is a single key. In some implementations, in combination with the above or below implementations, R 12 To be optionally controlled by one or more -OR 12a Replacement C6-C 10 Aryl, wherein R 12a It is H or C1-C6 alkyl. In some embodiments, in combination with the above or below embodiments, R 12 The phenyl group is substituted with -OCH3. In some embodiments, in combination with the above or below embodiments, R 6 For H. In some implementations, in combination with the above or below implementations, R 9 For H. In some implementations, in combination with the above or below implementations, R 7 For -OR b , where R b It is a C1-C6 alkyl group. In some embodiments, in combination with the above or below embodiments, R 7 For -OCH3. In some implementations, in combination with the above or below implementations, R 10 and R 11 A nitrogen-carbon double bond is formed between the nitrogen atom and the carbon atom to which they are attached. In some embodiments, combining the above or below embodiments, R” is C3-C 12 Alkylene. In some embodiments, in combination with the above or below embodiments, R” is a C3 alkylene. In some embodiments, in combination with the above or below embodiments, Y is O. In some embodiments, in combination with the above or below embodiments, Y’ is O. In some embodiments, in combination with the above or below embodiments, R 6’ R 7’ R 9’ R 10’ and R 11’ Selected from R respectively 6 R 7 and R 9 R 10 and R 11 Same group.

[0065] In some embodiments, the active ingredient comprises a PBD dimer of formula (IA) or a pharmaceutically acceptable salt thereof:

[0066]

[0067] Among them, Y, Y', R”, R 6 R 6’ R 7 R 7’ R 9 R 9’ and R x As defined in equation (I).

[0068] In some embodiments, the active ingredient comprises a PBD dimer of formula (IB) or a pharmaceutically acceptable salt thereof:

[0069]

[0070] Y, Y', and R” are defined as in equation (I).

[0071] In some embodiments, the active ingredient comprises a PBD dimer of formula (IC) or a pharmaceutically acceptable salt thereof:

[0072]

[0073] Where n = 3 to 12. In some embodiments, n = 3. In some embodiments, n = 4. In some embodiments, n = 5. In some embodiments, n = 6. In some embodiments, n = 3. In some embodiments, n = 7. In some embodiments, n = 8. In some embodiments, n = 9. In some embodiments, n = 10. In some embodiments, n = 11. In some embodiments, n = 12.

[0074] In some embodiments, the composition comprises a PBD dimer of formula (ID) or a pharmaceutically acceptable salt thereof:

[0075]

[0076] Payload joint

[0077] In some embodiments, the active ingredient or payload is directly coupled to the dextran backbone. In some embodiments, the active ingredient is attached to the dextran backbone via a linker. The linker may be cleavable or non-cleavable. In some embodiments, one or more therapeutic agents are attached via a biodegradable linker. In some embodiments, the biodegradable linker is acid-sensitive, such as a hydrazone linker. The use of acid-sensitive linkers enables drug delivery into cells and allows for drug release substantially within the cell. In some embodiments, the payload linker is a Val-Cit linker.

[0078] The payload connector may contain a urethane group. In some embodiments, the payload connector comprises a urethane group and a chain portion, wherein the urethane group is linked to the main chain monomer and the chain portion is linked to the urethane group and the active component. In some embodiments, the chain portion of the payload connector comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) units selected from the group consisting of: optionally substituted alkylene chains, optionally substituted CO-alkylene chains, peptide chains, polymer chains, and heteroatoms selected from the group consisting of O atoms, S atoms, and optionally substituted N atoms. In some embodiments, the chain portion comprises C1-C 12 Alkylene chain. In some embodiments, the chain portion comprises a C3-C7 alkylene chain. In some embodiments, the chain portion comprises a C6 alkylene chain. In some embodiments, the chain portion is a C6 alkylene chain. In some embodiments, the alkylene chain is substituted by one or more substituents selected from the group consisting of: oxo, OH, NH2, SH, C1-C 12 Alkyl, C1-C 12 Haloalkyl, O(C1-C) 12 Alkyl), O(C1-C) 12 Halogenated alkyl groups), NH (C1-C 12 alkyl), NH (C1-C) 12 Halogenated alkyl), N(C1-C) 12 Alkyl)2, N(C1-C 12 (halogenated alkyl)2, S(C1-C 12 Alkyl), S(C1-C 12 Halogenated alkyl groups), C(O)OH, C(O)O(C1-C 12 Alkyl), C(O)O(C1-C 12 Halogenated alkyl groups), C(O)NH(C1-C 12 Alkyl), C(O)NH(C1-C 12 Halogenated alkyl groups), C(O)N(C1-C 12 Alkyl)2, C(O)N(C1-C 12 (halogenated alkyl)2, C(O)S(C1-C 12 Alkyl) and C(O)S(C1-C 12 (Halogenated alkyl). In some embodiments, the alkylene chain is unsubstituted.

[0079] In some embodiments, the molar ratio between the target fraction (e.g., mannose) and PBD toxin is about 1:10 to about 10:1. In some embodiments, the molar ratio between the target fraction and PBD toxin is at least about 1:10 (e.g., about 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, and 4:1). In some embodiments, the molar ratio between the target fraction and PBD toxin is about 1:1. In some embodiments, the molar ratio between the target fraction and PBD toxin is about 1:2. In some embodiments, the molar ratio between the target fraction and PBD toxin is about 1:3. In some embodiments, the molar ratio between the target fraction and PBD toxin is about 1:4.

[0080] In some implementations, the payload connector comprises -C(O)-C 1-12 alkylene chains and urethane groups, wherein the urethane groups are attached to the main chain monomer and are -C(O)-C 1-12 The alkylene chain connects the urethane group and the payload.

[0081] Secondary payload and connector

[0082] In addition to the payload, the compounds disclosed herein may also include secondary agents that can be coupled to the dextran backbone to add additional functional capabilities. Typically, the secondary payload is coupled to the adapter in any manner similar to that used to couple the targeting portion to the targeting adapter.

[0083] In some embodiments, the secondary payload facilitates targeted delivery of the compositions described herein to macrophages or cancer cells. In some embodiments, the secondary payload is a hydrophobic payload (e.g., topoisomerase inhibitor I, topoisomerase inhibitor II, or temozolomide). In some embodiments, the secondary payload is a hydrophilic payload.

[0084] Secondary payloads may encompass additional agents, for example, for imaging, therapy, or other purposes. Specifically, in one embodiment, a combination of therapeutic and imaging agents may be linked to the dextran backbone to combine diagnostic and therapeutic functionalities. In another embodiment, various amino acids, such as cysteine ​​or lysine, may be coupled to a linker to crosslink the molecule to the target.

[0085] Secondary payload adapters are cleavable or non-cleavable adapters that connect the dextran backbone to the secondary payload portion. Cleavable adapters can be cleaved by enzymes (e.g., proteases), temperature changes, pH changes, chemical stimuli, or any combination thereof. Cleavable adapters may contain protease cleavage sites. In some embodiments, cleavable adapters can be cleaved by lysosomal proteases or endosomal proteases.

[0086] The secondary payload linker may comprise a urethane group. In some embodiments, the secondary payload linker comprises a urethane group and a chain portion, wherein the urethane group is linked to the main chain monomer and the chain portion is linked to the urethane group and the secondary agent. Hereinafter, the urethane functional group is used with a simple and common meaning derived from the field of organic chemistry. In some embodiments, the chain portion of the secondary payload linker comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) units selected from the group consisting of: optionally substituted alkylene chains, optionally substituted CO-alkylene chains, peptide chains, polymer chains, and heteroatoms selected from the group consisting of O atoms, S atoms, and optionally substituted N atoms. In some embodiments, the chain portion comprises C1-C... 12 Alkylene chain. In some embodiments, the chain portion comprises a C3-C7 alkylene chain. In some embodiments, the chain portion comprises a C6 alkylene chain. In some embodiments, the chain portion is a C6 alkylene chain. In some embodiments, the alkylene chain is substituted by one or more substituents selected from the group consisting of: oxo, OH, NH2, SH, C1-C 12 Alkyl, C1-C 12 Haloalkyl, O(C1-C) 12 Alkyl), O(C1-C) 12 Halogenated alkyl groups), NH (C1-C 12 alkyl), NH (C1-C) 12 Halogenated alkyl), N(C1-C) 12 Alkyl)2, N(C1-C 12 (halogenated alkyl)2, S(C1-C 12 Alkyl), S(C1-C 12 Halogenated alkyl groups), C(O)OH, C(O)O(C1-C 12 Alkyl), C(O)O(C1-C 12 Halogenated alkyl groups), C(O)NH(C1-C 12 Alkyl), C(O)NH(C1-C 12 Halogenated alkyl groups), C(O)N(C1-C 12 Alkyl)2, C(O)N(C1-C 12 (halogenated alkyl)2, C(O)S(C1-C 12 Alkyl) and C(O)S(C1-C 12 (Halogenated alkyl). In some embodiments, the alkylene chain is unsubstituted.

[0087] In some implementations, one or more secondary payload portions are attached to the dextran backbone via connectors. The connectors may be attached to approximately 1% to approximately 50% of the backbone portion.

[0088] In some embodiments, the compositions described herein comprise a compound of formula (A-1) or a pharmaceutically acceptable salt thereof:

[0089]

[0090] In some embodiments, unless otherwise indicated, the monomers of type a, b, or c in the compound of formula (A-1) may be arranged as block copolymers or dispersed (e.g., randomly arranged) within the polymer or any combination thereof. In some embodiments, a, b, and c of formula (A-1) may each independently refer to an integer from 0, at least 1, about 1 to about 165, about 16 to about 111, about 50 to about 65, or about 6 to about 6. In some embodiments, the dextran backbone of formula (A-1) is linear, branched, cyclic, or a combination thereof. In some embodiments, the end groups of the dextran backbone of formula (A-1) may be hydroxyl end groups of monomers. In some embodiments, the end groups of the dextran backbone of formula (A-1) may be any end groups that are known to those skilled in the art.

[0091] In some embodiments, the dextran backbone of formula (A-1) is linear, branched, cyclic, or a combination thereof; a, b, and c are each independently selected from the group consisting of: an integer of 0, an integer of at least 1, an integer from about 1 to about 165, an integer from about 16 to about 111, an integer from about 50 to about 65, and an integer from about 6 to about 16; and the terminal group of the dextran backbone is a hydroxyl terminal group of the monomer. In some embodiments, the dextran backbone of formula (A-1) is cyclic, and a, b, and c are each independently selected from the group consisting of: an integer of 0, an integer of at least 1, an integer from about 1 to about 165, an integer from about 16 to about 111, an integer from about 50 to about 65, and an integer from about 6 to about 16. In some embodiments, the dextran backbone of formula (A-1) is linear; a, b, and c are each independently selected from the group consisting of: an integer of 0, an integer of at least 1, an integer of about 1 to about 165, an integer of about 16 to about 111, an integer of about 50 to about 65, and an integer of about 6 to about 16; and the terminal groups of the dextran backbone are hydroxyl groups of the monomer. In some embodiments, the dextran backbone of formula (A-1) is branched; a, b, and c are each independently selected from the group consisting of: an integer of 0, an integer of at least 1, an integer of about 1 to about 165, an integer of about 16 to about 111, an integer of about 50 to about 65, and an integer of about 6 to about 16; and the terminal groups of the dextran backbone are hydroxyl groups of the monomer.

[0092] In some embodiments, in conjunction with the above or below embodiments, the dextran backbone of formula (A-1) is about 6 kDa, wherein the dextran backbone is dextran anhydride. In some embodiments, in conjunction with the above or below embodiments, the a, b, and c groups of formula (A-1) are dispersed. In some embodiments, in conjunction with the above or below embodiments, the terminal groups of the dextran backbone are natural glucose terminal groups, such as hydroxyl terminal groups. In some embodiments, in conjunction with the above or below embodiments, the ratio of the targeting portion to the backbone monomer of formula (A-1) is about 1:30 to 1:40 (e.g., 1:33) or about 1:33 to 1:40 (e.g., 1:37). In some embodiments, in conjunction with the above or below embodiments, the ratio of PBD to mannose of formula (A-1) is about 1:1 to 1:3 (e.g., 1:1) or about 1:3 to 1:5 (e.g., 1:4).

[0093] In some embodiments, this document provides a compound of formula (A-1) wherein the dextran backbone is dextran anhydride; the molecular weight of the dextran backbone is about 6 kDa; a, b, and c groups are dispersed; the end groups of the dextran backbone are natural glucose end groups, such as hydroxyl end groups; the ratio of the targeting moiety to the backbone monomer is about 1:30 to 1:40 (e.g., 1:33); and the ratio of PBD to mannose is about 1:1 to 1:3 (e.g., 1:1).

[0094] In some embodiments, this document provides a compound of formula (A-1) wherein the dextran backbone is dextran anhydride; the molecular weight of the dextran backbone is about 6 kDa; a, c, and d groups are dispersed; the end groups of the dextran backbone are natural glucose end groups, such as hydroxyl end groups; the ratio of the targeting moiety to the backbone monomer is about 1:33 to 1:40 (e.g., 1:37); and the ratio of PBD to mannose is about 1:3 to 1:5 (e.g., 1:4).

[0095] In some embodiments, the compositions described herein comprise a compound of formula (A-2) or a pharmaceutically acceptable salt thereof:

[0096]

[0097] In some embodiments, unless otherwise indicated, the monomers of type a, b, or c in the compound of formula (A-2) may be arranged as block copolymers or dispersed (e.g., randomly arranged) within the polymer or any combination thereof. In some embodiments, a, b, and c of formula (A-2) may each independently refer to an integer from 0, at least 1, about 1 to about 165, about 16 to about 111, about 50 to about 65, or about 6 to about 6. In some embodiments, the dextran backbone of formula (A-2) is linear, branched, cyclic, or a combination thereof. In some embodiments, the end groups of the dextran backbone of formula (A-2) may be hydroxyl end groups of monomers. In some embodiments, the end groups of the dextran backbone of formula (A-2) may be any end groups that are known to those skilled in the art.

[0098] In some embodiments, the dextran backbone of formula (A-2) is linear, branched, cyclic, or a combination thereof; a, b, and c are each independently selected from the group consisting of: an integer of 0, an integer of at least 1, an integer from about 1 to about 165, an integer from about 16 to about 111, an integer from about 50 to about 65, and an integer from about 6 to about 16; and the terminal group of the dextran backbone is a hydroxyl terminal group of the monomer. In some embodiments, the dextran backbone of formula (A-2) is cyclic, and a, b, and c are each independently selected from the group consisting of: an integer of 0, an integer of at least 1, an integer from about 1 to about 165, an integer from about 16 to about 111, an integer from about 50 to about 65, and an integer from about 6 to about 16. In some embodiments, the dextran backbone of formula (A-2) is linear; a, b, and c are each independently selected from the group consisting of: an integer of 0, an integer of at least 1, an integer of about 1 to about 165, an integer of about 16 to about 111, an integer of about 50 to about 65, and an integer of about 6 to about 16; and the terminal groups of the dextran backbone are hydroxyl groups of the monomer. In some embodiments, the dextran backbone of formula (A-2) is branched; a, b, and c are each independently selected from the group consisting of: an integer of 0, an integer of at least 1, an integer of about 1 to about 165, an integer of about 16 to about 111, an integer of about 50 to about 65, and an integer of about 6 to about 16; and the terminal groups of the dextran backbone are hydroxyl groups of the monomer.

[0099] In some embodiments, in conjunction with the above or below embodiments, the dextran backbone of formula (A-2) is about 6 kDa, wherein the dextran backbone is dextran anhydride. In some embodiments, in conjunction with the above or below embodiments, the a, b, and c groups of formula (A-2) are dispersed. In some embodiments, in conjunction with the above or below embodiments, the terminal groups of the dextran backbone are natural glucose terminal groups, such as hydroxyl terminal groups. In some embodiments, in conjunction with the above or below embodiments, the ratio of the targeting portion to the backbone monomer of formula (A-2) is about 1:30 to 1:40 (e.g., 1:33) or about 1:33 to 1:40 (e.g., 1:37). In some embodiments, in conjunction with the above or below embodiments, the ratio of PBD to mannose in formula (A-2) is about 1:1 to 1:3 (e.g., 1:1) or about 1:3 to 1:5 (e.g., 1:4).

[0100] In some embodiments, this document provides compounds of formula (A-2) wherein the dextran backbone is dextran anhydride; the molecular weight of the dextran backbone is about 6 kDa; a, b, and c groups are dispersed; the end groups of the dextran backbone are natural glucose end groups, such as hydroxyl end groups; the ratio of the targeting moiety to the backbone monomer is about 1:30 to 1:40 (e.g., 1:33); and the ratio of PBD to mannose is about 1:1 to 1:3 (e.g., 1:1).

[0101] In some embodiments, this document provides compounds of formula (A-2) wherein the dextran backbone is dextran anhydride; the molecular weight of the dextran backbone is about 6 kDa; a, c, and d groups are dispersed; the end groups of the dextran backbone are natural glucose end groups, such as hydroxyl end groups; the ratio of the targeting moiety to the backbone monomer is about 1:33 to 1:40 (e.g., 1:37); and the ratio of PBD to mannose is about 1:3 to 1:5 (e.g., 1:4).

[0102] Treatment

[0103] The compositions disclosed herein may be used to treat cancerous or non-malignant tumors (e.g., meningioma, hemangioblastoma, or giant cell tumor) in subjects of need. Treatment comprises administering a therapeutically effective amount of the compositions disclosed herein to the subject. The compositions disclosed herein may also be used to treat granulomatous diseases (e.g., sarcoidosis) or chronic inflammatory conditions (e.g., rheumatoid arthritis) in subjects of need. The compositions disclosed herein may also be used to treat lysosomal storage diseases. For example, lysosomal storage diseases include, but are not limited to, cholesterol ester storage diseases, Wolman disease, Hunter syndrome, Hurler's disease, Fabry disease, Gaucher disease, Krabb disease (globose cell leukodystrophy), metachromatic leukodystrophy, Niemann-Pick disease, Sandhoff disease, Tay-Sachs disease, Batten disease, cystinosis, Danon disease, and Pompe disease. The compositions disclosed herein can also be used to treat macrophage-dependent diseases. In some embodiments, non-malignant tumors include, but are not limited to, meningiomas of all grades (e.g., grade 1, 2, or 3 meningiomas), schwannomas, schwannomatosis, neurofibromas, neurofibromatosis type 1 (NF1), or neurofibromatosis type 2 (NF2).

[0104] In some implementations, cancer can be any cell in the subject undergoing unregulated growth. Cancer can be any cancerous cell capable of metastasis. For example, cancer can be sarcoma, lymphoma, leukemia, carcinoma, blastoma, or germ cell tumor. In some implementations, cancer is selected from the group consisting of: carcinoma, lymphoma, blastoma, sarcoma, leukemia, malignant lymphoma, squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal carcinoma, hepatocellular carcinoma, gastric cancer, stomach cancer, gastrointestinal cancer, esophageal squamous cell carcinoma, hepatocellular carcinoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer (e.g., HR+ / HER2-). Breast cancer, HR- / HER2- breast cancer, HR+ / HER2+ breast cancer, HR- / HER2+ breast cancer, triple-negative breast cancer or inflammatory breast cancer), colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer or kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, head and neck cancer, Merkel cell carcinoma, multiple myeloma, acute myeloid leukemia (AML), hemangioblastoma, and schwannoma. In some implementations, non-malignant tumors are meningiomas, hemangioblastomas, or giant cell tumors.

[0105] Methods for treating or preventing diseases or conditions using the disclosed compositions are provided. The disclosed compositions can be used to target CD205 (DEC205), CD206, CD207 (Langrin), CD209 (DC-SIGN), CD280 (ENDO180), or CD301 (MGL) present on or near tumors. The disclosed compounds can be used to target macrophages to treat intracellular pathogens (Mycobacterium tuberculosis, F. tularensis, Salmonella typhi). The disclosed compounds can be used to target tumor-associated macrophages, for example, for the treatment of cancer. The compositions and methods described herein can be used for macrophage-related and other diseases associated with high expression of CD205 (DEC205), CD206, CD207 (Langrin), CD209 (DC-SIGN), CD280 (ENDO180), or CD301 (MGL), including but not limited to: acute disseminated encephalomyelitis (ADEM), Addison's disease. Autoimmune diseases, including agammaglobulinemia, allergic diseases, alopecia areata, Alzheimer's disease, amyotrophic lateral sclerosis, ankylosing spondylitis, antiphospholipid syndrome, antisynthetic enzyme syndrome, plaque disease, asthma, atherosclerosis, atopic allergy, atopic dermatitis, autoimmune aplastic anemia, autoimmune cardiomyopathy, autoimmune enteropathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune hypothyroidism, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune uveitis, Balo disease / Balo concentric sclerosis, Behcet's disease, Berger's disease, and Bickerstaff's encephalitis. encephalitis, Blau syndrome, bullous pemphigoid, Castleman's disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, chronic obstructive pulmonary disease, chronic venous stasis ulcer, Churg-Strauss syndrome, cicatricial pemphigoid, Cogan syndrome, cold agglutinin disease, complement component 2 deficiency, contact dermatitis, cranial arteritis, CREST syndrome, Crohn's diseaseDiseases including: Cushing's Syndrome, cutaneous leukocytoclastic vasculitis, Dego's disease, Dercum's disease, herpetic dermatitis, dermatomyositis, type I diabetes, type II diabetes, diffuse systemic sclerosis of the cutaneous body, Dressler's syndrome, drug-induced lupus, discoid lupus erythematosus, eczema, emphysema, endometriosis, enthesitis-associated arthritis, eosinophilic fasciitis, eosinophilic gastroenteritis, eosinophilic pneumonia, acquired epidermolysis bullosa, erythema nodosum, erythroblastosis of fetus, primary mixed cryoglobulinemia, Evan's syndrome, progressive ossifying fibrosis, fibrous alveolitis (or idiopathic pulmonary fibrosis), gastritis, gastrointestinal pemphigoid, Gaucher's disease. Diseases including glomerulonephritis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's encephalopathy, Hashimoto's thyroiditis, heart disease, Henoch-Schonlein purpura, herpes gestationis, hidradenitis suppurativa, histiocytosis, Hughes-Stovin syndrome, hypogammaglobulinemia, infectious diseases (including bacterial infectious diseases), idiopathic inflammatory demyelinating diseases, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, IgA nephropathy, inclusion body myositis, inflammatory arthritis, inflammatory bowel disease, inflammatory dementia, interstitial cystitis, interstitial pneumonia, juvenile idiopathic arthritis (also known as juvenile rheumatoid arthritis), and Kawasaki disease. Diseases including: Lambert-Eaton myasthenic syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, linear IgA disease (LAD), lupus-like hepatitis (also known as autoimmune hepatitis), lupus erythematosus, lymphomatoid granulomatosis, Majeed syndrome, malignancies including cancer (e.g., sarcoma, lymphoma, leukemia, carcinoma, and melanoma), Meniere's disease, microscopic polyangiitis, Miller-Fisher syndrome, mixed connective tissue diseases, morphine scleroderma, and Mucha-Habermann disease.Disease (also known as acute pityriasis lichenoides), multiple sclerosis, myasthenia gravis, myositis, somnambulism, neuromyelitis optica (also known as Devic's disease), neuromuscular rigidity, ocular cicatricial pemphigoid, oculoclonus-myoclonus syndrome, Ord's thyroiditis, recurrent rheumatic diseases, PANDAS (streptococcal-associated childhood autoimmune neuropsychiatric disorders), paraneoplastic cerebellar degeneration, Parkinsonian disorder, paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, Parsonage-Turner syndrome. syndromes, pars plana inflammation of the ciliary body, pemphigus vulgaris, peripheral arterial disease, pernicious anemia, peripheral encephalomyelitis, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive inflammatory neuropathy, psoriasis, psoriatic arthritis, pyoderma gangrenosa, pure red cell aplasia, Rasmussen's encephalitis, Raynaud's phenomenon, relapsing polychondritis, Reiter's syndrome, restenosis, restless legs syndrome, retroperitoneal fibrosis, rheumatoid arthritis, rheumatic fever, Rosai-Dorfman disease, sarcoidosis, schizophrenia, Schmidt syndrome, Schnitzler syndrome, scleritis, scleroderma, sepsis, serum sickness, Sjögren's syndrome Syndrome, spondyloarthritis, Still's disease (adult-onset), stiff person syndrome, stroke, subacute bacterial endocarditis (SBE), Susac's syndrome, Sweet's syndrome, Sydenham chorea, sympathetic ophthalmia, systemic lupus erythematosus, Takayasu'sarteritis, temporal arteritis (also known as "giant cell arteritis"), thrombocytopenia, Tolosa-Hunt syndromeSyndrome, transplant rejection (e.g., heart / lung transplant), transverse myelitis, tuberculosis, ulcerative colitis, undifferentiated connective tissue disease, undifferentiated spondyloarthritis, urticarial vasculitis, vasculitis, vitiligo, and Wegener's granulomatosis.

[0106] Those skilled in the art will know of the various molecules and compounds that can be delivered to cells or tissues using the disclosed compounds.

[0107] In one aspect, this article provides a method for treating tuberculosis, the method comprising administering a compound as described herein to a subject in need.

[0108] On the other hand, this article provides a method for treating macrophage-mediated conditions, the method comprising administering an effective amount of a compound as described herein to a subject in need; and detecting the marker at a predetermined location on the subject.

[0109] On the other hand, this article provides a method for treating macrophage-mediated conditions, the method comprising administering an effective amount of a compound as described herein to a subject in need.

[0110] On the other hand, this article provides a method for targeting tumor-associated macrophages, the method comprising administering an effective amount of a compound as described herein to a subject in need.

[0111] On the other hand, this document provides methods according to any of those described herein, wherein a connector is used to attach one or more target portions and one or more therapeutic agents.

[0112] On the other hand, this article provides methods according to any of those described herein, wherein the disease is rheumatoid arthritis.

[0113] On the other hand, this article provides methods according to any of those described herein, wherein the condition is cancer.

[0114] On the other hand, this article provides methods according to any of those described herein, wherein the cancer is sarcoma, lymphoma, leukemia, carcinoma, blastoma, melanoma, or germ cell tumor.

[0115] Combination therapy

[0116] In some embodiments, the compositions disclosed herein may be administered in combination with a second therapeutic agent. In some embodiments, the compositions disclosed herein are administered to a patient in combination with a second therapeutic agent, adjuvant therapy, or radiotherapy. In some embodiments, at least two compounds or compositions are administered to a patient simultaneously such that an effective amount or concentration of each of the two or more compounds is found in the patient at a given time point. Although the compositions according to this disclosure may be administered to a patient simultaneously, co-administration includes administering two or more agents at the same time or at different times, provided that an effective concentration of all co-administered compounds or compositions is found in the subject at a given time. In certain preferred aspects of this disclosure, one or more of the above-described compositions of the invention are co-administered in combination with at least one additional bioactive agent.

[0117] application

[0118] In some embodiments, the compositions described herein may be administered in single or separate unit doses via oral, parenteral, or topical routes. The range of administration for the compositions can range from continuous (intravenous infusion) to several oral doses per day (e.g., QID), and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include penetration enhancers), buccal, sublingual, and suppository administration, via inhalation spray, rectal, vaginal, or via implanted reservoir, and other routes of administration. The most effective dosage form will depend on the pharmacokinetics of the specific agent selected and the severity of the patient's disease.

[0119] The disclosed compositions can be administered by any suitable method. The disclosed compositions can be administered parenterally to the parenchyma or circulation, allowing the disclosed compounds to reach the target tissue (e.g., where cancer cells may be located). The disclosed compositions can be administered directly to or near a tumor mass. The disclosed compositions can be administered intravenously. In other embodiments, the disclosed compositions can be administered orally, intraperitoneally, intramuscularly, subcutaneously, intracavitarily, or transdermally.

[0120] If used, parenteral administration of the compound is typically characterized by injection. Injectable formulations can be prepared in conventional forms as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in a liquid prior to injection, or emulsions. Modified methods for parenteral administration involve the use of slow-release or sustained-release systems to maintain a constant dose.

[0121] preparation

[0122] In another aspect, this specification provides therapeutic or pharmaceutical compositions comprising an effective amount of the composition according to this disclosure, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient.

[0123] Typical formulations are prepared by mixing the compositions of this disclosure with excipients such as carriers and / or diluents. Suitable carriers, diluents, and other excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. The specific carrier, diluent, or other excipient used will depend on the means and purpose of applying the compound. Other pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts, or electrolytes such as lysozyme sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0124] The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, and other known additives.

[0125] Patients or subjects in need of therapy using the compositions according to this disclosure may be treated by administering an effective amount of the compositions according to this disclosure to the patient (subject). The compositions are contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient for the desired indication without causing serious toxicity in the treated patient. It should be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, time of administration, excretion rate, drug combination, as well as the judgment of the treating physician and the severity of the specific disease or condition being treated.

[0126] Reagent test kit

[0127] In some respects, kits for cancer treatment are provided. Such kits may include the compositions described herein.

[0128] In some embodiments, the kit may include instructions for use with any of the treatments described herein. The included instructions provide guidance on administering the pharmaceutical composition to a subject to achieve the intended activity (e.g., treating a subject's disease or condition, such as cancer). In some embodiments, the instructions for use with the pharmaceutical composition described herein may include information about the dosage, dosing regimen, and route of administration for the intended treatment. The container may be a unit dose, a bulk package (e.g., a multi-dose package), or a subunit dose. The instructions provided in the kits disclosed herein are typically written instructions on a label or packaging insert. The label or packaging insert indicates that the pharmaceutical composition is used to treat a subject's disease or condition, delay its onset, and / or alleviate said disease or condition.

[0129] In some embodiments, the kits provided herein are packaged appropriately. Appropriate packaging includes, but is not limited to, vials, bottles, cans, flexible packaging, etc. Packaging for use in combination with specific devices such as inhalers, nasal delivery devices, or infusion devices is also envisioned. In some embodiments, the kit may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper that can be punctured by a hypodermic needle).

[0130] In some implementations, the kits provided herein include additional therapeutic agents that can be used to treat cancers as described herein.

[0131] General synthesis methods

[0132] The compositions will now be described with reference to the illustrative synthetic schemes for the general preparation of the compositions disclosed herein and the subsequent specific examples. Those skilled in the art will recognize that, in order to obtain the various compositions described herein, starting materials may be suitably selected such that the final desired substituent will, as appropriate, complete the reaction scheme with or without protection to produce the desired product. Alternatively, instead of the final desired substituent, it may be necessary or desirable to employ suitable groups that complete the reaction scheme and, where appropriate, be replaced by the desired substituent. Furthermore, those skilled in the art will recognize that protecting groups can be used to protect certain functional groups (amino, carboxyl, or side-chain groups) from the effects of reaction conditions and, where appropriate, to remove such groups under standard conditions.

[0133] Chromatography, recrystallization, and other conventional separation procedures can also be used for intermediates or final products when it is desired to obtain a specific isomer of the compound or to purify the reaction product in other ways.

[0134] A general method for preparing the compositions described herein is depicted in the following exemplary methods.

[0135] In some embodiments, the compositions described herein may be synthesized according to a procedure as shown in Scheme A1.

[0136] Option A1

[0137]

[0138] Option A2

[0139]

[0140] As can be seen in the above schemes, a dextran compound (such as dextran or cyclodextrin) is reacted with an activator. The resulting activated dextran derivative can then be reacted with a suitable reagent to introduce a targeted portion coupled to the dextran backbone via a targeting linker, and an active component connected to the dextran backbone via a payload linker. Those skilled in the art will recognize that the above schemes are illustrative and that the order of the various reagents and synthetic steps can be varied as needed to obtain the desired final product. For example, a, b, and c can each independently refer to 0, at least 1, at least 1, about 1 to about 165, about 16 to about 111, about 50 to about 65, or about 6 to about 16. It should be understood that, unless otherwise indicated, monomers of the type labeled a, c, or c can be arranged in block copolymers or dispersed (e.g., randomly arranged) within the polymer or any combination thereof. It should also be understood that the dextran backbone in the above schemes can be linear, branched, cyclic, or a combination thereof. Any group not specified in the above scheme, such as any end group of the dextran backbone, can be any end group that is known to those skilled in the art. For example, the end group of the dextran backbone can be a hydroxyl end group of the monomer.

[0141] Example

[0142] The following examples are included for illustrative purposes only and are not intended to limit the scope of this disclosure.

[0143] Example 1. Synthesis of PBD dimer —NH2 (compound X-1)

[0144]

[0145] Model reaction: Coupling of aniline with the potential linker motif Fmoc-Val-Cit-PAB-PNP

[0146]

[0147] To test the feasibility of linking the PBD dimer to the potential linker Fmoc-Val-Cit-PAB-PNP and forming an active component-loaded linker moiety that can be used as a precursor for the compositions described herein, a model reaction was carried out according to scheme 1-0 and compound 4 was successfully synthesized. This clearly demonstrates the feasibility of coupling the aniline unit to the Fmoc-Val-Cit-PAB-PNP linker moiety.

[0148] Step 1. Synthesis of 4-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2-nitrobenzoic acid (compound A)

[0149]

[0150] As shown in Scheme 1-1, 4-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2-nitrobenzoic acid (compound A) is synthesized from compound 1.

[0151] Step 2. Synthesis of (3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-3-ol (compound B)

[0152]

[0153] As shown in Scheme 1-2, (3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-3-ol (compound B) is synthesized from compound 2. Specifically, steps 1, 2, and 3 of the four steps are further shown in Schemes 1-2-1, 1-2-2, and 1-2-3, respectively.

[0154]

[0155]

[0156] In step 1, as shown in Scheme 1-2-1, compound 2 was reacted with MeOH and H2SO4 in DCM at 40°C for 20 hours to give compound 5 (99.4 g, 94% yield). In step 2, as shown in Scheme 1-2-2, 5.00 g of LiCl (1.3 equivalents) and NaBH4 (1.3 equivalents) were mixed in THF / water and stirred at 17°C for 5 hours. Then, additional LiCl (0.6 equivalents) and NaBH4 (0.6 equivalents) were added and stirred at room temperature for 19 hours. After 19 hours, TLC showed no starting material and compound 6 (3.93 g, 87% yield) was formed. In step 3, compound 6 was mixed with TBDMSCl and Et3N and stirred in toluene at 60°C for 18 hours. Compound 7 was successfully synthesized.

[0157] Step 3. Synthesis of building block (compound C)

[0158]

[0159] The building blocks of the active component—NH2 (compound C)—are synthesized from compounds A and B. Specifically, steps 5 and 8 of the synthesis are shown in schemes 1-3-5 and 1-3-8, respectively.

[0160]

[0161]

[0162] In step 5, as shown in Scheme 1-3-5, compound 23 was reacted with PTSA in THF / water at room temperature for 1 day to form compound 24 (6.60 g, 68% yield). In step 8, compound 26 was mixed with Tf₂O (9.0 equivalents) and pyridine (11.0 equivalents) at room temperature and stirred for 6 hours. After 6 hours, compound C (18 mg, 25% yield) was successfully synthesized.

[0163] Step 4. Synthesis of compound D and PBD dimer —NH2

[0164]

[0165] Starting with compound C, compound D was synthesized. By combining compounds C and D, the PBD dimer —NH2 (compound X-1) was successfully synthesized.

[0166] Example 2. Synthesis of the compound of formula (A-1)

[0167]

[0168] Step 1. (11S,11aS)-11-acetoxy-8-(3-bromopropoxy)-7-methoxy-2-(4-methoxyphenyl)-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diaza Synthesis of 2,2,2-trichloroethyl 10(5H)-formic acid (compound 40)

[0169]

[0170] As shown in Scheme 2-1, compound 31 was mixed with 1,3-dibromopropane (compound 39) and K2CO3, and the mixture was stirred in acetone. Compound 40 was successfully obtained.

[0171] Step 2. Synthesis of Compound 63

[0172]

[0173] As shown in Scheme 2-2, compound 47 was mixed with LiOAc and the mixture was stirred in DMF / water. Compound 63 was successfully obtained.

[0174] Step 3. Synthesis of Compound 64

[0175]

[0176] As shown in Scheme 2-3, compounds 40 and 63 were mixed with K2CO3 and stirred in acetone. Compound 64 was successfully obtained.

[0177] Step 4. Synthesis of Compound 65

[0178]

[0179] As shown in schemes 2-4, the -NHBoc group in the linker portion was successfully deprotected. Compound 64 was then reacted with TFA and DCM to successfully obtain compound 65.

[0180] Step 5. Synthesis of protected PBD dimer with protected connector (compound 51)

[0181]

[0182] As shown in schemes 2-5, compound 65 was reacted with Fmoc-Val-Cit-PNP, DIPEA and DMF to successfully obtain compound 51 (32 mg, 78% yield).

[0183] Step 6. Synthesis of protected PBD dimer (compound X-2) with deprotected joints

[0184]

[0185] As shown in Scheme 2-6, compound 51 was mixed with piperidine in DMF to successfully obtain compound (X-2) (7 mg, 79% yield).

[0186] Step 7. Link compound (X-2) to the main chain.

[0187]

[0188] Following scheme 2-7, the as-synthesized compound (X-2) was first reacted with the dextran backbone in DIPEA, HOBt, DMSO, and pyridine at room temperature for 90 min. Then, the targeting moiety—the targeting linker (compound 4)—was added to the reaction mixture, and the mixture was stirred at room temperature for 20 h. 15 mg of compound 69 was successfully obtained. As-synthesized compound 69 possessed 3 mol% PBD dimer and 12 mol% mannose.

[0189] Step 8. Synthesis of the compound of formula (A-1)

[0190]

[0191] First, a precursor of the compound of formula (A-1) (compound 69) was synthesized from compound (X-2) according to scheme A-1. Then, compound 69 was reacted with Zn, AcOH and DMSO to give the compound of formula (A-1) (9 mg). As determined by NMR, the synthesized compound of formula (A-1) has ~3 mol% PBD dimer and ~12 mol% mannose.

[0192] Example 3. Synthesis of the compound of formula (A-2)

[0193]

[0194] Compound (A-2) was synthesized using a procedure similar to that used for compound (A-1), but with an inexcised linker. Following steps 1-4 of Example 2, compound 65 was obtained, which is a precursor to the active component-loaded linker portion of the compound (A-2). Compound 65 was then attached to the main chain as shown in Scheme A-1. After attachment, the protecting groups on the PBD dimer were removed following a procedure similar to step 8 of Example 2. Compound (A-2) was obtained.

[0195] Example 4. Selectivity and toxicity of compounds of formula (A-1) and (A-2) to mouse macrophages

[0196] The selectivity and toxicity of the synthesized compounds of formula (A-1) and (A-2) to mouse macrophages were tested. Poly-L-lysine-coated 6-well plates (all wells) were prepared by adding 2 mL of sterile water to each well, followed by 20 μl of poly-L-lysine stock solution (1 mg / mL), mixing, and incubating the wells at 37°C for 1 hour or overnight. Complete culture medium was prepared by thawing MaGS, FBS, and P / S (Sciencell) at 37°C and adding them all to macrophage medium (MaM) when the MaGS was completely dissolved. The wells were rinsed with sterile water (2×) and 3 mL of complete culture medium was added to each well. The cells were completely thawed and resuspended in a 37°C water bath, and 150 μL of macrophages were added to each well and gently dispersed by shaking. The cells were allowed to settle and adhere to the wells for at least 16 hours before the culture medium was replaced.

[0197] Once cells adhered, for M1 differentiation, LPS (6.25 μl of 500x stock solution) + 50 ng / ml mouse IFN-γ (1.5 μl of 100 μg / ml stock solution) was added; and for M2 differentiation, 10 ng / ml IL-4 (0.3 μl of 0.1 mg / ml stock solution) + 10 ng / ml IL-13 (0.3 μl of 0.1 mg / ml stock solution) was added. After 3 days, cells were separated from the culture dish using 0.05% trypsin at 37°C for less than 10 min. The mixture was collected for staining (centrifuged and resuspended in 100 μl of staining buffer). Separation was achieved using macrophage separation solution promo cell C-41330 (>1 hour for separation). The recommended CD206 staining concentration was 10 μL / 10 6 Cells were used, and 2 μL was used for this experiment. Cells were from Sciencel catalog number: M1920-57, and all cell conditions and differentiation protocols were followed according to the manufacturer's instructions. Polarization was performed using bone marrow-derived cells. M1 differentiation was achieved by 1×LPS and 50 ng / mL mouse IFN-γ. M2 differentiation was achieved by 10 ng / mL IL-4 and 10 ng / mL IL-13. The differentiation process took three days, followed by 48 hours, and cells were treated with compounds of formula (A-1) and (A-2) and a 3 μM astrococcal toxicity control, followed by CellTier Flo viability readout (Spectramax).

[0198] Images of mouse M1 and M2 morphology are respectively in Figure 1 and Figure 2 The results of treating mouse cells with the compound of formula (A-1) are summarized in [the table / reference]. Figure 3 , Figure 4 And in Table 4-1. The results of treating mouse cells with the compound of formula (A-2) are summarized in Table 4-1. Figure 5 , Figure 6 As shown in Table 4-2, and as seen in Table 4-1, M2 macrophages were 4 times more sensitive to A1 cytotoxicity than M1 macrophages and 7 times more sensitive than 3T3 cells. This is consistent with the fact that M2 macrophages expressed higher levels of CD206 (the A1-targeting receptor) than M1 macrophages, and that 3T3 cells did not express the A1 target. This result is consistent with the higher uptake by M2 cells at lower A1 concentrations. The IC50 results in Table 4-2 indicate that none of the three cell types were strongly affected by A2, suggesting that the cleavable adaptor confers greater biological activity on both dividing and non-dividing cells.

[0199] Table 4-1

[0200] M1 M2 3T3 Lowest vitality (%) 4.614 4.007 2.388 Highest vitality (%) 110.2 93.64 105.7 <![CDATA[IC 50 (mM)]]> 0.8641 0.2020 1.439 Hill slope -2.054 -0.8116 -3.857

[0201] Table 4-2

[0202] M1 M2 3T3 Lowest vitality (%) -2.971 -4.027 9.489 Highest vitality (%) 116 115.8 109.7 <![CDATA[IC 50 (mM)]]> 1.055 2.131 1.946 Hill slope -2.054 -0.8116 -3.857

[0203] Example 5. Maximum tolerated dose (MTD) of TA in CD-1 mice after IV administration of the compound of formula (A-1).

[0204] The maximum tolerated dose of formula (A-1) was examined in CD-1 mice. Twenty-five (25) female CD-1 mice were randomly divided into five groups and all animals were monitored for up to day 7. After day 7, the animals were weighed and assigned to treatment groups based on their weight using a randomization procedure. The start date for randomization and administration of treatment was designated as day 0. The compound of formula (A-1) was administered to mice by a single slow IV bolus at doses of 0.3 mg / kg (G1); 1.0 mg / kg (G2); 3.0 mg / kg (G3); 10.0 mg / kg (G4); or 30.0 mg / kg (G5). Animals were closely monitored after administration. The weight and food intake of all mice were monitored and recorded for seven days. On day 7, the mice were euthanized and autopsied. Serum was collected from all mice for clinical chemistry and whole blood for hematology.

[0205] Figure 7A and 7B The changes in weight and the percentage of weight change are shown for all five treatment groups. Figure 7A Studies B showed that animals in all groups experienced a weight loss of less than 5%, and their weight gradually recovered over 7 days. Similarly, Figure 8 The study shows minor differences in food intake among the five treatment groups. During the gross autopsy performed on day 7, all organs were observed to be normal.

[0206] Analysis of blood hematology and serum clinical chemistry results did not show any significant differences between all groups. Figure 9A-9L The results showed that no treatment group exhibited any differences in hematological parameters. Similarly, Figure 10A-10T The results showed no difference in serum components between the treatment groups.

[0207] These data indicate that the compound of formula (A-1) is tolerable in the range of 0.3 mg / kg to 30 mg / kg. The maximum tolerated dose of formula (A-1) in CD-1 mice was not defined in this study. Treatment of mice in a mouse tumor model at a dose of at least 30 mg / kg up to once weekly is anticipated.

[0208] Example 6. In vivo anticancer efficacy of the compound of formula (A-1)

[0209] The initial anticancer efficacy of the compound of formula (A-1) was examined in a PDX myxofibrosarcoma model. Twenty (20) male PDX mice were randomly assigned to three different treatment groups based on tumor size and were administered saline, doxorubicin, or formula (A-1). Mice were administered the corresponding treatment intravenously at a concentration of 1 mg / kg once weekly for three weeks, for a total of three doses (days 0, 7, and 14). Figure 11 The tumor volume observed in mice treated with formula (A-1) was comparable to that in mice treated with doxorubicin. Both mice treated with formula (A-1) and mice treated with doxorubicin experienced lower tumor burden compared to mice treated with saline.

Claims

1. A composition comprising: i) Targeting of tumor-associated macrophages; ii) a dextran backbone, wherein the dextran backbone comprises multiple backbone monomers; iii) Contains pyrrolobenzodiazepines The active component of the (PBD) dimer, wherein the active component is coupled to the dextran backbone; and iv) Connect the targeting portion to a targeting connector of the dextran backbone, wherein the targeting connector comprises a carbamate group and a chain portion, and wherein the carbamate group is connected to the backbone monomer and the chain portion connects the carbamate group and the tumor-associated macrophage targeting portion.

2. The composition of claim 1, wherein the PBD dimer is a compound of formula (I): in: A is C6-C 10 Alpha-aryl and X-selection freedom and The group formed where R N Choose from the group consisting of H and C1-C4 alkyl groups; and the asterisk indicates the group with Q. 2 Attachment point; Q 1 and Q 2 Each is independently selected from single bonds, -Z-(CH2). n - or -CH=CH-, where Z is selected from the group consisting of free single bonds, O, S and NH, and the subscript n is from 1 to 3; R 12 For C6-C 10 aryl, which is optionally selected by one or more choices -OR 12a and -COOR 12b The group consists of substituents, where R is substituted. 12a and R 12b Each is independently H or C1-C6 alkyl; R 6 、R 7 and R 9 Each independently chooses H and R. b 、-OR b -SR b -NR b R c The group consisting of -NO2, -SnMe3 and halogenated compounds; Where R b and R c Each is independently selected from C1-C6 alkyl groups, 4- to 10-membered heterocyclic groups, and C5-C6 alkyl groups. 20 A group consisting of aryl groups, each of which is optionally substituted; R 10 and R 11 Each can independently choose H and -OR. 11a and-SO Z The group consists of M, where R 11a It is H or C1-C6 alkyl, the subscript Z is 2 or 3, and M is a pharmaceutically acceptable cation; or R 10 and R 11 A nitrogen-carbon double bond is formed between the nitrogen atom and the carbon atom to which they are attached; R” represents C3-C 12 Alkylenes, whose chains are optionally selected from one or more elements of O, S, and NR. N2 The heteroatom of the group is interrupted, where R N2 It is H or C1-C4 alkyl, and / or is C5-C 10 Aromatic group interruption; Y and Y' each independently choose from the groups composed of O, S, and NH; and R 6’ R 7’ R 9’ R 10’ and R 11’ Selected from R respectively 6 R 7 and R 9 R 10 and R 11 Same group.

3. The composition of claim 1 or 2, wherein the plurality of main chain monomers comprises a plurality of D-glucose monomers in an α-1,6 glycosidic bond or a β-1,4 glycosidic bond.

4. The composition of claim 3, wherein the plurality of D-glucose monomers is n, wherein n = 16 to 111.

5. The composition of claim 3 or 4, wherein the plurality of D-glucose monomers is n, wherein n = 50 to 65.

6. The composition according to any one of claims 1 to 5, wherein the dextran backbone is a linear dextran molecule.

7. The composition according to any one of claims 1 to 5, wherein the dextran backbone is a cyclodextrin molecule, wherein n = 6 to 16.

8. The composition of any one of claims 1 to 7, wherein the tumor-associated macrophage targeting portion comprises mannose, galactose, collagen, fucose, sulfated N-acetylgalactosamine, N-acetylglucosamine, luteinizing hormone, thyroid-stimulating hormone, phospholipase A2 or a fragment thereof, or chondroitin sulfate.

9. The composition of any one of claims 1 to 8, wherein the targeted portion is mannose.

10. The composition of claim 9, wherein the ratio of mannose to main-chain monomer is about 1:5 to about 1:

25.

11. The composition of claim 9 or 10, wherein the ratio of mannose to main-chain monomer is about 1:6 to about 1:

19.

12. The composition according to any one of claims 1 to 8, wherein the degree of substitution of mannose on the cyclodextrin is in the range of about 0.1 to about 7.

13. The composition according to any one of claims 1 to 9 or 12, wherein the degree of substitution of mannose on the cyclodextrin is in the range of about 0.5 to 5.

14. The composition of any one of claims 1 to 13, wherein the targeting connector is connected to the dextran backbone via the oxygen atom of the urethane group.

15. The composition of any one of claims 1 to 14, wherein the chain portion of the target connector comprises a C3-C7 alkylene chain.

16. The composition of any one of claims 1 to 15, wherein the chain portion of the target connector comprises a C6-alkylene moiety.

17. The composition of any one of claims 1 to 16, wherein the chain portion of the target connector is an unsubstituted C6-alkylene portion.

18. The composition of any one of claims 1 to 17, wherein when the connector is attached to mannose, the carbon atom of the carbamate group of the targeting connector is a unique sp2 hybrid carbon.

19. The composition of any one of claims 1 to 18, wherein the tumor-associated macrophage targeting portion is a portion that targets CD205 (DEC205), CD206, CD207 (Langrin protein), CD209 (DC-SIGN), CD280 (ENDO180), or CD301 (MGL).

20. The compound of claim 19, wherein the tumor-associated macrophage targeting portion is a CD206 targeting portion.

21. The composition of any one of claims 1 to 20, wherein the molar ratio between the TAM-targeting portion of the composition and the PBD toxin is about 1:1 to about 1:

10.

22. The composition of any one of claims 1 to 20, wherein the molar ratio between the TAM targeting portion and the PBD toxin is about 1:1, about 1:2, or about 1:

3.

23. The composition of claim 1, wherein the active component is coupled to the dextran backbone via a load cell.

24. The composition of claim 23, wherein the payload connector is an uncuttable connector.

25. The composition of claim 24, wherein the payload connector comprises a urethane group and a chain portion, wherein the urethane group is connected to the main chain monomer and the chain portion connects the urethane group and the active component.

26. The composition of claim 23, wherein the payload connector is a cuttable connector.

27. The composition of claim 26, wherein the cleavable connector is capable of being cleaved by a protease.

28. The composition of claim 27, wherein the protease is a lysosomal protease or an endosomal protease.

29. The composition of claim 26, wherein the cuttable connector is capable of being cut due to pH changes.

30. The composition of claim 26, wherein the payload connector comprises a Val-Cit portion.

31. A compound of formula (A-1):

32. A compound of formula (A-2):

33. A method of delivering a drug to tumor-associated macrophages, the method comprising contacting the macrophages with a composition as described in any one of claims 1 to 30 or a compound as described in claim 31 or 32.

34. A method of treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the composition of any one of claims 1 to 30 or the compound of claim 31 or 32.

35. The method of claim 34, wherein the cancer is selected from the group consisting of: carcinoma, lymphoma, blastoma, sarcoma, leukemia, malignant tumors of the lymphatic system, squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal carcinoma, hepatocellular carcinoma, gastric cancer or stomach cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer or kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, and head and neck cancer.

36. The method of claim 34 or 35, wherein the cancer is a sarcoma or glioblastoma.

37. The method of any one of claims 34 to 36, wherein the cancer is a soft tissue sarcoma.

38. A method of treating a non-malignant tumor in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the composition of any one of claims 1 to 30 or the compound of claim 31 or 32.

39. The method of claim 38, wherein the non-malignant tumor is a meningioma, hemangioblastoma, or giant cell tumor.

40. The method of any one of claims 34 to 37, wherein the subject is administered a second therapeutic agent, adjunctive therapy, or radiotherapy.

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