Stereocomplexes for the delivery of anticancer drugs

Abstract

To provide stereocomplexes for delivery of one or more anticancer agents.SOLUTION: Disclosed herein are stereocomplexes for the delivery of one or more anti-cancer agents. The stereocomplexes exhibit low toxicity and are biodegradable while also providing for controlled release of one or more anti-cancer agents at tumor sites. The stereocomplexes can be designed such that the anti-cancer agents operate synergistically and may optionally include additional targeting groups and functionalities. The stereocomplexes disclosed herein can be combined with pharmaceutically-acceptable carriers and / or excipients to form pharmaceutical compositions. By varying the amount of each anti-cancer agent in the stereocomplex, specific types of tumors and cancer cell lines can be treated.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 775,076, filed December 4, 2018, and U.S. Provisional Patent Application No. 62 / 893,863, filed August 30, 2019, which applications are incorporated herein by reference in their entireties. [Background technology]

[0002] background The delivery of hydrophobic drugs to the appropriate tissues in the body has long been a challenge for medical researchers, who must minimize toxicity while maximizing biocompatibility. An ideal delivery vehicle avoids premature release of its cargo, thereby delivering a higher dose of drug to the effective site. Furthermore, to maximize treatment of the target area and avoid systemic effects, it is highly desirable to avoid affecting non-target tissues. This is particularly a concern in cancer research, where many anti-cancer chemotherapeutic agents are hydrophobic and may have toxic side effects. Chemotherapeutic agents, especially those with low molecular weights, may enter all types of cells by random diffusion, which reduces their availability at the tumor site and also leads to systemic side effects. Random diffusion may also result in rapid cellular uptake rather than prolonged therapeutic effect. Finally, drugs can be rapidly removed from the bloodstream by filtration through the kidneys.

[0003] Furthermore, personalized cancer treatment is becoming increasingly possible.Using this approach, chemotherapeutic agents or combinations of chemotherapeutic agents can be selected to treat specific tumors of interest more effectively than general chemotherapy treatments.Ideally, chemotherapeutic agents can be selected based on tests such as biopsy, cell culture and sensitivity assay, rather than carrying out expensive genetic tumor profiling.

[0004] Furthermore, in some cases, it may be clinically desirable to simultaneously treat cancer patients with more than one chemotherapeutic agent.However, individual chemotherapeutic agents often exhibit toxic side effects, and the combined side effects of two or more chemotherapeutic agents may be intolerable to patients.

[0005] Currently, drug polymer conjugates have attracted much attention due to their desirable properties, including low toxicity and local delivery, in treating various forms of cancer.Although many drug polymer conjugates have been successfully tested, tumor cells often develop resistance to single-drug therapy.Combination therapies using drug polymer conjugates have been developed, but most of these have not yet been extensively tested in vivo.

[0006] What is needed is a method for treating cancer or reducing tumor size in a subject, which minimizes toxicity and is biocompatible, and provides targeted delivery of anticancer drugs to tumor cells by drug polymer conjugates or similar means without adversely affecting surrounding tissue, and shows sustained release rate control for anticancer drugs, and allows the synergistic combination of two or more anticancer drugs without simultaneously increasing side effects.Ideally, this method can also be customized for each individual patient. Summary of the Invention [Means for solving the problem]

[0007] overview Disclosed herein are stereocomplexes for the delivery of one or more anticancer drugs. The stereocomplexes also achieve controlled release of one or more anticancer drugs at tumor sites while exhibiting low toxicity and being biodegradable. The stereocomplexes can be designed so that the anticancer drugs act synergistically, and may optionally contain additional targeting and functional groups. The stereocomplexes disclosed herein can be combined with pharmaceutically acceptable carriers and / or excipients to form pharmaceutical compositions. By varying the amount of each anticancer drug in the stereocomplex, specific types of tumors and cancer cell lines can be treated.

[0008] The advantages of the materials, methods, and devices described herein are set forth in part in the description which follows or may be learned by the practice of the embodiments described hereinafter. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive.

[0009] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several aspects described below. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 shows a schematic diagram of the stereocomplexes disclosed herein containing two different drugs based on the stereocomplex formation between PLLA and PDLA.

[0011] [Figure 2]Figure 2 shows a schematic diagram of a polymer-conjugated drug (PCD) for stereocomplex formation. In panel (a), the hydrophilic element protrudes into the solution, while the hydrophobic element is located in the particle core of the stereocomplex. In panel (b), examples of anticancer drugs conjugated to a hydrophobic moiety with a cleavable linker are shown. In one example form, mertansine (DM1) is conjugated using a disulfide bond, while docetaxel (DTX) is conjugated using a hydrazone bond (Linker 1), a disulfide bond (Linker 2), or an ester bond (Linker 3).

[0012] [Figure 3] Figure 3 shows the structures of cRGD-PEG-PDLA, FA-PEG-PLLA and methyl-α-glucose-PEG-PDLA.

[0013] [Figure 4] Figure 4 shows the synthetic scheme for producing mPEG-PDLA-SS-DM1.

[0014] [Figure 5] Figure 5 shows the H NMR of mPEG-PDLA-SS-DM1 in DMSO-d6. The lettered peaks correspond to the same letters in the inset structure; a: -CH- of PDLA; b and c: -CH of DM1.

[0015] [Figure 6] FIG. 6 shows the synthetic scheme for producing mPEG-PLLA-hydrazone-DTX.

[0016] [Figure 7] Figure 7 shows the H NMR of mPEG-PLLA-hydrazone-DTX in DMSO-d. The lettered peaks correspond to the same letters in the inset structure; a: -NH- for DTX-hydrazone-OH; e: -CH- for PLLA.

[0017] [Figure 8] Figure 8 shows the H NMR of mPEG-PLLA-ester-DTX in CDCl. Lettered peaks correspond to the same letters in the inset structure; c and d: -CH for DTX; e: -CH for PLLA.

[0018] [Figure 9] FIG. 9 shows the synthetic scheme for producing mPEG-PLLA-SS-DTX.

[0019] [Figure 10] Figure 10 shows the H NMR of cRGD-amide-PEG-PDLA in DMSO-d. The lettered peaks correspond to the same letters in the inset structure: a: =CH- of cRGD; b: -CH- of cRGD; c: -CH- of PDLA.

[0020] [Figure 11] Figure 11 shows the H NMR of folate-amide-PEG-PLLA in DMSO-d. The lettered peaks correspond to the same letters in the inset structure: a: =CH- for folate; b: -CH- for folate; c: -CH- for PDLA.

[0021] [Figure 12] Figure 12 shows the H NMR of methyl-α-glucose-PEG-PDLA in CDCl. The lettered peaks correspond to the same letters in the inset structure: a: -CH- of PDLA; b: -CH- of PEG; c: -CH of glucose.

[0022] [Figure 13]Figure 13 shows the combination index (CI, displayed on the vertical axis) of free DM1 and DTX in various cell lines at various ratios of DM1 to DTX. CI is used to quantitatively determine synergy between two combined drugs. Synergy is represented by a CI < 1, an additive effect occurs when CI = 1, and antagonism occurs when CI > 1. The cell lines include A549 (human alveolar basal epithelial adenocarcinoma cells; red circles), NCI-H460 (non-small cell lung cancer cells; black squares), MiA PaCa-2 (pancreatic cancer cells; blue triangles), SGC-7901 (gastric cancer cells; teal triangles), and Hep3B2.1-7 (liver cancer cells; pink triangles).

[0023] [Figure 14] Figure 14A shows the particle sizes of the prodrugs mPEG-PDLA-SS-DM1 (D-DM1) and mPEG-PLLA-hydrazone-DTX (L-DTX). Figure 14B shows the particle sizes of the complexes produced by dialysis (left panel) and after lyophilization and reconstitution (right panel). Figure 14C shows the particle sizes of the complexes produced by rotary evaporation (left panel) and after lyophilization and reconstitution (right panel).

[0024] [Figure 15] Figures 15A-15B show DSC results evaluating the melting temperature (Tm) of various formulations. Figure 15A shows the free DM1 powder (triangles), lyophilized powders of mPEG-PDLA-SS-DM1 (circles), and lyophilized powders of mPEG-PDLA (squares). Figure 15B shows the lyophilized powders of mPEG-PLLA-hydrazone-DTX (squares), mPEG-PDLA-SS-DM1 (circles), and the lyophilized powders of the complex formed from the two previously mentioned polymers (triangles).

[0025] [Figure 16]Figures 16A-16B show the release of drug from the complex over time. Figure 16A is a graph showing the release of docetaxel from the complex over time at pH 7.4 (squares) and pH 5.5 (circles). This difference is due to the pH sensitivity of the hydrazone linker. Figure 16B shows the release of DM1 over time from prodrug D-DM1 formulations and complexes with and without glutathione (GSH) at pH 7.4. The complexes provide significantly slower release than the GSH-containing prodrugs (circles and squares, respectively), while the DM1 conjugates with redox-sensitive disulfide linkers prevent the premature release of the GSH-free DM1 (complexes are represented by inverted triangles, and prodrugs are represented by triangles overlapping the inverted triangles).

[0026] [Figure 17] Figure 17A shows the tolerability of various formulations in tumor-free mice with injections given on days 1, 8, 15, and 22. Figure 17B shows the weight change of tumor-free mice over 3 weeks after injection of the complex at 3.6 mg / kg DM1 once a week for three injections, 5 mg / kg DM1 once every two weeks for two injections, and 7 mg / kg DM1 once a week for only one injection, respectively.

[0027] [Figure 18]Figures 18A-18D show the in vivo antitumor efficacy of the complex in a subcutaneous BGC-823 (gastric) tumor model administered intravenously. A human gastric cancer cell suspension was injected subcutaneously into the back of mice to establish the tumor model. When tumor volumes reached approximately 60 mm, groups of tumor-bearing mice (n=5) were injected with the stereocomplex via the tail vein on the days indicated by the arrows in panel (a) (i.e., days 1, 8, and 15, at doses of 4 mg / kg DM1 and 36 mg / kg DTX per injection). Figure 18A shows tumor size measurements for the control group (squares) and the treated group (circles). No significant weight loss was observed in the treated or control groups (Figure 18B). Significant tumor reduction was achieved in the complex-treated group (resected tumors are shown in Figure 18C), and a greater overall reduction in tumor weight was achieved in the stereocomplex-treated group (Figure 18D).

[0028] [Figure 19] Figures 19A-19B show the in vivo antitumor efficacy of the complex in a subcutaneous MIA PaCa-2 (pancreatic) tumor model via intravenous injection. A cell suspension was injected subcutaneously into the back of mice to establish the tumor model. When tumor volumes reached approximately 140 mm, groups of tumor-bearing mice (n=5) were injected with the complex via the tail vein once every two weeks. After two injections (i.e., on days 1 and 14 at doses of 5 mg / kg DM1 and 40 mg / kg DTX per injection), one mouse was tumor-free on day 24, and a total of three mice were tumor-free by day 38. Figure 19A shows the tumor size change for the complex-treated group (circles) versus the control group (squares). Figure 19B shows control mice (top row of photographs) and treated mice (bottom row of photographs) on day 29 of the study.

[0029] [Figure 20]Figures 20A-20B show a comparison of in vivo antitumor efficacy and toxicity between the complex and the prodrug in subcutaneous MIA PaCa-2 tumors when the treatment was delivered by intravenous injection. A cell suspension was injected subcutaneously into the back of mice to establish the tumor model. When tumor volumes reached approximately 140 mm, groups of tumor-bearing mice (n=5) were injected with the complex via the tail vein. Similar antitumor effects were observed after four injections of the D-DM1 prodrug and two injections of the complex (circles and triangles, respectively, in Figure 20A). However, prodrug treatment induced mouse death and significant weight loss (Figure 20B, circles), whereas the complex-treated group showed weight gain during the treatment period (Figure 20B, triangles).

[0030] [Figure 21] Figures 21A-21D show a comparison of in vivo antitumor efficacy and toxicity between the complex and a control (no complex administration) in a subcutaneous Hep 3B2.1-7 (liver) tumor model when treatment was delivered by intravenous injection. A cell suspension was injected subcutaneously into the back of the mouse to establish the tumor model. When tumor volumes reached approximately 130 mm, groups of tumor-bearing mice (n=5) were injected with the complex via the tail vein. Figure 21A shows that tumor volume continued to grow in the control group (squares) but decreased in the complex-treated group (circles). Figure 21B shows that body weight in the complex-treated group remained approximately the same throughout the study (circles), whereas it decreased significantly in the control group (squares). Figure 21C shows tumors excised from the control group (top row) and the complex group (bottom row), and Figure 21D shows a comparison of tumor weight between the control group (left bar) and the complex group (right bar).

[0031] [Figure 22]Figures 22A-22D show tumor size changes in the complex-treated group versus the control group in a subcutaneous HT-29 (colon) tumor model. A cell suspension was injected subcutaneously into the back of the mouse to establish the tumor model. When tumors reached approximately 100 mm, groups of tumor-bearing mice (n=5) were injected with the composition via the tail vein. Figure 22A shows that untreated mice (squares) showed a more significant increase in tumor volume, while mice treated with the complex (circles) showed smaller final tumor volumes (arrows indicate the injection date). Figure 22B shows the weight changes in the control and treatment groups. Figure 22C shows excised tumors from the control group (top row) and the stereocomplex-treated group (bottom row). Figure 22D shows a comparison of tumor weights between the control group (left) and the stereocomplex-treated group (right).

[0032] [Figure 23] Figure 23 shows a comparison of in vivo antitumor efficacy between the complex and the prodrug (D-DM1) in a subcutaneous CNE (nasopharyngeal) tumor model when the treatment was delivered by intravenous injection. A cell suspension was injected subcutaneously into the back of mice to establish the tumor model. When tumor volumes reached approximately 100 mm, groups of tumor-bearing mice (n=5) were injected with the complex via the tail vein. As shown, with an equivalent DM1 dose, tumor volume continued to grow in the prodrug group (squares), while the complex treatment (circles) demonstrated good tumor growth inhibitory efficacy.

[0033] [Figure 24]Figures 24A-24B show the in vivo antitumor efficacy of the complex in a subcutaneous NCI-H526 (small cell lung cancer) tumor model via intravenous injection. The tumor model was established by subcutaneous injection of a cell suspension into the back of mice. When tumor volumes reached approximately 100 mm, groups of tumor-bearing mice (n=5) were injected with the complex via the tail vein once a week. After three injections, one mouse was tumor-free on day 18, and all mice were tumor-free by day 32. Figure 24A shows the tumor size change for the complex-treated group (circles) versus the control group (squares). Figure 24B shows control mice (top row of photographs) and treated mice (bottom row of photographs) on day 18 of the study.

[0034] [Figure 25] Figures 25A-25D show the in vivo antitumor efficacy of the complex in a subcutaneous NCI-H1975 (non-small cell lung cancer) tumor model via intravenous injection. A cell suspension was injected subcutaneously into the back of the mouse to establish the tumor model. When tumors reached approximately 130 mm3, groups of tumor-bearing mice (n=5) were injected with the composition via the tail vein. Figure 25A shows that untreated mice (squares) showed a more significant increase in tumor volume, while mice treated with the complex (circles) showed a smaller final tumor volume (arrows indicate the injection date) after only one injection. Figure 25B shows the weight changes of the control and treatment groups. Figure 25C shows excised tumors from the control group (top row) and the stereocomplex-treated group (bottom row). Figure 25D shows a comparison of tumor weights between the control group (left) and the stereocomplex-treated group (right).

[0035] [Figure 26]Figures 26A-26D show the in vivo antitumor efficacy of the complex in a subcutaneous MDA-MB-231 (triple-negative breast cancer) tumor model. A cell suspension was injected subcutaneously into the back of mice to establish the tumor model. When tumors reached approximately 100 mm3, groups of tumor-bearing mice (n=6) were injected with the composition via the tail vein. Figure 26A shows that untreated mice (squares) experienced a more significant increase in tumor volume, while mice treated with the complex (circles) exhibited a smaller final tumor volume after only one injection. Figure 26B shows the weight changes of the control and treatment groups. Figure 26C shows the excised tumors of the control group (top row) and the stereocomplex-treated group (bottom row). Notably, one mouse remained tumor-free from day 23. Figure 26D shows a comparison of tumor weights between the control group (left) and the stereocomplex-treated group (right).

[0036] [Figure 27] Figures 27A-27B show the in vivo antitumor efficacy of the complex in a subcutaneous MX-1 (breast) tumor model by intravenous injection. The tumor model was established by subcutaneous injection of a cell suspension into the back of mice. When the tumor volume reached approximately 530 mm, a group of tumor-bearing mice (n=5) was injected with the complex via the tail vein. After just one injection, as shown in Figure 27A, the tumor size continuously decreased over the following 20 days, demonstrating the efficacy of the complex even in large tumors. No weight loss was observed with this treatment (Figure 27B).

[0037] [Figure 28]Figures 28A-28D show the in vivo antitumor efficacy of the complex in a subcutaneous MCF-7 (breast) tumor model. A cell suspension was injected subcutaneously into the back of mice to establish the tumor model. When tumors reached approximately 100 mm, groups of tumor-bearing mice (n=8) were injected with the composition via the tail vein. Figure 28A shows that untreated mice (squares) experienced a more significant increase in tumor volume, while mice treated with the complex (circles) exhibited a smaller final tumor volume after two injections (arrows indicate the injection dates). Figure 28B shows the weight changes of the control and treatment groups. Figure 28C shows the excised tumors of the control group (top row) and the stereocomplex-treated group (bottom row). Note that one mouse was tumor-free by day 25, and three mice were tumor-free at the end of the study. Figure 28D shows a comparison of tumor weights between the control group (left) and the stereocomplex-treated group (right).

[0038] [Figure 29] Figures 29A-29D show the in vivo antitumor efficacy of the complex in a subcutaneous RT112 (bladder) tumor model. A cell suspension was injected subcutaneously into the back of mice to establish the tumor model. When tumors reached approximately 100 mm3, groups of tumor-bearing mice (n=5) were injected with the composition via the tail vein. Figure 29A shows that untreated mice (squares) showed a more significant increase in tumor volume, while mice treated with the complex (circles) showed a smaller final tumor volume after three injections (arrows indicate the injection dates). Figure 29B shows the weight changes in the control and treatment groups. Figure 29C shows excised tumors from the control group (top row) and the stereocomplex-treated group (bottom row). Figure 29D shows a comparison of tumor weights between the control group (left) and the stereocomplex-treated group (right).

[0039] [Figure 30]Figures 30A-30D show the in vivo antitumor efficacy of the complex in a subcutaneous TT (esophageal) tumor model. A cell suspension was injected subcutaneously into the back of mice to establish the tumor model. When tumors reached approximately 110 mm3, groups of tumor-bearing mice (n=5) were injected with the composition via the tail vein. Figure 30A shows that untreated mice (squares) showed a more significant increase in tumor volume, while mice treated with the complex (circles) showed a smaller final tumor volume after three injections (arrows indicate the injection dates). Figure 30B shows the weight changes of the control and treatment groups. Figure 30C shows the excised tumors of the control group (top row) and the stereocomplex-treated group (bottom row). Notably, one mouse was tumor-free from day 27 onward. Figure 30D shows a comparison of tumor weights between the control group (left) and the stereocomplex-treated group (right).

[0040] [Figure 31] Figures 31A-31D show the in vivo antitumor efficacy of the complex in a subcutaneous U251 (glioblastoma) tumor model. A cell suspension was injected subcutaneously into the back of mice to establish the tumor model. When tumors reached approximately 150 mm, groups of tumor-bearing mice (n=5) were injected with the composition via the tail vein. Figure 31A shows that untreated mice (squares) experienced a more significant increase in tumor volume, while mice treated with the complex (circles) exhibited a smaller final tumor volume after two injections (arrows indicate the injection dates). Figure 31B shows the weight changes in the control and treatment groups. Figure 31C shows excised tumors from the control group (top row) and the stereocomplex-treated group (bottom row). Figure 31D shows a comparison of tumor weights between the control group (left) and the stereocomplex-treated group (right).

[0041] [Figure 32]Figures 32A-32D show the in vivo antitumor efficacy of the complex in a subcutaneous Caki-1 (kidney) tumor model. A cell suspension was injected subcutaneously into the back of mice to establish the tumor model. When tumors reached approximately 170 mm, groups of tumor-bearing mice (n=5) were injected with the composition via the tail vein. Figure 32A shows that untreated mice (squares) experienced a more significant increase in tumor volume, while mice treated with the complex (circles) exhibited a smaller final tumor volume after three injections (arrows indicate the injection dates). Figure 32B shows the weight changes in the control and treatment groups. Figure 32C shows excised tumors from the control group (top row) and the stereocomplex-treated group (bottom row). Figure 32D shows a comparison of tumor weights between the control group (left) and the stereocomplex-treated group (right).

[0042] [Figure 33] Figures 33A-33D show the in vivo antitumor efficacy of the complex in a subcutaneous NCI-H522 (non-small cell lung cancer) tumor model. A cell suspension was injected subcutaneously into the back of mice to establish the tumor model. When tumors reached approximately 130 mm3, groups of tumor-bearing mice (n=5) were injected with the composition via the tail vein. Figure 33A shows that untreated mice (squares) showed a more significant increase in tumor volume, while mice treated with the complex (circles) showed a smaller final tumor volume after two injections (arrows indicate the injection dates). Figure 33B shows the weight changes in the control and treatment groups. Figure 33C shows the excised tumors in the control group (top row) and the stereocomplex-treated group (bottom row). Note that three mice were tumor-free at the end of the study. Figure 33D shows a comparison of tumor weights in the control group (left) and the stereocomplex-treated group (right).

[0043] [Figure 34]Figures 34A-34D show the in vivo antitumor efficacy of the complex in a subcutaneous NCI-H226 (non-small cell lung cancer) tumor model. A cell suspension was injected subcutaneously into the back of mice to establish the tumor model. When tumors reached approximately 120 mm, groups of tumor-bearing mice (n=4) were injected with the composition via the tail vein. Figure 34A shows that untreated mice (squares) showed a more significant increase in tumor volume, while mice treated with the complex (circles) showed a smaller final tumor volume after two injections (arrows indicate the injection dates). Figure 34B shows the weight changes in the control and treatment groups. Figure 34C shows excised tumors from the control group (top row) and the stereocomplex-treated group (bottom row). Figure 34D shows a comparison of tumor weights between the control group (left) and the stereocomplex-treated group (right).

[0044] [Figure 35] Figures 35A-35D show the in vivo antitumor efficacy of the complex in a subcutaneous Ovcar-3 (ovarian) tumor model. A cell suspension was injected subcutaneously into the back of mice to establish the tumor model. When tumors reached approximately 150 mm, groups of tumor-bearing mice (n=5) were injected with the composition via the tail vein. Figure 35A shows that untreated mice (squares) experienced a more significant increase in tumor volume, while mice treated with the complex (circles) exhibited a smaller final tumor volume after only one injection. Figure 35B shows the weight changes of the control and treatment groups. Figure 35C shows excised tumors from the control group (top row) and the stereocomplex-treated group (bottom row). Figure 35D shows a comparison of tumor weights between the control group (left) and the stereocomplex-treated group (right).

[0045] [Figure 36]Figures 36A-36D show the in vivo antitumor efficacy of the complex in a subcutaneous PC-3 (prostate) tumor model. A cell suspension was injected subcutaneously into the back of mice to establish the tumor model. When tumors reached approximately 130 mm3, groups of tumor-bearing mice (n=5) were injected with the composition via the tail vein. Figure 36A shows that untreated mice (squares) showed a more significant increase in tumor volume, while mice treated with the complex (circles) showed a smaller final tumor volume after three injections (arrows indicate the injection dates). Figure 36B shows the weight changes in the control and treatment groups. Figure 36C shows excised tumors from the control group (top row) and the stereocomplex-treated group (bottom row). Figure 36D shows a comparison of tumor weights between the control group (left) and the stereocomplex-treated group (right).

[0046] [Figure 37] Figures 37A-37B show the in vivo antitumor efficacy of the complex in a subcutaneous Raji (lymphoma) tumor model via intravenous injection. The tumor model was established by subcutaneous injection of a cell suspension into the back of mice. When the tumor volume reached approximately 130 mm, groups of tumor-bearing mice (n=4) were injected with the complex via the tail vein. After only one injection, three mice were tumor-free on day 15, and all mice were tumor-free from day 22 onwards. Figure 37A shows the change in tumor size for the complex-treated group (circles) versus the control group (squares). Figure 37B shows photographs of control mice (top row) and treated mice (bottom row) on day 25 of the study.

[0047] [Figure 38]Figures 38A-38B show blood parameters in nude mice after a single intravenous injection of the complex. Mice (four per group) were injected intravenously with the complex at a dose of 5 mg / kg DM1 and 32.5 mg / kg DTX, and then sacrificed on days 3, 7, and 14. Blood samples were collected and analyzed for the following general parameters: white blood cell count (WBC); red blood cell count (RBC); hemoglobin concentration (HGB), and platelet count (PLT). Compared with the control (no injection) labeled day 0, RBC and HGB showed no statistical difference in all tests. Furthermore, lower WBC and PLT were observed on day 3, which all recovered on day 7 and remained normal on day 14.

[0048] [Figure 39] Figure 39 shows clinical chemistry in nude mice after a single iv injection of the complex formulation. Mice (4 per group) were injected with the complex once iv at a dose of 5 mg / kg DM1 and 32.5 mg / kg DTX, and then sacrificed on days 3, 7, and 14. Blood samples were collected and analyzed for the following parameters: alanine aminotransferase (ALT); aspartate aminotransferase (AST); alkaline phosphatase (ALP), creatinine (CREA), and urea (UREA). Compared with the control (no injection) labeled day 0, ALT and AST increased after injection but recovered on day 14. There was no obvious difference in UREA and CREA, indicating the absence of any nephrotoxicity.

[0049] [Figure 40]Figures 40 and 41 show histopathological analysis of organs in the complex-treated group (complex) versus the untreated group (control) and the prodrug-treated group (D-DM1) in a CNE (nasopharyngeal) tumor model. A cell suspension was subcutaneously injected into the back of the mice to establish the tumor model. When tumors reached approximately 100 mm, groups of tumor-bearing mice (n=5) were injected weekly via the tail vein for 4 consecutive weeks with the composition at doses of 4 mg / kg DM1 for the D-DM1 group and 4 mg / kg DM1 with 26 mg / kg DTX for the complex group. After harvesting the heart, kidney, spleen, lungs, and liver, sections were stained with hematoxylin and eosin for observation. Compared to the control and D-DM1 treatments, complex treatment did not induce any damage to the organs. [Figure 41] Figures 40 and 41 show histopathological analysis of organs in the complex-treated group (complex) versus the untreated group (control) and the prodrug-treated group (D-DM1) in a CNE (nasopharyngeal) tumor model. A cell suspension was subcutaneously injected into the back of the mice to establish the tumor model. When tumors reached approximately 100 mm, groups of tumor-bearing mice (n=5) were injected weekly via the tail vein for 4 consecutive weeks with the composition at doses of 4 mg / kg DM1 for the D-DM1 group and 4 mg / kg DM1 with 26 mg / kg DTX for the complex group. After harvesting the heart, kidney, spleen, lungs, and liver, sections were stained with hematoxylin and eosin for observation. Compared to the control and D-DM1 treatments, complex treatment did not induce any damage to the organs.

[0050] [Figure 42]Figures 42A-42B show the in vivo antitumor efficacy of a glucose-containing complex in a subcutaneous Raji (lymphoma) tumor model via intravenous injection. A cell suspension was injected subcutaneously into the back of mice to establish the tumor model. When the tumor volume reached approximately 130 mm, groups of tumor-bearing mice (n=4) were injected with the complex via the tail vein. After only one injection, three mice were tumor-free on day 15, and all mice were tumor-free from day 18 onwards. Figure 42A shows the change in tumor size for the complex-treated group (circles) versus the control group (squares). Figure 42B shows photographs of control mice (top row) and mice treated with a glucose-containing complex (bottom row) on day 25 of the study.

[0051] [Figure 43] Figure 43 shows stereocomplex pre- and post-treatment PET / CT images of patient 1. By comparison, the intensity of the subcarinal lymph nodes was significantly reduced by treatment.

[0052] [Figure 44] Figure 44 shows sagittal MR imaging of patient 3 before and after treatment with a stereocomplex. Before treatment, sagittal MR of the spine showed multiple large, irregularly shaped masses occupying most of the spinal canal from L1 to S1, with minimal visible CSF space. After treatment, MR revealed significant tumor mass reduction in the spinal canal between L1 and S1. Only small residual masses were observed behind L4 and L5, with readily identifiable CSF space and cauda equina nerve fibers.

[0053] [Figure 45] Figure 45 shows PET / CT images of patient 4 before and after treatment with stereocomplex. Tumor size decreased with treatment.

[0054] [Figure 46]Figure 46 shows stereocomplex pre- and post-treatment PET / CT images of patient 4. Mediastinal, hilar, and abdominal aortic lymph node uptake intensity was reduced.

[0055] [Figure 47] Figure 47 shows stereocomplex PET / CT images of patient 4 before and after treatment. Before treatment, the tumor was found to invade the parietal pleura. However, after treatment, the tumor and the parietal pleura were found to be completely separated. DETAILED DESCRIPTION OF THE INVENTION

[0056] Detailed Description Before the present materials, articles, and / or methods are disclosed and described, it is to be understood that the embodiments described below are not limited to specific compounds, synthetic methods, or uses, which may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0057] In this specification and in the claims that follow, reference will be made to a number of terms that will be defined to have the following meanings.

[0058] It must be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to an "anticancer agent" includes mixtures of two or more such anticancer agents, and the like.

[0059] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, the compositions described herein may optionally contain one or more targeting groups, which may or may not be present.

[0060] As used herein, the term "about" is used to provide flexibility to endpoint numerical ranges by indicating that a given value may be "slightly above" or "slightly below" the endpoints without affecting the desired result. For purposes of this disclosure, "about" refers to a range extending from 10% lower to 10% higher. For example, if the numerical value is 10, "about 10" means between 9 and 11, inclusive of the endpoints 9 and 11.

[0061] Throughout this specification, unless the context specifically supports otherwise, the word "comprise," or variations such as "comprises" or "comprising," will be understood to mean the inclusion of a specified integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps. It is also contemplated that the term "comprise" and variations thereof can be replaced by other transitional phrases such as "consisting of" and "consisting essentially of."

[0062] "Miscible" or "mixture" refers to the combination of two components together in the absence of a chemical reaction or physical interaction. The terms "miscible" and "mixture" can also include a chemical or physical interaction between any of the components described herein when mixed to produce a composition. The components can be mixed alone in water, in another solvent, or in a combination of solvents.

[0063] The term "solid tumor," as defined herein, is an abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors can be benign (not cancerous) or malignant (cancer). Various types of solid tumors are named for the type of cells that form the tumor. Examples of solid tumors are sarcomas, carcinomas, and lymphomas.

[0064] The term "subject," as defined herein, is any organism in need of cancer treatment and / or prevention. In one embodiment, the subject is a mammal, including, but not limited to, humans, domestic animals (e.g., dogs, cats, horses), livestock (e.g., cows, pigs), and wild animals.

[0065] The term "treat," as used herein, is defined as maintaining or reducing the symptoms of an already existing condition. For example, the compositions described herein are used to treat cancer.

[0066] The term "prevent" as used herein is defined as eliminating or reducing the likelihood of one or more symptoms of a disease or disorder occurring. For example, the compositions described herein can be used to prevent or slow the rate of tumor cell regrowth.

[0067] The term "inhibit" as used herein refers to the ability of the compounds described herein to completely eliminate or reduce activity when compared with the same activity in the absence of the compound.For example, the compositions described herein can be used to inhibit the growth and / or spread of cancer in the body of a subject.

[0068] A "biodegradable" material is capable of being broken down by bacteria, fungi or other organisms, or by enzymes in a subject's body.

[0069] "Biocompatible" materials are materials that perform their desired function without inducing harmful or deleterious changes to the subject in which they are implanted or to which they are applied locally or systemically. In one aspect, the compositions disclosed herein are biocompatible.

[0070] As used herein, "toxicity" refers to the harmful effect a substance has on an organism, such as a human or mammal, or on cells within that organism. A compound or composition with high toxicity would be unsuitable for use as a medical treatment, while a compound or composition with low toxicity would be acceptable for use as a medical treatment. In one aspect, the compounds and compositions disclosed herein exhibit low toxicity.

[0071] The term "alkyl group," as used herein, refers to a branched or unbranched saturated hydrocarbon group of 1 to 25 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. Examples of longer chain alkyl groups include, but are not limited to, oleate or palmitate groups. A "lower alkyl" group is an alkyl group containing 1 to 6 carbon atoms.

[0072] The term "aryl group," as used herein, refers to any carbon-based aromatic group, including, but not limited to, benzene, naphthalene, and the like. The term "aryl group" also includes "heteroaryl groups," which are defined as aromatic groups having at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. Aryl groups can be substituted or unsubstituted. When substituted, aryl groups can be substituted with one or more groups, including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxyl, carboxylic acid, or alkoxy.

[0073] The term "alkoxy group," as used herein, is defined as RO-, where R is an alkyl or aryl group, as defined herein.

[0074] The term "halogenated group" refers to any organic group, such as, for example, an alkyl or aryl group, that has at least one halogen (F, Cl, Br, I).

[0075] References herein and in the concluding claims to parts by weight of a particular element in a composition or article represent the weight relationship between the element or component and any other element or component in the composition or article to which the parts by weight are expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a weight ratio of 2:5, regardless of whether additional components are included in the compound. Component weight percentages are based on the total weight of the formulation or composition in which the component is included, unless specifically stated to the contrary.

[0076] As used herein, a plurality of articles, structural elements, compositional elements, and / or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list were individually identified as a separate and unique member. Accordingly, the individual members of any such list should not be construed as de facto equivalents of any other members of the same list solely based on their presentation in a common group, absent indication to the contrary.

[0077] Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It should be understood that such range format is used merely for convenience and brevity and, therefore, should be interpreted flexibly to include not only the numerical values ​​explicitly recited as range limits, but also all individual numerical values ​​or subranges subsumed within that range, as if each numerical value and subrange were explicitly recited. By way of illustration, a numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly recited value of about 1 to about 5, but also each individual value and subrange within the stated range. Thus, this numerical range includes individual values ​​such as 2, 3, and 4, subranges such as 1 to 3, 2 to 4, and 3 to 5, as well as 1, 2, 3, 4, and 5 individually. The same principle applies to ranges reciting only one numerical value as the minimum or maximum value. Moreover, such interpretation should apply regardless of the breadth of the range or the characteristics being described.

[0078] Disclosed herein are materials and components that can be used for, can be used in conjunction with, can be used in the preparation of, or are products of the disclosed compositions and methods.These and other materials are disclosed herein, and when combinations, subsets, interactions, groups, etc. of these materials are disclosed, it is understood that each of the various individual and collective combinations and permutations of these compounds is specifically contemplated and described herein, although specific reference may not be explicitly disclosed.For example, when anticancer drugs are disclosed and several different linkers are discussed, unless specifically indicated to the contrary, all possible combinations of anticancer drugs and linkers are specifically contemplated.For example, when classes of molecules A, B, and C, and classes of molecules D, E, and F, and the exemplary combination of A+D are disclosed, each is individually and collectively contemplated, even if each is not individually listed. Thus, in this example, the combinations A+E, A+F, B+D, B+E, B+F, C+D, C+E, and C+F are each specifically contemplated and should be considered in light of the disclosure of the exemplary combinations of A, B, and C; D, E, and F, and A+D. Likewise, any subset or combination of these is also specifically contemplated and disclosed. Thus, for example, the subgroups A+E, B+F, and C+E are specifically contemplated and should be considered in light of the disclosure of the exemplary combinations of A, B, and C; D, E, and F, and A+D. This concept applies to all aspects of the present disclosure, including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, if there are various additional steps that can be performed with any specific embodiment or combination of embodiments of the disclosed methods, each such combination should be considered specifically contemplated and disclosed. Components in the stereocomplex

[0079] The stereocomplexes described herein are useful for delivering one or more anticancer drugs to a subject. In one embodiment, the stereocomplexes are composed of at least two components, each of which has a hydrophilic group, an isotactic polylactic acid portion, a linker, and an anticancer drug.

[0080] In one aspect, the following components: X 1 -Y 1 -L 1 -Z 1 (I) X 2 -Y 2 -L 2 -Z 2 (II) (In the formula, X 1 and X 2 is a hydrophilic group, and Y 1 and Y 2 is PDLA or PLLA, L 1 and L 2 is a cleavable linker, and Z 1 is an anticancer drug, Z 2 is an anti-cancer drug or imaging agent, and Z 2 If is an anticancer drug, Z 1 and Z 2 are different anticancer drugs, and (1)Y 1 If is PDLA, then Y 2 is PLLA, and Y 1 If is PLLA, Y 2 is PDLA, and (2) the ratio of the total number of D-lactic acid units in the stereocomplex to the total number of L-lactic acid units in the stereocomplex is 0.9:1.1 to 1.1:0.9. Disclosed herein is a stereocomplex having

[0081] Without wishing to be bound by theory, stereocomplexes are formed when the PDLA and PLLA units present in components (I) and (II) form an extensive three-dimensional network driven by hydrogen bonding. The stereocomplexes described herein have properties such as enhanced tensile strength, Young's modulus, and elongation at break compared to either component (I) or component (II) alone. The stereocomplexes have high stability and high resistance to hydrolytic degradation, thereby eliminating premature drug release (i.e., before the stereocomplex reaches its target tissue) and increasing the circulation time of the stereocomplex in the blood.

[0082] Figure 1 shows a schematic diagram of an exemplary stereocomplex containing two different drugs based on the stereocomplex formation between PDLA and PLLA. Figure 2 shows a schematic diagram of an exemplary polymer-conjugated drug for stereocomplex formation. Without wishing to be bound by theory, the hydrophilic elements protrude into the solution, while the hydrophobic elements cluster in the particle core (Figure 2A). An exemplary anticancer drug conjugated to a hydrophobic moiety with a cleavable linker is presented in Figure 2B. Referring to Figure 2B, mertansine (DM1) is linked to a carrier with a disulfide bond (D-DM1), and docetaxel (DTX) is linked to a carrier with a hydrazone bond, ester bond, or disulfide bond (L-DTX).

[0083] Each of the components used to prepare the stereocomplex, as well as methods for making and using it, are described in detail herein. a.Hydrophilic group

[0084] The components used to generate the stereocomplexes disclosed herein contain hydrophilic groups. In one embodiment, X in components (I) and (II) 1 and X 2are different hydrophilic groups. 1 and X 2 are the same hydrophilic group. 1 and X 2 are each polyalkylene glycols.

[0085] "Polyalkylene glycol," as used herein, refers to a condensation polymer of ethylene oxide or propylene oxide and water. Polyalkylene glycols are typically colorless liquids with high molecular weights and are soluble in water and some organic solvents. In one embodiment, the hydrophilic group in the stereocomplexes disclosed herein is a polyalkylene glycol. In another embodiment, the polyalkylene glycol is polyethylene glycol and / or polypropylene glycol. In another embodiment, the polyalkylene glycol is monomethoxypolyethylene glycol. The general structure of a polyalkylene glycol is as follows: [ka] Substitutions in selected polyalkylene glycols are presented in Table 1: [Table 1]

[0086] In a further aspect, the polyalkylene glycol has a molecular weight small enough that the chemical nature of the terminal group (usually, but not always, hydroxyl) still affects the performance of the polymer. In addition to being hydrophilic, the polyalkylene glycol can modify the viscosity of the stereocomplexes disclosed herein and can aid in the formation of emulsions. In another aspect, the polyalkylene glycol is biocompatible and / or biodegradable. In yet another aspect, the polyalkylene glycol and / or other hydrophilic groups used herein are non-toxic.

[0087] In one embodiment, X in components (I) and (II) 1 and X 2 is a polyalkylene glycol, X 1 and X 2 has a molecular weight of about 1,000 Da to about 5,000 Da, or 1,500 Da to 4,500 Da, or 2,000 Da to 4,000 Da, or has a molecular weight of about 1,000 Da, 1,500 Da, 2,000 Da, 2,500 Da, 3,000 Da, 3,500 Da, 4,000 Da, 4,500 Da, or about 5,000 Da, any value can be the lower and upper endpoints of a range (e.g., 2,000 Da to 4,000 Da).

[0088] In another embodiment, X in components (I) and (II) of the stereocomplex disclosed herein 1 and X 2 are monomethoxypolyethylene glycols having a molecular weight of about 1,000 to about 5,000 Da, or 1,500 Da to 4,500 Da, or 2,000 Da to 4,000 Da, respectively, or about 1,000 Da, 1,500 Da, 2,000 Da, 2,500 Da, 3,000 Da, 3,500 Da, 4,000 Da, 4,500 Da, or about 5,000 Da, either of which values ​​can be the lower and upper endpoints of a range (e.g., 2,000 Da to 4,000 Da). In one embodiment, X in components (I) and (II) of the stereocomplex disclosed herein 1 and X 2 are each monomethoxypolyethylene glycols having the same molecular weight. b.PDLA / PLLA

[0089] Polylactic acid is a polyester derived from lactic acid. The polyester is composed of lactic acid units as illustrated in the structure below, where m indicates the number of lactic acid units. Lactic acid units are represented by an asterisk ( * ), where m is the number of lactic acid units: [ka]

[0090] Polylactic acid polymerization can be initiated from D- or L-lactic acid, or a mixture thereof, or lactide, a cyclic diester. The properties of polylactic acid can be fine-tuned by controlling the ratio of D to L enantiomers used in the polymerization, and polylactic acid polymers can also be synthesized using only D or L starting materials rather than a mixture of the two. Polylactic acid prepared exclusively from D starting materials is referred to as poly-D-lactide (PDLA) (i.e., composed exclusively of D-lactic acid units), while polylactic acid prepared exclusively from L starting materials is poly-L-lactide (or PLLA) (i.e., composed exclusively of L-lactic acid units).

[0091] As used herein, D-lactic or L-lactic units refer to monomer units within the polylactic acid polymers described herein, as shown in Table 2, where the D-lactic units are derived from a D-lactic acid or D-lactide starting material and the L-lactic units are derived from an L-lactic acid or L-lactide starting material: [Table 2]

[0092] The polylactic acid in components (I) and (II) is Y 1 and Y 2 and Y 1 If is PDLA, then Y 2 Is PLLA or alternatively, Y 1 If is PLLA, Y 2 is PDLA.

[0093] In one embodiment, the ratio of the total number of D-lactic acid units in the stereocomplex to the number of L-lactic acid units in the stereocomplex is 0.9:1.1 to 1.1:0.9. In another embodiment, the ratio of the total number of D-lactic acid units to the number of L-lactic acid units is 0.9:1.1, 0.95:1.05, 1:1, 1.05:0.95, or 1.1:0.9. In one embodiment, the ratio of the total number of D-lactic acid units to the number of L-lactic acid units is close to 1:1. In other words, in some embodiments, the total number of D-lactic acid units and L-lactic acid units in the stereocomplex is approximately equal.

[0094] PDLA and PLLA are present in components (I) and (II). However, as discussed in more detail below, additional components can be used to prepare the stereocomplexes herein that contain PDLA or PLLA. These components add to the total number of D-lactic acid units or L-lactic acid units present in the stereocomplex.

[0095] In one embodiment, the PDLA and PLLA present in components (I) and (II) have a molecular weight of about 700 Da to about 5,000 Da, or about 750 Da to 4,000 Da, or about 1,000 Da to about 3,000 Da. Further, in this embodiment, the PDLA and PLLA have a molecular weight of about 700 Da, 750 Da, 800 Da, 900 Da, 1,000 Da, 1,250 Da, 1,500 Da, 2,000 Da, 2,500 Da, 3,000 Da, 3,500 Da, 4,000 Da, 4,500 Da, or 5,000 Da, any of which can be the lower and upper endpoints of the range (e.g., 1,000 Da to 3,000 Da). In another embodiment, the PDLA and PLLA present in components (I) and (II) have equal or nearly equal molecular weights.

[0096] In another embodiment, the number of D-lactic acid units present in PDLA and L-lactic acid units present in PLLA in components (I) and (II) is 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100, any value can be the lower or upper endpoint of a range (e.g., 10 to 60). In another embodiment, the PDLA and PLLA present in components (I) and (II), respectively, have the same number of D-lactic acid units and L-lactic acid units.

[0097] The hydrophilic groups in components (I) and (II) are covalently attached to PDLA or PLLA. In one embodiment, when the hydrophilic group is monomethoxypolyethylene glycol, the terminal hydroxyl group can react with the terminal carboxyl group of PDLA or PLLA to form a new ester. Exemplary methods for attaching hydrophilic groups to PDLA or PLLA are provided in the Examples. c. cleavable linker

[0098] In one embodiment, the stereocomplex disclosed herein comprises a cleavable linker. The cleavable linker comprises at least one cleavable group, so that the anticancer drug is released upon cleavage. The cleavable group can be cleaved, for example, by enzymes, hydrolysis, or pH changes.

[0099] In one embodiment, components (I) and L present in (I) 1 and L 2 are different cleavable linkers. Further, in this embodiment, L 1 and L 2can exhibit different cleavage rates (e.g., hydrolysis, enzymes, pH) due to the presence of different cleavable groups, and thus can release the linked anticancer drug at various controlled rates. In one aspect, the selection of the cleavable linker and the rate of hydrolytic degradation of the linker can reduce the required concentration of the anticancer drug or enhance the synergistic effect of the anticancer drug present in the stereocomplex. Thus, L 1 and L 2 may be selected to achieve sequential or simultaneous release of two different anti-cancer drugs. 1 and L 2 is the same cleavable linker.

[0100] In one aspect, L 1 and L 2 independently comprise a cleavable group, including, but not limited to, a disulfide group, an ester group, a hydrazone group, an acetal group, an imine group, a β-thiopropionate group, an amide group, or any combination thereof. A cleavable linker molecule can comprise one or more of these groups. A cleavable linker can also comprise an additional functional group, such that the cleavable linker can be covalently attached to PDLA or PLLA. In one embodiment, the cleavable linker comprises a functional group capable of reacting with the terminal hydroxyl group of PDLA or PLLA to generate a new covalent bond. For example, the cleavable linker can comprise a carboxyl group (e.g., a carboxylic acid, an ester, an anhydride) that reacts with the hydroxyl group of PDLA or PLLA. Exemplary methods for attaching a cleavable linker to PDLA or PLLA are provided in the Examples and Figures herein. Disulfide groups

[0101] As used herein, a disulfide group is a functional group having the structure (-SS-). Upon cleavage of the disulfide group, the anticancer drug is released. In one embodiment, the L of the stereocomplexes disclosed herein 1 Or L 2 , or L 1and L 2 Both of these linkers contain disulfide groups. Without wishing to be bound by theory, disulfide groups are sensitive to glutathione redox. Glutathione (GSH) in cancer cells is involved in regulating the oncogenic mechanism; sensitivity to cytotoxic drugs, ionizing radiation, and some cytokines; DNA synthesis; and cell proliferation and death. GSH can cleave disulfide bonds to release anticancer drugs present in stereocomplexes and generate the corresponding thiols. Representative linkers with disulfide groups are presented herein. Ester group

[0102] As used herein, an ester group is a functional group having the following structure: [ka]

[0103] In one aspect, the L of the stereocomplexes disclosed herein 1 Or L 2 , or L 1 and L 2 Both of these linkers contain an ester group. Upon cleavage of the ester group, the anticancer drug is released. Exemplary methods for preparing and using cleavable linkers having an ester group are provided in the Examples and Figures herein. hydrazone group

[0104] As used herein, a hydrazone group is a functional group having the following structure, where R and R' can be the same or different: [ka]

[0105] In one aspect, the L of the stereocomplexes disclosed herein 1 Or L 2 , or L 1 and L 2Both of these linkers contain a hydrazone group. Upon cleavage of the hydrazone group, the anticancer drug is released. Exemplary methods for preparing and using cleavable linkers having a hydrazone group are provided in the Examples and Figures herein. Acetal group

[0106] As used herein, an acetal group is a functional group having the following structure, where R, R′, and R″ can be the same or different: [ka]

[0107] In one aspect, the L of the stereocomplexes disclosed herein 1 Or L 2 , or L 1 and L 2 Both contain an acetal group, upon cleavage of the acetal group, the anticancer drug is released. Imine group

[0108] As used herein, an imine group is a functional group having the following structure: [ka]

[0109] In one aspect, the L of the stereocomplexes disclosed herein 1 Or L 2 , or L 1 and L 2 Both contain an imine group, upon cleavage of the imine group, the anticancer drug is released. β-thiopropionate group

[0110] As used herein, a β-thiopropionate group is a functional group having the following structure, where R and R′ can be the same or different: [ka]

[0111] In one aspect, the L of the stereocomplexes disclosed herein 1 Or L 2 , or L 1 and L 2 Both contain a β-thiopropionate group. Upon cleavage of the β-thiopropionate group, the anticancer drug is released. amide group

[0112] As used herein, an amide group is a functional group having the following structure: [ka]

[0113] In one aspect, the L of the stereocomplexes disclosed herein 1 Or L 2 , or L 1 and L 2 Both contain an amide group. Upon cleavage of the amide group, the anticancer drug is released. d.Anticancer drugs

[0114] In one embodiment, the stereocomplexes described herein contain two or more anticancer drugs. As used herein, an "anticancer drug" is a compound used to kill cancer cells in a subject's body, slow the growth of cancer in a subject, prevent cancer from spreading in a subject, or prevent surgically removed tumors from returning. Anticancer drugs can work in a variety of ways, including, but not limited to, by alkylating DNA (which can prevent DNA replication enzymes from helicalizing and recognizing it), interfering with the production of DNA, interfering with the production of proteins in cancer cells, preventing cancer cells from dividing, or slowing the growth of hormone-dependent cancers. The anticancer drug is covalently attached to a cleavable linker.

[0115] The relative amounts of each anticancer agent present in the stereocomplex can be varied to achieve additive and / or synergistic therapeutic effects with particular types of cancer, a feature of stereocomplexes described in more detail below.

[0116] In one embodiment, the anticancer drug is paclitaxel, doxorubicin, gemcitabine, cisplatin, methotrexate, 5-fluorouracil, betulinic acid, amphotericin B, diazepam, nystatin, propofol, testosterone, docetaxel, maytansinoid, PD-1 inhibitor, PD-L1 inhibitor, protein kinase inhibitor, P-glycoprotein inhibitor, autophagy inhibitor, PARP inhibitor, aromatase inhibitor, monoclonal antibody, photosensitizer, radiosensitizer, interleukin, antiandrogen, or any combination thereof. In one embodiment, when the anticancer drug is a maytansinoid, the anticancer drug can be ansamitocin, mertansine (DM1), ravtansine, or another maytansinoid. In a further embodiment, the anticancer drug can be classified into more than one of the above categories simultaneously. For example, the aromatase inhibitor can also be an anti-androgen, and the PD-1 inhibitor can also be a monoclonal antibody.

[0117] In one embodiment, the anticancer agent is a PD-1 inhibitor or a PD-L1 inhibitor. PD-1 inhibitors and PD-L1 inhibitors are immune checkpoint inhibitors that inhibit the association of programmed death ligand 1 (PD-L1) with programmed death protein 1 (PD-1). This protein-ligand interaction is involved in suppressing the immune system in certain types of cancer. In one embodiment, the compositions disclosed herein include a PD-1 and / or PD-L1 inhibitor. In a further embodiment, the PD-1 inhibitor can be pembrolizumab, nivolumab, pidilizumab, AMP-224, AMP-514, or PDR001. In yet another embodiment, the PD-L1 inhibitor can be atezolizumab, avelumab, durvalumab, or BMS0936559. Without wishing to be bound by theory, when PD-L1 on cancer cells interacts with PD-1 on T cells, functional signals of the T cells are reduced, thereby preventing the immune system from attacking tumor cells. Therefore, blocking this interaction allows the immune system to target tumor cells. In one embodiment, advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, Hodgkin's lymphoma, and other cancers can be treated with PD-1 and PD-L1 inhibitors.

[0118] In one embodiment, the anti-cancer agent is a monoclonal antibody. In monoclonal antibody therapy, the monoclonal antibody binds monospecifically to target cells and / or proteins, stimulating the subject's immune system to attack those cells. In some embodiments, monoclonal antibody therapy is used in conjunction with radiation therapy. In one embodiment, the compositions disclosed herein comprise a monoclonal antibody. The monoclonal antibody can be murine (suffix -omab), chimeric (suffix -ximab), humanized (suffix -zumab), or human (suffix -umab). In one embodiment, the monoclonal antibody is selected from the group consisting of ramucirumab, 3F8, 8H9, abagovomab, abituzumab, adalimumab, afutuzumab, alacizumab pegol, amatuximab, anatumomab mafenatox, andecaliximab, anetumab ravtansine, apolizumab, arcitumomab, asclinbacumab, atezolizumab, avelumab, azintuxizumab vedotin, bavituximab, BCD-100, and bera Intamab mafodotin, belimumab, bemarituzumab, besilesomab, bevacizumab, bivatuzumab mertansine, brentuximab vedotin, brontiximab, cabilalizumab, camidanlumab tesirin, camrelizumab, cantuzumab mertansine, cantuzumab lavtansine, carotuximab, cantumaxomab, cBR96-doxorubicin immunoconjugate, semi Primab, sergituzumab amnaleukin, cetrelimab, cetuximab, civisatamab, sitatuzumab bogatox, cixutumumab, clivatuzumab tetraxetan, codrituzumab, cofetuzumab peridotin, coltuximab ravtansine, conatumumab, cusatuzumab, dacetuzumab, darotuzumab, daratumumab, demcizumab, denituzumab mafodotin, depatuxizumab mafodotin, delroti Ximab biotin, Detumomab, Dinutuximab, Drozitumab, DS-8201, Durigotuzumab, Durvalumab, Dusitgitumab, Duvortuximab, Eclomeximab, Edrecolomab, Elgemtuzumab, Elotuzumab, Emactuzumab, Emibetuzumab, Enapotomab vedotin, Enavatuzumab, Enfortumab vedotin, Enoblituzumab, Ensituximab,Epratuzumab, Ertumaxomab, Etaracizumab, Faricimab, Farletuzumab, FBTA05, Ficlatuzumab, Figitumumab, Framvotumab, Flotetuzumab, Futuximab, Galiximab, Gancotamab, Ganitumab, Gatipotuzumab, Gemtuzumab Ozogamicin, Girentuximab, Glembatumumab Vedotin, IBI308, Ibritumomab Tiuxetan, Icrucumab, Iradatuzumab Vedotin, IMAB362, Imalumab, Imgatuzumab, Indatuximab Rabtansine, Indusatumab Vedotin, Inebilisumab Intetumumab, ipilimumab, iratumumab, isatuximab, istiratumab, labetuzumab, lacunotuzumab, radazilatuzumab vedotin, lenzilumab, lexatumumab, rifastuzumab vedotin, loncastuzumab tesirin, rosatuximab vedotin, rilotumab satetraxetan, lintuzumab, lirilumab, lorvotuzumab mertansine, lucatumumab, lumiliximab, lumletuzumab, MABp1, mapatumumab, margetuximab, matuzumab, milatuzumab, mirvetuximab soravtansine, mitumomab, modotuximab , mogamulizumab, monalizumab, mosunetuzumab, moxetumomab pasudotox, nacolomabutafenatox, naptumomab estafenatox, narutumab, navicixizumab, naxitumab, necitumumab, nesbacumab, nimotuzumab, nivolumab, nofetumomab merpentan, obinutuzumab, ocalatuzumab, ofatumumab, olaratumab, olecurumab, onartuzumab, ontuxizumab, oportuzumab monatox, oregovomab, otlertuzumab, pamrevlumab, panitumumab, pancomab, palsatuzumab, pasotuzumab Cisizumab, patritumab, PDR001, pembrolizumab, pemtumomab, pertuzumab, pidilizumab, pinatuzumab vedotin, polatuzumab vedotin, pritumumab, racotumomab, radletuzumab, ramucirumab, rilotumumab, rituximab, lobatumumab, rosmantuzumab, rovalpituzumab tesirin, sacituzumab govitecan, samalizumab, samrotuzumab vedotin, seribantumab, sibrotuzumab, SGN-CD19A, siltuximab, siltratuzumab vedotin, sofituzumab vedotin, solitomab,Spartalizumab, tabalumab, tacatuzumab tetraextan, tapitumumab paptox, tarexitumab, taborimab, telisotuzumab vedotin, tenatumomab, tepotizimab, tetulomab, TGN1412, tigatuzumab, timigituzumab, tilagotumab, tislezulizumab, tisotuzumab vedotin, TNX-650, tobetumab, trastuzumab, trastuzumab emtansine, TRBS07, tremelimumab, Therapeutic options include tucotuzumab celmoleukin, ublituximab, urocupulumab, urelumab, utomilumab, vadastuximab butarilin, bundletuzumab vedotin, vanticutuzumab, vanucizumab, valisacumab, varlilumab, veltuzumab, besencumab, volociximab, bonlerolizumab, borsetuzumab mafodotin, votumumab, XMAB-5574, zalutumumab, zatuximab, xenoctuzumab, zolbetuximab, or tositumomab. In another aspect, the monoclonal antibody is directed to a cancer targeting advanced malignancies and lymphomas (such as non-Hodgkin's lymphoma), and to a cancer targeting advanced malignancies and lymphomas (such as non-Hodgkin's lymphoma), including neuroblastoma, sarcoma, metastatic brain cancer, ovarian cancer, prostate cancer, breast cancer (including triple-negative breast cancer), lymphoma, non-small cell lung cancer, gastric cancer, gastroesophageal junction adenocarcinoma, hematological cancers, melanoma, squamous cell carcinoma, Hodgkin's lymphoma, anaplastic large cell lymphoma, pancreatic cancer, acute lymphoblastic leukemia, acute myeloid leukemia, hepatocellular carcinoma, colorectal cancer, angiosarcoma, head and neck cancer, ovarian cancer, solid tumors, multiple myeloma, glioblastoma, testicular cancer, B-cell malignancies, urothelial cancer, chronic lymphocytic leukemia, adrenocortical carcinoma, It can be used to treat adenocortical carcinoma, acute myeloid leukemia, clear cell renal carcinoma, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, small cell lung cancer, hairy cell leukemia, renal cell carcinoma, nasopharyngeal carcinoma, glioma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, and other cancers.

[0119] In one embodiment, the anticancer drug is a photosensitizer. Photosensitizers are used in conjunction with light and molecular oxygen to induce cell death. In one embodiment, the compositions disclosed herein include a photosensitizer. Without wishing to be bound by theory, a first photosensitizer is administered in the absence of light until the photosensitizer reaches a critical concentration in the tissue to be treated. Subsequently, the photosensitizer is activated by exposure to a level of light sufficient to activate the photosensitizer while minimizing damage to nearby healthy tissue. In a further embodiment, malignant cancers of the head and neck, lung, bladder, and skin (including Kaposi's sarcoma and non-melanoma skin cancer), metastatic breast cancer, gastrointestinal cancer, and bladder cancer may be particularly sensitive to photosensitizers. In one embodiment, the photosensitizer may be a porphyrin, chlorine, or dye. In another embodiment, the photosensitizer is 5-aminolevulinic acid (Levulan), silicon phthalocyanine Pc4, naphthalocyanine, metallo-naphthalocyanine, purpurinse(IV), copper octaethylbenzochlorin, purpurin zinc(II), m-tetrahydroxyphenylchlorin, mono-L-aspartylchlorin e6, Allumera, Photofrin, Visdyne (verteporfin), Foscan, Metvix, Hexvix, Cysview, Laserphyrin, Antrin, Photochlor, Photosens, Photrex, Purlytin, Lutex, Lumacan, Cevira, Visonac, BF-200ALA, Amphigenez, azadipyrromethene, zinc phthalocyanine, or another photosensitizer.

[0120] In one embodiment, the anticancer drug is a protein kinase inhibitor.Protein kinase inhibitors block the action of one or more protein kinases.Protein kinases may be overexpressed in certain types of cancer.In some embodiments, the compositions disclosed herein comprise one or more protein kinase inhibitors. In further aspects, the protein kinase inhibitor can be afatanib, axitinib, bosutinib, cetuximab, cobimetinib, crizotinib, cabozantinib, dasatinib, entrectinib, erlotinib, fostamatinib, gefihitinib, ibrutinib, imatinib, lapatinib, lenvatinib, mubritinib, nilotinib, pazopanib, pegaptanib, ruxolitinib, sorafenib, sunitinib, SU6656, vandetanib, vemurafenib, or another protein kinase inhibitor. In some embodiments, protein kinase inhibitors are particularly useful against non-small cell lung cancer, renal cell carcinoma, chronic myeloid leukemia, advanced melanoma, metastatic medullary thyroid carcinoma, neruoblastoma, colorectal cancer, breast cancer, thyroid cancer, renal cancer, myelofibrosis, renal cell carcinoma, or gastrointestinal stromal tumors.

[0121] In one embodiment, the anticancer drug can be a p-glycoprotein inhibitor. P-glycoprotein is a promiscuous drug efflux pump, which may reduce the bioavailability of drugs at tumor sites. Without wishing to be bound by theory, p-glycoprotein inhibitors can enhance the intracellular accumulation of anticancer drugs. In one embodiment, this is achieved by binding to the p-glycoprotein transporter, which can inhibit transmembrane transport of the anticancer drug. Inhibition of transmembrane transport can result in an increased intracellular concentration of the anticancer drug, which can ultimately enhance its cytotoxicity. In a further aspect, the p-glycoprotein inhibitor is selected from the group consisting of verapamil, cyclosporine, tamoxifen, calmodulin antagonists, dexverapamil, dexniguldipine, valspodar (PSC833), biriquidar (VX-710), tariquidar (XR9576), zosuquidar (LY335979), laniquidar (R101933), elacridar (GF120918), timcodar (VX-853), taxifolin, naringenin, diosmin, quercetin, diltiazem, bepridil, nicardipine, nifedipine, felodipine, isradipine, trifluoperazine, clopenthixol, trifluopromazine, flupenthixol, emopamil, gallopamil, Ro11-2933, amiodarone, clarithromycin, colchicine, erythromycin, lansoprazole, omeprazole, another proton pump inhibitor, paroxetine, sertraline, quinidine, or any combination thereof. In one embodiment, p-glycoprotein inhibitors are particularly effective in treating drug-resistant cancers, including as part of a combination therapy.

[0122] In one embodiment, the anticancer drug is an autophagy inhibitor. Autophagy, as used herein, is a mechanism of intracellular degradation that depends on lysosomes. Autophagy involves multiple proteins, including some protein kinases. Autophagy inhibitors can target the early stage of autophagy (i.e., the pathway involved in the initial step of core autophagy machinery) or the later stage (i.e., the function of lysosomes). In one embodiment, the composition disclosed herein comprises one or more autophagy inhibitors. In further embodiments, the autophagy inhibitor can be 3-methyladenine, wortmannin, LY294002, PT210, GSK-2126548, spautin-1, SAR405, Compound 31, VPS34-IN1, PIK-III, Compound 6, MRT68921, SBI-0206965, pepstatin A, E64d, bafilomycin A1, clomipramine, lucanthone, chloroquine, hydroxychloroquine, Lys05, ARN5187, Compound 30, or another autophagy inhibitor. In further embodiments, the autophagy inhibitor can be useful in treating non-small cell lung cancer, chronic myeloid leukemia, metastatic prostate cancer, castration-resistant prostate cancer, metastatic colorectal cancer, breast cancer, brain metastasis, relapsed and refractory multiple myeloma, glioblastoma multiforme, and other cancers.

[0123] In one embodiment, the anticancer drug is a radiosensitizer. Radiosensitizers make tumor cells more sensitive to radiation therapy. In one embodiment, the compositions disclosed herein comprise one or more radiosensitizers. In one embodiment, the radiosensitizer is a fluoropyrimidine, gemcitabine, platinum analog (such as cisplatin), NBTXR3, Nimoral, trans sodium crocetinate, NVX-108, misonidazole, metronidazole, tirapazamine, or another radiosensitizer. Without wishing to be bound by theory, radiosensitizers interfere with the regulation of cell cycle checkpoints in tumor cells, particularly those caused by DNA damage caused by radiation therapy. Some radiosensitizers may crosslink DNA strands, exacerbating the DNA damage caused by radiation therapy. In one embodiment, the radiosensitizer may be particularly useful in soft tissue sarcomas of the extremities and trunk wall, hepatocellular carcinoma, prostate cancer, oral squamous cell carcinoma, squamous cell carcinoma of the head and neck, and glioblastoma.

[0124] In one embodiment, the anticancer drug is a PARP inhibitor. PARP inhibitors act on the enzyme poly ADP-ribose polymerase. In one embodiment, the composition disclosed herein comprises one or more PARP inhibitors. Without wishing to be bound by theory, PARP inhibitors can block PARP activity, prevent DNA damage repair, and localize PARP protein at the site of DNA damage, thereby blocking DNA replication and thus being cytotoxic. In one embodiment, PARP inhibitors are effective against recurrent platinum-sensitive ovarian cancer, tumors caused by BRCA1, BRCA2 or PALB2 mutation, PTEN-deficient tumors (e.g., certain prostate cancers), fast-growing tumors with low oxygen levels, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, squamous cell lung cancer, hematological malignancies, advanced or recurrent solid tumors, non-small cell lung cancer, triple-negative breast cancer, colorectal cancer, metastatic breast cancer and ovarian cancer, and metastatic melanoma. In one embodiment, the PARP inhibitor is MK-4827 (also known as niraparib), rucaparib, iniparib, talazoparib, olaparib, veliparib, CEP9722, E7016, BGB2-290, 3-aminobenzamide, or another PARP inhibitor.

[0125] In one embodiment, the anti-cancer agent is an interleukin. Interleukins are cytokines, or signaling molecules, typically expressed by white blood cells. In some embodiments, exogenously synthesized interleukins can be used as cancer treatments. In one embodiment, the compositions disclosed herein include one or more interleukins. In a further embodiment, the interleukin can be PROLEUKIN® (also known as IL-2 and aldesleukin) or another interleukin. Without wishing to be bound by theory, interleukins can help promote the growth of killer T cells and other immune cells as they become associated with emerging tumor cells, thereby enhancing the function of the subject's immune system. In another embodiment, interleukins can be effective against kidney cancer and melanoma.

[0126] In one embodiment, the anticancer drug is an mTOR inhibitor. An mTOR inhibitor is a drug that inhibits the mechanistic target of rapamycin. mTOR is a serine / threonine-specific protein kinase and is important for regulating metabolism, growth, and cell proliferation. In one embodiment, the compositions disclosed herein include one or more mTOR inhibitors. In a further embodiment, the mTOR inhibitor can be rapamycin, sirolimus, temsirolimus, everolimus, ridaforolimus, deforolimus, dactolisib, sapanisertib, AZD8055, AZD2014, or another mTOR inhibitor. Without wishing to be bound by theory, mTOR inhibitors act on T cell proliferation and proliferative responses induced by various cytokines, including processes related to tumor angiogenesis. In one embodiment, certain mTOR inhibitors can be primarily effective against tumors with specific genetic determinants or mutations. mTOR inhibitors may be particularly effective against renal cell carcinoma, subependymal giant cell astrocytoma, advanced neuroendocrine tumors of pancreatic origin, or advanced breast cancer. In another embodiment, mTOR inhibitors may be used as monotherapy for disease stabilization or as part of combination therapy for many cancer types.

[0127] In one embodiment, the anti-cancer agent is an aromatase inhibitor. Aromatase inhibitors are useful for the treatment and prevention of breast cancer and ovarian cancer, particularly in postmenopausal women, high-risk women, and women with hormone-sensitive tumors. In one embodiment, the compositions disclosed herein contain one or more aromatase inhibitors. Without wishing to be bound by theory, aromatase inhibitors block the conversion of various precursors, including androstenedione and testosterone. In one embodiment, the aromatase inhibitor is an irreversible steroid inhibitor, which can act by forming a permanent bond with the aromatase enzyme. In another embodiment, the aromatase inhibitor is a non-steroid inhibitor, which reversibly competes with the substrate for the aromatase enzyme. In yet another embodiment, the specific mechanism of action of the aromatase inhibitor may be unknown. In one aspect, the aromatase inhibitor can be aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, 1,4,6-androstatriene-3,17-dione, 4-androstene-3,6,17-trione, or another aromatase inhibitor.

[0128] In one embodiment, the anticancer drug is an antiandrogen.Antiandrogens or androgen synthesis inhibitors prevent the biosynthesis of androgen hormones.In one embodiment, the compositions disclosed herein contain one or more antiandrogens.Without wishing to be bound by theory, antiandrogens can act at various different steps in the androgen synthesis pathway, including, but not limited to, inhibiting the conversion of cholesterol to steroid hormone precursors or inhibiting the conversion of pregnane steroids to androgens.In one embodiment, the antiandrogen can be aminoglutethimide (which also acts as an aromatase inhibitor), ketoconazole, abiraterone acetate, seviteronel, or another antiandrogen. e. Imaging agents

[0129] The stereocomplex disclosed herein may contain one or more imaging agents.As used herein, "imaging agent" refers to a compound or composition that enhances contrast, visibility or other properties during medical imaging procedures, such as, for example, X-ray, computed tomography and single-photon emission computed tomography, ultrasound, MRI (magnetic resonance imaging), nuclear medicine procedures (including positron emission tomography and related techniques), optical imaging, near-infrared imaging, angiography, venography, endoscopy, voiding cystourethrography, hysterosalpingography, intravenous urography or other medical imaging procedures.Imaging agents are generally non-toxic and stable in vivo.An ideal imaging agent should be rapidly excreted from the bloodstream, bind to specific target tissues and accumulate there.

[0130] In one embodiment, Z in component (II) 2 is an imaging agent, and the imaging agent is covalently attached to component (II). In another embodiment, the stereocomplex comprises the following components: X 1 -Y 1 -L 1 -Z 1 (I) X 2 -Y 2 -L 2 -Z 2 (II) (In the formula, X 1 and X 2 is a hydrophilic group, and Y 1 and Y 2 is PDLA or PLLA, L 1 and L 2 is a cleavable linker, and Z 1 is an anticancer drug, Z 2 is an imaging agent, and (1) Y 1 If is PDLA, then Y 2 is PLLA, and Y 1 If is PLLA, Y 2is PDLA, and (2) the ratio of the total number of D-lactic acid units in the stereocomplex to the total number of L-lactic acid units in the stereocomplex is 0.9:1.1 to 1.1:0.9. It consists of:

[0131] In another embodiment, the stereocomplex comprises the following components: X 1 -Y 1 -L 1 -Z 1 (I) X 2 -Y 2 -L 2 -Z 2 (II) X 5 -Y 5 -L 5 -Z 5 (IX) (In the formula, X 1 , X 2 and X 5 is a hydrophilic group, and Y 1 , Y 2 and Y 5 is PDLA or PLLA, L 1 , L 2 and L 5 is a cleavable linker, and Z 1 and Z 5 is a different anticancer drug, Z 2 is an imaging agent, and the ratio of the total number of D-lactic acid units in the stereocomplex to the total number of L-lactic acid units in the stereocomplex is 0.9:1.1 to 1.1:0.9. It consists of:

[0132] In one aspect, the imaging agent is 11 CL-methyl-methionine, 18 F-fluorodeoxyglucose, 18 F - sodium fluoride, 18 F fluorocholine, 18 F desmethoxyfalipride, 67 Ga-Ga 3+ , 68 Ga-dotatoc,68 Ga-PSMA, 111 In-diethylenetriaminepentaacetic acid, 111 In-white blood cells, 111 In-platelets, 111 In-Penetreotide, 111 In-octreotide, 123 I-iodide, 123 Io-iodine hiprate, 123 Im-iodobenzylguanidine, 123 I-FP-CIT, 125 I-fibrinogen, 131 I-iodide, 131 Im-iodobenzylguanidine, 81 Kr m -gas, 81 Kr m -aqueous solution, 13 N-ammonia, 15 O-water, 75 Se-selenolcholesterol, 75 Se-seleno-25-homo-tauro-cholate, 120 Tl-Tl + , 133 Xe-gas, 133 Xe (in isotonic sodium chloride solution), 99 Tc m -Pertechnetate, containing macroaggregates or microspheres 99 Tc m human albumin, 99 Tc m phosphonates and / or phosphates, 99 Tc m -diethylenetriaminepentaacetic acid, 99 Tc m -dimercaptosuccinic acid, 99 Tc m -colloid, 99 Tc m -hepatic iminodiacetic acid, 99 Tc m whole red blood cells, 99 Tc m -Mercaptoacetyltriglycine, containing examethasone-labeled leukocytes 99 Tc m Examethadime, 99 Tcm sester-methoxyisobutylisonitrile, 99 Tc m IMMU-MN3 mouse Fab'-SH anti-granulocyte monoclonal antibody fragment, 99 Tc m -Technegas, 99 Tc m human immunoglobulin, 99 Tc m - tetrofosmin, 99 Tc m -ethyl cysteine ​​dimer, or another radiopharmaceutical. In yet another embodiment, the radiopharmaceutical is a metal ion associated with a chelator.

[0133] In another embodiment, the imaging agent can be a radiological contrast agent. In a further embodiment, the imaging agent can be an iodinated contrast agent, which can be ionic, such as, for example, diatrizoate, metrizoate, iothalamate, or ioxaglate, or non-ionic, such as, for example, iopamidol, iohexol, ioxilan, iopromide, iodixanol, ioversol, or another iodinated contrast agent. In a further embodiment, the imaging agent can be based on barium sulfate or a gadolinium-based contrast agent, such as, for example, gadoterate, gadodiamide, gadobenate, gadopentetate, gadoteridol, gadofosveset, gadoversetamide, gadoxetate, gadobutrol, or another gadolinium chelator.

[0134] In yet another embodiment, the imaging agent can be an optical imaging agent useful for fluorescence, chromoendoscopy, or another optical imaging technique. In a further embodiment, the imaging agent can be methylene blue, indigo carmine, or another nonspecific dye. In an alternative embodiment, the imaging agent can be a fluorophore, such as, for example, fluorescein isothiocyanate, indocyanine green, rosamine, BODIPY (boron-dipyrromethane) derivatives, chalcone, xanthone, oxazole yellow, thiazole orange, fluorescein, luciferin, Texas red, squaraine, porphyrin, phthalocyanine, polymethine cyanine dyes (e.g., Cy3, Cy5, Cy5.5, Cy7), Alexa fluor, or a precursor molecule (e.g., 5-aminolevulinic acid) for a fluorescent metabolite (e.g., protoporphyrin X). In one embodiment, the fluorophore can be a metal chelator.

[0135] "Quantum dots" as referred to herein are nanoparticles made of semiconductor materials. Quantum dots have properties that differ from larger semiconductor particles and materials. These properties can be tuned by the size and shape of the particle. Quantum dots can be useful for medical imaging. In one aspect, imaging agents useful herein can include quantum dots that can be uncoated or coated or encapsulated by polymers or hydrogels. In one aspect, quantum dots have a high extinction coefficient and are useful for fluorescence-based imaging techniques. Additional Components

[0136] In addition to components (I) and (II), additional components can be used to generate the stereocomplex. In one aspect, the stereocomplexes disclosed herein can be used to perform functions such as maintaining the formation of stereocomplexes with various ratios of anticancer drugs, or to incorporate one or more additional anticancer drugs (Z 1 and Z 2The stereocomplex may contain one or more additional components to confer a specific function (other than the above), to target a particular cell or tissue type, or to exert another function. a. Anticancer drug ratio modifier

[0137] In one embodiment, additional component (VII): X 3 -Y 3 (VII) (In the formula, X 3 is the hydrophilic group previously described, and Y 3 is PDLA or PLLA).

[0138] In certain embodiments, two different anti-cancer drugs (Z 1 and Z 2 In cases where a 1:1 ratio of Z is desired, equimolar amounts of components (I) and (II) may be used. However, in certain embodiments, Z 1 and Z 2 The desired ratio of one anti-cancer agent to a second anti-cancer agent will depend on the type of cancer being treated in the subject.

[0139] The inclusion of component (VII) allows for the modification of the molar ratio of the anticancer drug present in the stereocomplex while maintaining the optimal ratio of D-lactic acid units to L-lactic acid units for the formation of the stereocomplex. As an example, the following scheme shows the formation of a stereocomplex containing Z 1 :Z 2 is presented to demonstrate how to generate a stereo complex with a 2:1 ratio. X 1 -PDLA-L 1 -Z 1 (I) (1 molar equivalent) X 2 -PLLA-L 2 -Z 2 (II) (0.5 molar equivalents) X 3 -PLLA (VII) (0.5 molar equivalents)

[0140] In this example, components (I), (II), and (VII) are mixed, and the number of D-lactic acid units in component (I) is equal to or approximately equal to the sum of the L-lactic acid units present in components (II) and (VII). Therefore, by varying the amount of component (VII) added as component (II) is reduced, the Z-lactic acid units present in the stereocomplex can be adjusted. 1 and Z 2 It is still possible to vary the relative amounts of D-lactic acid units and L-lactic acid units to produce a stereocomplex and still balance the total number of D-lactic acid units and L-lactic acid units (i.e., the ratio of the total number of D-lactic acid units in the stereocomplex to the total number of L-lactic acid units in the stereocomplex is 0.9:1.1 to 1.1:0.9).

[0141] In one embodiment, the PDLA or PLLA present in component (VII) has a molecular weight of about 700 Da to about 5,000 Da, or about 750 Da to 4,000 Da, or about 1,000 Da to about 3,000 Da. Further, in this embodiment, the PDLA and PLLA have a molecular weight of about 700 Da, 750 Da, 800 Da, 900 Da, 1,000 Da, 1,250 Da, 1,500 Da, 2,000 Da, 2,500 Da, 3,000 Da, 3,500 Da, 4,000 Da, 4,500 Da, or 5,000 Da, any value can be the lower or upper endpoint of the range (e.g., 1,000 Da to 3,000 Da). In another embodiment, the PDLA or PLLA present in component (VII) has about the same molecular weight as the PDLA and PLLA present in components (I) and (II).

[0142] In another embodiment, the number of D-lactic acid units present in PDLA or L-lactic acid units present in PLLA in component (VII) is 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100, any value can be the lower or upper endpoint of a range (e.g., 10 to 60). In another embodiment, the PDLA or PLLA present in component (VII) has the same number of D-lactic acid units and L-lactic acid units as the PDLA and PLLA present in components (I) and (II).

[0143] In one embodiment, X in component (VII) 3 is a polyalkylene glycol having a molecular weight of about 1,000 Da to about 5,000 Da, or 1,500 Da to 4,500 Da, or 2,000 Da to 4,000 Da, or having a molecular weight of about 1,000 Da, 1,500 Da, 2,000 Da, 2,500 Da, 3,000 Da, 3,500 Da, 4,000 Da, 4,500 Da, or about 5,000 Da, any value can be the lower and upper endpoints of a range (e.g., 2,000 Da to 4,000 Da).

[0144] In another embodiment, X in component (VII) 3 is a monomethoxypolyethylene glycol having a molecular weight of about 1,000 to about 5,000 Da, or 1,500 Da to 4,500 Da, or 2,000 Da to 4,000 Da, or having a molecular weight of about 1,000 Da, 1,500 Da, 2,000 Da, 2,500 Da, 3,000 Da, 3,500 Da, 4,000 Da, 4,500 Da, or about 5,000 Da, any value can be the lower and upper endpoints of the range (e.g., 2,000 Da to 4,000 Da). In one embodiment, X in components (I), (II), and (VII) of the stereocomplex disclosed herein 1 , X 2 and X 3 are each monomethoxypolyethylene glycols having the same molecular weight. b. Targeting group

[0145] In one aspect, the stereocomplexes disclosed herein also comprise component (VIII): TA-X 4 -Y 4 (VIII) (In the formula, X 4 is a hydrophilic group as previously discussed, and Y 4 is PDLA or PLLA, and TA is a targeting agent or targeting group). In a further embodiment, the stereocomplex comprises two or more components (VIII) with different targeting groups. The targeting group TA is a hydrophilic group X 4 is covalently bonded to

[0146] In one embodiment, X 4 may be a polyalkylene glycol having a molecular weight of about 1,000 Da to about 5,000 Da. 4 The molecular weights of X in components (I) and (II) are 1 and X 2 The molecular weight is larger than that of

[0147] In one embodiment, X in component (VIII) 4 is a polyalkylene glycol having a molecular weight of about 1,000 Da to about 5,000 Da, or 1,500 Da to 4,500 Da, or 2,000 Da to 4,000 Da, or having a molecular weight of about 1,000 Da, 1,500 Da, 2,000 Da, 2,500 Da, 3,000 Da, 3,500 Da, 4,000 Da, 4,500 Da, or about 5,000 Da, any value can be the lower and upper endpoints of a range (e.g., 2,000 Da to 4,000 Da).

[0148] In another embodiment, X in component (VIII) 4is a polyethylene glycol having a molecular weight of about 1,000 to about 5,000 Da, or about 1,000 Da to about 5,000 Da, or 1,500 Da to 4,500 Da, or 2,000 Da to 4,000 Da, or having a molecular weight of about 1,000 Da, 1,500 Da, 2,000 Da, 2,500 Da, 3,000 Da, 3,500 Da, 4,000 Da, 4,500 Da, or about 5,000 Da, any value can be the lower and upper endpoints of a range (e.g., 2,000 Da to 4,000 Da).

[0149] In one embodiment, the PDLA or PLLA present in component (VIII) has a molecular weight of about 700 Da to about 5,000 Da, or about 750 Da to 4,000 Da, or about 1,000 Da to about 3,000 Da. Further, in this embodiment, the PDLA and PLLA have a molecular weight of about 700 Da, 750 Da, 800 Da, 900 Da, 1,000 Da, 1,250 Da, 1,500 Da, 2,000 Da, 2,500 Da, 3,000 Da, 3,500 Da, 4,000 Da, 4,500 Da, or 5,000 Da, any value can be the lower or upper endpoint of the range (e.g., 1,000 Da to 3,000 Da). In another embodiment, the PDLA or PLLA present in component (VIII) has about the same molecular weight as the PDLA or PLLA present in components (I) and (II).

[0150] In another embodiment, the number of D-lactic acid units present in PDLA or L-lactic acid units present in PLLA in component (VIII) is 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100, any value can be the lower or upper endpoint of a range (e.g., 10 to 60). In another embodiment, the PDLA or PLLA present in component (VII) has the same number of D-lactic acid units and L-lactic acid units as the PDLA and PLLA present in components (I) and (II).

[0151] The use of a targeting group in compound (VIII) having a stereocomplex described herein can better localize anticancer drugs to specific sites in the body or in specific tissue types. Furthermore, in these embodiments, the targeting group improves the specificity of the stereocomplex to cancer cells. In a further embodiment, such targeting reduces the systemic side effects of the anticancer drug. In one embodiment, the targeting group can be an antibody, antibody fragment, aptamer, peptide, oligosaccharide or other carbohydrate, lectin, or similar molecule. A structure complementary to a cell surface antigen or receptor can be used as the targeting group. In one embodiment, the targeting group is an antibody, antibody fragment, sugar, epitope-binding peptide, or aptamer. In a further embodiment, the targeting group can be a monosaccharide, disaccharide, oligosaccharide, or methacryloylated sugar unit; an antibody such as IgG (rat immunoglobulin) or an antibody fragment; a protein such as transferrin or melanocyte-stimulating hormone (MSH); or a peptide. In another embodiment, the targeting group can be galactosamine, galactose, glucose, glucosamine, mannosamine, fucosylamine, lactose, a folic acid derivative, a hormone (e.g., MSH, secretin), an opiate, a monoclonal antibody, or a polyclonal antibody. In one embodiment, the targeting group can be a Fab' derived from the OV-TL16 antibody specific for CD47 (expressed on the majority of ovarian cancer cells) or an antibody directed against prostate-specific membrane antigen (PSMA).

[0152] In one embodiment, the targeting group can be a peptide, such as arginylglycylaspartic acid (RGD), which is a specific sequence recognized by integrins. As used herein, integrins are proteins that function to attach the cytoskeleton to the extracellular matrix (ECM) and sense whether this adhesion occurs. Furthermore, in this embodiment, integrins are involved in cell adhesion to ECM and its prevention in apoptosis, tissue regeneration, and other processes related to cancer cell proliferation. In yet another embodiment, integrins are overexpressed on tumor cells and tumor vasculature. In one embodiment, the RGD targeting group used herein helps deliver higher concentrations of the stereocomplexes disclosed herein to tumor tissues while minimizing interaction with nearby healthy cells. In a further embodiment, the RGD targeting group can be linear or cyclic (i.e., cRGD).

[0153] In another embodiment, the targeting group can be folic acid or folate. Furthermore, in this embodiment, folate has a high affinity for folate receptors, which capture the ligand and concentrate folate in the cytosol using endocytosis mechanisms. In one embodiment, folate receptors are overexpressed on the surface of malignant cancer cells and activated macrophages. In some embodiments, activated macrophages are found in inflamed tissues and tissues with a wide range of disease symptoms. Furthermore, in this embodiment, using a folate ligand as a targeting group can help localize the stereocomplexes disclosed herein in the vicinity of tumors or other areas of diseased tissues.

[0154] In one embodiment, component VIII has the structure [ka] (In the formula, n 3 is 45 to 90, m 3 is 15 to 60, C aThe stereochemistry in is R or S) It has.

[0155] In one embodiment, the targeting group (TA) in structure XV can be an unsubstituted or substituted sugar. Examples of sugars useful herein include, but are not limited to, glucose, ribose, galactose, mannose, fructose, fuculose, glucosamine, or fucoidan. In one embodiment, the targeting group in structure XV is glucose or a substituted glucose. In another embodiment, the targeting group in structure XV is glucose substituted with one or more alkyl groups, as defined herein, and one or more hydroxyl protons of glucose can be replaced by alkyl groups. In another embodiment, the targeting group in structure XV is glucose substituted with one or more methyl, ethyl, or propyl groups. In another embodiment, the targeting group in structure XV is glucose substituted with one methyl group. In another embodiment, the targeting group in structure XV is glucose in which the C1 hydroxyl proton is replaced by a methyl group. In one embodiment, the targeting group in structure XV is methyl-α-glucose or methyl-β-glucose. In another embodiment, the targeting group in structure XV is methyl-α-glucose, and the methylated glucose moiety is covalently attached to the carbonyl group in structure XV at the C6 hydroxyl position, as illustrated in Figure 3.

[0156] Although not wishing to be bound by theory, according to the Warburg effect, cancer cells require more glucose for faster proliferation. In some embodiments, glucose transport is supported by the GLUT family and the SGLT family. SGLT transporters are found in both the early and late stages of tumor growth, while upregulated GLUT transporters are usually found in the later stages of tumor development. Furthermore, in this embodiment, the use of sugars, such as glucose or substituted glucose, as targeting groups can increase the uptake and penetration of the stereocomplexes described herein into the vicinity of or within tumors, which ultimately leads to improved therapeutic efficacy.

[0157] In one embodiment, the targeting group is a ligand for a cell-surface receptor on a cell, such as a cancer cell or an endothelial cell that is part of the vasculature of a solid tumor. In one embodiment, biorecognition of the targeting group on the cell surface results in increased uptake of the stereocomplex by receptor-mediated endocytosis, pinocytosis, or another selective mechanism. In a further embodiment, this increased uptake results in improved therapeutic efficacy.

[0158] In another embodiment, intracellular targeting to specific organelles can be achieved by using specific targeting agents.In a further embodiment, mitochondria can be targeted using a positively charged triphenylphosphonium ion linked to the stereocomplex disclosed herein previously described.In a related embodiment, nuclear targeting can be achieved by using a steroid hormone as a targeting group.An example of component (VIII) is presented in Figure 3.

[0159] The inclusion of component (VIII) allows for the modification of the molar ratio of the anticancer drug present in the stereocomplex while maintaining the optimal ratio of D-lactic acid units to L-lactic acid units for the formation of the stereocomplex. As an example, the following scheme shows the formation of Z-lactic acid units using component (VIII): 1 :Z 2is presented to demonstrate how to generate a stereocomplex with a 2:1 ratio, where the total number of D-lactic acid units is equal to the total number of L-lactic acid units. X 1 -PDLA-L 1 -Z 1 (I) (1 molar equivalent) X 2 -PLLA-L 2 -Z 2 (II) (0.5 molar equivalents) TA-X 4 -PLLA (VIII) (0.5 molar equivalents)

[0160] In this example, components (I), (II), and (VIII) are mixed, and the number of D-lactic acid units in component (I) is equal to or approximately equal to the sum of the L-lactic acid units present in components (II) and (VIII). Therefore, by varying the amount of component (VIII) added as component (II) is reduced, the Z-lactic acid units present in the stereocomplex can be adjusted. 1 and Z 2 It is still possible to vary the relative amounts of D-lactic acid units and L-lactic acid units to produce a stereocomplex and still balance the total number of D-lactic acid units and L-lactic acid units (i.e., the ratio of the total number of D-lactic acid units in the stereocomplex to the total number of L-lactic acid units in the stereocomplex is 0.9:1.1 to 1.1:0.9).

[0161] In another embodiment, component (VII) can be added to components (I), (II) and (VIII) to form a stereocomplex. By way of example, the following scheme illustrates the Z 1 :Z 2 is presented to demonstrate how to generate a stereocomplex with a 2:1 ratio, where the total number of D-lactic acid units is equal to the total number of L-lactic acid units. X 1 -PDLA-L 1 -Z 1 (I) (1 molar equivalent) X 2 -PLLA-L2 -Z 2 (II) (0.5 molar equivalents) X 3 -PLLA (VII) (0.25 molar equivalents) TA-X 4 -PLLA (VIII) (0.25 molar equivalents) c. Additional anticancer drugs

[0162] In another aspect, the stereocomplexes disclosed herein have the formula (IX): X 5 -Y 5 -L 5 -Z 5 (IX) (In the formula, X 5 is the hydrophilic group previously described, and Y 5 is PDLA or PLLA, L 5 is a cleavable linker, and each Z 5 is an anticancer agent described herein, and Z 5 is Z 1 and Z 2 (different from The composition may include one or more components having the formula:

[0163] In one embodiment, X 5 In another embodiment, X in component (IX) may be a polyalkylene glycol having a molecular weight of about 1,000 Da to about 5,000 Da. 5 is a polyalkylene glycol having a molecular weight of about 1,000 Da to about 5,000 Da, or 1,500 Da to 4,500 Da, or 2,000 Da to 4,000 Da, or having a molecular weight of about 1,000 Da, 1,500 Da, 2,000 Da, 2,500 Da, 3,000 Da, 3,500 Da, 4,000 Da, 4,500 Da, or about 5,000 Da, any value can be the lower and upper endpoints of a range (e.g., 2,000 Da to 4,000 Da).

[0164] In another embodiment, X in component (IX) 5is a polyethylene glycol having a molecular weight of about 1,000 to about 5,000 Da, or 1,500 Da to 4,500 Da, or 2,000 Da to 4,000 Da, or having a molecular weight of about 1,000 Da, 1,500 Da, 2,000 Da, 2,500 Da, 3,000 Da, 3,500 Da, 4,000 Da, 4,500 Da, or about 5,000 Da, any value can be the lower and upper endpoints of a range (e.g., 2,000 Da to 4,000 Da).

[0165] In one embodiment, the PDLA or PLLA present in component (IX) has a molecular weight of about 700 Da to about 5,000 Da, or about 750 Da to 4,000 Da, or about 1,000 Da to about 3,000 Da. Further, in this embodiment, the PDLA and PLLA have a molecular weight of about 700 Da, 750 Da, 800 Da, 900 Da, 1,000 Da, 1,250 Da, 1,500 Da, 2,000 Da, 2,500 Da, 3,000 Da, 3,500 Da, 4,000 Da, 4,500 Da, or 5,000 Da, any value can be the lower or upper endpoint of the range (e.g., 1,000 Da to 3,000 Da). In another embodiment, the PDLA or PLLA present in component (IX) has about the same molecular weight as the PDLA and PLLA present in components (I) and (II).

[0166] In another embodiment, the number of D-lactic acid units present in PDLA or L-lactic acid units present in PLLA in component (IX) is 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100, any value can be the lower or upper endpoint of a range (e.g., 10 to 60). In another embodiment, the PDLA or PLLA present in component (IX) has the same number of D-lactic acid units and L-lactic acid units as the PDLA and PLLA present in components (I) and (II).

[0167] In one aspect, L 5includes a cleavable group as described herein, including, but not limited to, a disulfide group, an ester group, a hydrazone group, an acetal group, an imine group, a β-thiopropionate group, or an amide group. 5 may contain one or more of these groups. 5 may also contain additional functional groups so that the cleavable linker can be covalently attached to the PDLA or PLLA.

[0168] In some embodiments, by incorporating one or more components of formula (VIII) into the stereocomplex in this manner, additional anti-cancer drugs can be administered to the subject. In one embodiment, three, four, or more than four anti-cancer drugs can be incorporated into the stereocomplexes described herein.

[0169] The inclusion of component (IX) allows for the modification of the molar ratio of the anticancer drug present in the stereocomplex while maintaining the optimal ratio of D-lactic acid units to L-lactic acid units for the formation of the stereocomplex. As an example, the following scheme illustrates the formation of Z-lactic acid units using component (IX): 1 :Z 2 :Z 5 is presented to demonstrate how to generate a stereocomplex with a 2:1:1 ratio, where the total number of D-lactic acid units is equal to the total number of L-lactic acid units. X 1 -PDLA-L 1 -Z 1 (I) (1 molar equivalent) X 2 -PLLA-L 2 -Z 2 (II) (0.5 molar equivalents) X 5 -PLLA-L 5 -Z 5 (IX) (0.5 molar equivalents)

[0170] In this example, components (I), (II), and (IX) are mixed, and the number of D-lactic acid units in component (I) is equal to or approximately equal to the sum of the L-lactic acid units present in components (II) and (VIII). Therefore, by varying the amount of component (IX) added as component (II) is reduced, the Z present in the stereocomplex can be adjusted. 1 , Z 2 and Z 5 It is still possible to vary the relative amounts of D-lactic acid units and L-lactic acid units to produce a stereocomplex and still balance the total number of D-lactic acid units and L-lactic acid units (i.e., the ratio of the total number of D-lactic acid units in the stereocomplex to the total number of L-lactic acid units in the stereocomplex is 0.9:1.1 to 1.1:0.9).

[0171] In other embodiments, components (VII) and / or (VIII) can be added to components (I), (II) and (IX) to form a stereocomplex. d. adjuvant

[0172] In one embodiment, one or more adjuvants can be incorporated into the stereocomplexes described herein. For example, an adjuvant can be combined with components I and II described herein to produce a stereocomplex containing the adjuvant.

[0173] In one aspect, the adjuvant targets stromal cells. As used herein, "stromal cells" refer to connective tissue cells in any organ that collectively form the stroma. In a further aspect, the interaction of stromal cells and cancer cells plays a role in cancer progression. In yet another aspect, stromal cells can release growth factors that promote cell division or provide an extracellular matrix that supports tumor cells. In a further aspect, a stroma-rupturing agent can be used in the compositions disclosed herein. In one aspect, the stroma-rupturing agent can be, for example, an angiotensin receptor blocker such as losartan, azilsartan, candesartan, eprosartan, irbesartan, olmesartan, telmisartan, valsartan, or a combination thereof. In another embodiment, the stroma-rupturing agent can be a flavonoid such as, for example, luteolin, quercetin, genistein, catechin, cyaniding, naringenin, delphinidin, malvidin, petunidin, peonidin, pelargonidin, gallocatechin, catechin-3-gallate, epicatechin, epigallocatechin, daidzein, glycetein, equol, kaempferol, myricetin, eriodictyol, hesperitin, taxifolin, or a combination thereof.

[0174] In another embodiment, the adjuvant can target fibrosis and / or cancer-promoted fibrosis. In a further embodiment, fibrosis is a component of the tumor microenvironment and can significantly affect cancer behavior. In a further embodiment, fibrosis is characterized by the infiltration and proliferation of multipotent stromal cells (i.e., mesenchymal cells) in the interstitial space. In a further embodiment, an antifibrotic agent can be used in the compositions disclosed herein. In one embodiment, the antifibrotic agent can be, for example, a pyridine such as pirfenidone, mimosine, ciclopirox, diodon, bemeglide, deferiprone, or a combination thereof. In another embodiment, the antifibrotic agent can be N-acetylcysteine, etanercept, bosentan, sildenafil, nintedanib, colchicine, or a combination thereof.

[0175] In another embodiment, the adjuvant may be an aromatase inhibitor (anastrozole, letrozole, exemestane), an estrogen blocker (tamoxifen, toremifene, fulvestrant, fulvestrant), an ovarian function blocker (goserelin, leuprolide), a gonadotropin-releasing hormone agonist (buserelin, histrelin, leuprorelin, triptorelin, nafarelin), an estrogen modulator (toremifene citrate), a progestin therapeutic agent (megestrol acetate), an LHRH agonist (pharmagon), an androgen-lowering agent (abiraterone, ketoconazole), an antiandrogen (flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide, darolutamide), or the like. In some embodiments, these therapies may be used as adjuvants in the methods disclosed herein.

[0176] In yet another embodiment, immunotherapies can be used as adjuvants in conjunction with the methods disclosed herein. In one embodiment, these can include immunosuppressants, including corticosteroids (hydrocortisone), methotrexate, and interferons (e.g., interferon alpha-2A, alpha-2b, alpha-n3, beta-1a, beta-1b, gamma-1b, etc.). e. Exemplary Constituents and Stereocomplexes

[0177] In one aspect, disclosed herein is a stereocomplex wherein component (I) has the following features: X 1 is a monomethoxypolyethylene glycol having a molecular weight of about 2,000 Da to about 4,000 Da, and the number of L-lactic acid units or D-lactic acid units is about 15 to about 60, and L 1 contains a disulfide group, and Z 1 is mertansine (DM1). Additionally, in this embodiment, the components can be abbreviated as Lss-DM1 and / or Dss-DM1, which further specify the polymer stereochemistry, linker group, and anticancer drug.

[0178] In another embodiment, component (I) has structure (III): [ka] (In the formula, n 1 is 45 to 90, m 1 is 15 to 60, o is 1 to 4; C a The stereochemistry in is R or S) Disclosed herein is a stereocomplex having the formula:

[0179] In a further embodiment, o in formula (III) is 2.

[0180] In another aspect, disclosed herein are stereocomplexes wherein component (II) has the following features: X 2 is a monomethoxypolyethylene glycol having a molecular weight of about 2,000 Da to about 4,000 Da, and the number of L-lactic acid units or D-lactic acid units is about 15 to about 60, and L 2 contains an ester, hydrazone or disulfide group, and Z 2 is docetaxel. In any of these embodiments, docetaxel may be abbreviated as DTX (e.g., Lss-DTX refers to a stereocomplex component having PLLA, a disulfide linkage, and docetaxel).

[0181] In another embodiment, component (II) has structure (IV): [ka] (In the formula, n 2 is 45 to 90, m 2 is 15 to 60, p is 0 to 7; C a The stereochemistry in is R or S) Disclosed herein is a stereocomplex having the formula:

[0182] In one embodiment, p in formula (IV) is 2.

[0183] In yet another embodiment, component (II) has structure (V): [ka] (In the formula, n 2 is 45 to 90, m 2 is 15 to 60, each p is independently 0 to 7; q is 1 to 7; C aThe stereochemistry in is R or S) Disclosed herein is a stereocomplex having the formula:

[0184] In a further embodiment, each p is 2 and q is 3.

[0185] In yet another embodiment, component (II) has structure (VI): [ka] (In the formula, n 2 is 45 to 90, m 2 is 15 to 60, each p is independently 0 to 7; C a The stereochemistry in is R or S) Disclosed herein is a stereocomplex having the formula:

[0186] In another embodiment, in structure (VI), each p is 2. f. Pharmaceutical Compositions

[0187] The stereocomplexes described herein can be combined with at least one pharmaceutically acceptable carrier to produce a pharmaceutical composition. Pharmaceutical compositions can be prepared using techniques known in the art. In one embodiment, the pharmaceutical composition is prepared by mixing the stereocomplexes with a pharmaceutically acceptable carrier.

[0188] Pharmaceutically acceptable carriers are known to those skilled in the art and are most typically standard carriers including solutions such as sterile water, saline, and buffered solutions at physiological pH for administration to humans and / or other mammals.

[0189] The molecules intended for pharmaceutical delivery may be formulated into pharmaceutical compositions. In addition to the stereocomplexes described herein, the pharmaceutical compositions may include carriers, thickeners, diluents, buffers, preservatives, surfactants, etc. The pharmaceutical compositions may also include one or more additional active ingredients, such as antimicrobial agents, anti-inflammatory agents, anesthetics, etc.

[0190] The pharmaceutical compositions can be administered in several ways, depending on whether local or systemic treatment is desired and on the area to be treated. Administration can be parenteral, oral, subcutaneous, intralesional, intraperitoneal, intravenous, or intramuscular.

[0191] Preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous carriers include alcoholic / aqueous solutions, emulsions, or suspensions containing saline and buffered media. Parenteral vehicles, if necessary for concomitant use with the disclosed compositions and methods, include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's solution, or fixed oils. Intravenous vehicles, if necessary for concomitant use with the disclosed compositions and methods, include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases, and the like.

[0192] In one aspect, provided herein is a pharmaceutical composition comprising a stereocomplex described herein and a pharmaceutically acceptable carrier or excipient. Preparation and characterization of stereocomplexes

[0193] In any of the above embodiments, a solution of PLLA- and PDLA-conjugated polymers dissolved in a compatible organic solvent and an anticancer drug and / or imaging agent can be mixed together with stirring, and then the solvent can be replaced with a buffer to prepare the stereocomplexes described herein. As with the precursor components, in some embodiments, the particle size of the stereocomplexes can be characterized using dynamic light scattering. In further embodiments, the melting temperatures of the crystalline anticancer drug, the prepared prodrug, and the stereocomplexes can be characterized using techniques such as differential scanning calorimetry. Non-limiting methods for generating stereocomplexes are provided in the Examples.

[0194] In one embodiment, the stereocomplexes herein are nanoparticles. In a further embodiment, the stereocomplexes have an average diameter of 50 to 500 nm, 100 to 400 nm, or 100 to 200 nm. In yet another embodiment, the diameter of the nanoparticles can be measured using dynamic light scattering (DLS), transmission electron microscopy (TEM), scanning electron microscopy (SEM), atomic force microscopy (AFM), photon correlation spectroscopy (PCS), X-ray diffraction (XRD), or other methods. Stereo Complex Applications

[0195] The stereocomplexes described herein are effective for delivering one, preferably two or more, anticancer drugs to a subject using a single delivery device. The selection of cleavable linkers can be varied for each component in the stereocomplex to deliver each anticancer drug at a specific rate (e.g., immediate release, delayed release, controlled release). Depending on the type of cancer being treated, the selection of anticancer drug and cleavable linker can be fine-tuned to maximize the efficacy of the stereocomplex in treating cancer. As demonstrated below, stereocomplexes enable the safe delivery of two anticancer drugs while minimizing unwanted side effects associated with coadministration of the drugs. Furthermore, stereocomplexes enable the delivery of anticancer drugs such that the drugs affect each other synergistically.

[0196] In one aspect, when the stereocomplex is a nanoparticle, tumor targeting is improved by utilizing the "enhanced permeability and retention (EPR) effect." As used herein, "enhanced permeability and retention (EPR) effect" refers to the tendency of nanoparticles to accumulate more in tumor tissue than in healthy tissue. In one aspect, the stereocomplexes disclosed herein, due to their average particle size, tend to accumulate in or near cancer cells in the absence of, or in addition to, any specific cell targeting.

[0197] In another aspect, the stereocomplexes have improved resistance to hydrolytic degradation. Without wishing to be bound by theory, the hydrophilic nature of the stereocomplexes allows the hydrophilic linker to form a thick dynamic hydration shell around the nanoparticles, which can prevent serum protein absorption to the nanoparticle surface. Furthermore, the hydrophilic linker of the stereocomplexes can reduce opsonization and clearance by the mononuclear phagocyte system (MPS), thereby extending blood circulation time.

[0198] In another aspect, provided herein is a method for treating cancer in a subject, the method comprising administering to the subject a stereocomplex disclosed herein. In a further aspect, the cancer can be pancreatic cancer, non-small cell lung cancer, small cell lung cancer, ovarian cancer, nasopharyngeal cancer, breast cancer, ovarian cancer, prostate cancer, colon cancer, gastric adenocarcinoma, head cancer, neck cancer, brain cancer, oral cancer, pharyngeal cancer, thyroid cancer, esophageal cancer, gallbladder cancer, liver cancer, rectal cancer, kidney cancer, uterine cancer, bladder cancer, testicular cancer, lymphoma, myeloma, melanoma, leukemia, or nonspecific solid tumor.

[0199] In an alternative aspect, provided herein is a method for reducing the size of a tumor in a subject, the method comprising administering to the subject a stereocomplex disclosed herein. In one aspect, the stereocomplex can reduce the weight or volume of an existing tumor by 10% to 100% when compared to a control (i.e., without treatment with the stereocomplex). In another aspect, the stereocomplex can reduce the weight or volume of an existing tumor by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, any value representing the lower and upper endpoints of a range (e.g., 30% to 70%, 50% to 90%, etc.). In one aspect, the stereocomplex can eliminate the tumor so that it is no longer present and will not return (i.e., remission). In another embodiment, the stereocomplexes can prevent (ie, inhibit) the growth of existing tumors.

[0200] In one embodiment, the stereocomplexes disclosed herein can be administered to a subject in need of cancer treatment by intravenous injection, either alone or in combination with a pharmaceutically acceptable carrier or excipient to form a pharmaceutical composition. In one embodiment, the stereocomplexes can be administered to a subject at least once a week, at least twice a week, or at least three times a week. In other embodiments, the stereocomplexes can be administered every 2 weeks, 3 weeks, 4 weeks, 6 weeks, or 8 weeks.

[0201] In another embodiment, different populations of stereocomplexes can be administered to a subject. For example, a specific ratio of anticancer drugs (e.g., 2:1 Z 1 :Z 2 A first population of stereocomplexes composed of components (I) and (II) having a Z 1:1 ratio can be prepared and administered, followed by a second population (e.g., a 1:1 Z 1:1 ratio). 1 :Z 2 Alternatively, the second population may be subsequently administered a different anti-cancer drug combination (Z 1 :Z 5 or Z 2 :Z 5 ) may be included.

[0202] In one embodiment, anticancer agent Z 1 and anti-cancer drug Z 2 is 10:1 to 1:10, or about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10, any value can be the lower and upper endpoints of a range (e.g., 5:1 to 1:5).

[0203] In a further embodiment, Z in component (I) 1 is mertansine, and Z in component (I) 2is docetaxel. In another embodiment, the stereocomplex has a molar ratio of mertansine to docetaxel of about 4:1 to about 1:10, or a ratio of 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10, any of which can represent the lower and upper endpoints of the range (e.g., 5:1 to 1:5). In one embodiment, the ratio of mertansine to docetaxel is about 1:6 to about 1:10.

[0204] In another embodiment, when the stereocomplex contains mertansine and docetaxel as anticancer drugs, the molar ratio of each drug can vary depending on the cancer being treated. Below is a table presenting the molar ratios of the components described herein to generate stereocomplexes for treating various types of cancer (cell lines are in parentheses, components (III), (IV), and (V) as defined above). [Table 3]

[0205] In one embodiment, the dosage of DM1 administered to a subject as a stereocomplex is about 2 mg / kg to about 5 mg / kg of body weight per single dose, or about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, or about 5 mg / kg, either of which can be the lower and upper endpoints of a range (e.g., about 2.5 mg / kg to about 4 mg / kg, about 3.5 mg / kg to about 4.5 mg / kg, etc.). In another embodiment, the dose of docetaxel administered to a subject in the stereocomplex is about 12 mg / kg to about 50 mg / kg of body weight per single dose, or about 12, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50 mg / kg, any of which can be the lower and upper endpoints of a range (e.g., about 15 mg / kg to about 40 mg / kg, about 25 to about 35 mg / kg, etc.).

[0206] In one embodiment, the single unit dose of DM1 administered to a subject in a stereocomplex is about 0.5 mg / m2 ~about 15mg / m 2 and the unit is mg / m 2 is the body surface area calculated relative to height and weight. In another embodiment, a single unit dose of DM1 administered to a subject in a stereocomplex is about 0.5 mg / m 2 , 1 mg / m 2 , 1.5 mg / m 2 , 2 mg / m 2 , 2.5 mg / m 2 , 3 mg / m 2 , 3.5 mg / m 2 , 4 mg / m 2 , 4.5 mg / m 2 , 5 mg / m 2 , 5.5 mg / m 2 , 6 mg / m 2 , 6.5 mg / m 2 , 7 mg / m 2 , 7.5 mg / m 2 , 8 mg / m 2 , 8.5 mg / m 2 , 9 mg / m 2 , 9.5 mg / m 2 , 10 mg / m 2 , 10.5 mg / m 2 , 11 mg / m 2 , 11.5 mg / m 2 , 12 mg / m 2 , 12.5 mg / m 2 , 13 mg / m 2 , 13.5 mg / m 2 , 14 mg / m 2 , 14.5 mg / m 2 , 15 mg / m 2 and either value can be the lower or upper endpoint of a range (e.g., about 1 mg / m 2 ~about 6mg / m 2 , about 3mg / m 2 ~about 5mg / m 2 etc.).

[0207] In one embodiment, the single unit dose of docetaxel administered to a subject in a stereocomplex is about 3 mg / m 2 ~about 135mg / m 2 and the unit is mg / m 2is the body surface area calculated relative to height and weight. In another embodiment, the single unit dose of docetaxel administered to a subject in a stereocomplex is about 3 mg / m 2 , 5 mg / m 2 , 10 mg / m 2 , 15 mg / m 2 , 20 mg / m 2 , 25 mg / m 2 , 30 mg / m 2 , 35 mg / m 2 , 40 mg / m 2 , 45 mg / m 2 , 50 mg / m 2 , 55 mg / m 2 , 60 mg / m 2 , 65 mg / m 2 , 70 mg / m 2 , 75 mg / m 2 , 80 mg / m 2 , 85 mg / m 2 , 90 mg / m 2 , 95 mg / m 2 , 100 mg / m 2 , 105 mg / m 2 , 110 mg / m 2 , 115 mg / m 2 , 120 mg / m 2 , 125 mg / m 2 , 130 mg / m 2 , 135 mg / m 2 and either value can be the lower or upper endpoint of a range (e.g., about 5 mg / m 2 ~about 70mg / m 2 , about 20mg / m 2 ~about 60mg / m 2 etc.).

[0208] In one aspect, chemotherapy with the stereocomplexes disclosed herein can be used in combination with one or more other treatment strategies, including, but not limited to, surgical resection of all or part of the tumor or affected organ or tissue, radiation therapy, high intensity focused ultrasound, magnetic hyperthermia, photothermia, immunotherapy, or a combination thereof. Aspects

[0209] The following list of exemplary embodiments is supported by and is supported by the disclosure provided herein.

[0210] Aspect 1: Components X 1 -Y 1 -L 1 -Z 1 (I) X 2 -Y 2 -L 2 -Z 2 (II) (In the formula, each X 1 and X 2 is a hydrophilic group, Each Y 1 and Y 2 is PDLA or PLLA, Each L 1 and L 2 is a cleavable linker, Z 1 is an anticancer drug, Z 2 is an anti-cancer drug or imaging agent, and Z 2 If is an anticancer drug, Z 1 and Z 2 are different anticancer drugs, (1) Y 1 If is PDLA, then Y 2 is PLLA, and Y 1 If is PLLA, Y 2 is PDLA, and (2) the ratio of the total number of D-lactic acid units in the stereocomplex to the total number of L-lactic acid units in the stereocomplex is 0.9:1.1 to 1.1:0.9. Stereo Complex, including.

[0211] Aspect 2: X 1 and X 2 are different hydrophilic groups.

[0212] Aspect 3: X 1 and X2 are the same hydrophilic group.

[0213] Aspect 4: X 1 and X 2 and each is a polyalkylene glycol.

[0214] Aspect 5: X 1 and X 2 and each are a polyalkylene glycol having a molecular weight of 1,000 Da to 5,000 Da.

[0215] Aspect 6:X 1 and X 2 and each are polyethylene glycol having a molecular weight of 1,000 Da to 5,000 Da.

[0216] Aspect 7:X 1 and X 2 and each are monomethoxypolyethylene glycol having a molecular weight of 1,000 Da to 5,000 Da.

[0217] Embodiment 8: A stereocomplex according to any one of embodiments 1 to 7, wherein PDLA and PLLA have a molecular weight of 700 Da to 5,000 Da.

[0218] Aspect 9: L 1 and L 2 A stereocomplex according to any one of embodiments 1 to 8, wherein are different linkers.

[0219] Aspect 10: L 1 and L 2 are the same linker.

[0220] Aspect 11: L 1 and L 2Aspect 9. The stereocomplex of any one of aspects 1 to 8, wherein independently contain a disulfide group, an ester group, a hydrazone group, an acetal group, an imine group, a β-thiopropionate group, or an amide group.

[0221] Aspect 12: Z 1 and Z 2 are independently paclitaxel, doxorubicin, gemcitabine, cisplatin, methotrexate, 5-fluorouracil, betulinic acid, amphotericin B, diazepam, nystatin, propofol, testosterone, estrogen, prednisolone, prednisone, 2,3 mercaptopropanol, progesterone, docetaxel, maytansinoid, PD-1 inhibitor, PD-L1 inhibitor, protein kinase inhibitor, P-glycoprotein inhibitor, autophagy inhibitor, PARP inhibitor, aromatase inhibitor, monoclonal antibody, photosensitizer, radiosensitizer, interleukin, antiandrogen, or any combination thereof.

[0222] Embodiment 13: A stereocomplex according to embodiment 12, wherein the maytansinoid is ansamitocin, mertansine (DM1), or ravtansine.

[0223] Aspect 14:Z 1 and Z 2 14. The stereocomplex according to any one of aspects 1 to 13, wherein the molar ratio of

[0224] Aspect 15:Z 1 is mertansine, and Z 2 15. The stereocomplex according to any one of embodiments 1 to 14, wherein is docetaxel.

[0225] Aspect 16: Regarding component I, X 1 is a monomethoxypolyethylene glycol having a molecular weight of 2,000 Da to 4,000 Da, the number of L-lactic acid units or D-lactic acid units is 15 to 60, and L 1contains a disulfide group, and Z 1 16. The stereocomplex according to any one of aspects 1 to 15, wherein is mertansine (DM1).

[0226] Aspect 17: Component I has the following structure: [ka] (In the formula, n 1 is 45 to 90, m 1 is 15 to 60, o is 1 to 4; C a The stereochemistry in is R or S) 17. The stereocomplex according to embodiment 16, having the formula:

[0227] Embodiment 18: A stereocomplex according to embodiment 17, wherein o is 2.

[0228] Aspect 19: Regarding component II, X 2 is a monomethoxypolyethylene glycol having a molecular weight of 2,000 Da to 4,000 Da, the number of L-lactic acid units or D-lactic acid units is 15 to 60, and L 2 contains an ester, hydrazone, or disulfide group, and Z 2 Aspect 19. The stereocomplex according to any one of aspects 16 to 18, wherein is docetaxel.

[0229] Aspect 20: A stereocomplex according to aspect 19, wherein the molar ratio of mertansine to docetaxel is from 4:1 to 1:10.

[0230] Aspect 21: Component II has the following structure: [ka] (In the formula, n 2 is 45 to 90, m 2 is 15 to 60, p is 0 to 7; C a The stereochemistry in is R or S) 20. The stereocomplex according to embodiment 19, having the formula:

[0231] Embodiment 22: A stereocomplex according to embodiment 21, wherein p is 2.

[0232] Aspect 23: Component II has the following structure: [ka] (In the formula, n 2 is 45 to 90, m 2 is 15 to 60, each p is independently 0 to 7; q is 1 to 7; C a The stereochemistry in is R or S) 20. The stereocomplex according to embodiment 19, having the formula:

[0233] Embodiment 24: A stereocomplex according to embodiment 23, wherein each p is 2 and q is 3.

[0234] Aspect 25: Component II has the following structure: [ka] (In the formula, n 2 is 45 to 90, m 2 is 15 to 60, each p is independently 0 to 7; C a The stereochemistry in is R or S) 20. The stereocomplex according to embodiment 19, having the formula:

[0235] Embodiment 26: A stereocomplex according to embodiment 25, wherein each p is 2.

[0236] Aspect 27: Component VII X 3 -Y 3 (VII) (In the formula, X 3 is a hydrophilic group, Y 3 is PDLA or PLLA) 27. The stereocomplex of any one of embodiments 1 to 26, further comprising:

[0237] Aspect 28:X 3 is a polyalkylene glycol having a molecular weight of 1,000 Da to 5,000 Da.

[0238] Aspect 29:X 3 is a polyethylene glycol having a molecular weight of 1,000 Da to 5,000 Da.

[0239] Aspect 30:X 3 is monomethoxypolyethylene glycol having a molecular weight of 1,000 Da to 5,000 Da.

[0240] Aspect 31:X 3 is monomethoxypolyethylene glycol having a molecular weight of 2,000 Da to 4,000 Da, and the number of L-lactic acid units or D-lactic acid units present in PDLA or PLLA is 15 to 60.

[0241] Aspect 32: Component VIII TA-X 4 -Y 4 (VIII) (In the formula, X 4 is a hydrophilic group, Y 4 is PDLA or PLLA, TA is a targeting group 32. The stereocomplex according to any one of embodiments 1 to 31, further comprising:

[0242] Aspect 33:X 4 is a polyalkylene glycol having a molecular weight of 1,000 Da to 5,000 Da, and X 4 The molecular weight of X 1 and X 2 33. The stereocomplex according to embodiment 32, wherein the molecular weight of

[0243] Aspect 34:X 4 is polyethylene glycol having a molecular weight of 1,000 Da to 5,000 Da, and X 4 The molecular weight of X 1 and X 2 33. The stereocomplex according to embodiment 32, wherein the molecular weight of

[0244] Aspect 35:X 4 is polyethylene glycol having a molecular weight of 2,000 Da to 4,000 Da, and the number of L-lactic acid units or D-lactic acid units present in PDLA or PLLA is 15 to 60.

[0245] Embodiment 36: A stereocomplex according to embodiment 32, wherein TA is a ligand.

[0246] Aspect 37: Component VIII has the structure: [ka] (In the formula, n 3 is 45 to 90, m 3 is 15 to 60, C a The stereochemistry in is R or S) 33. The stereocomplex according to embodiment 32, having the formula:

[0247] Embodiment 38 A stereocomplex according to embodiment 32, wherein TA is an unsubstituted or substituted sugar.

[0248] Embodiment 39: A stereocomplex according to embodiment 38, wherein the sugar is ribose, galactose, mannose, fructose, fuculose, glucosamine or fucoidan.

[0249] Embodiment 40: A stereocomplex according to embodiment 32, wherein TA is glucose or a substituted glucose.

[0250] Embodiment 41: A stereocomplex according to embodiment 40, wherein TA is an alkyl-substituted glucose.

[0251] Embodiment 42: A stereocomplex according to embodiment 40, wherein TA is methyl-α-glucose or methyl-β-glucose.

[0252] Aspect 43: Formula IX X 5 -Y 5 -L 5 -Z 5 (IX) (In the formula, X 5 is a hydrophilic group, Y 5 is PDLA or PLLA, L 5 is a cleavable linker, Z 5 is an anticancer drug, Z 5 is Z 1 and Z 2 (different from 43. The stereocomplex according to any one of embodiments 1 to 42, further comprising one or more components of:

[0253] Aspect 44:Z 2 is an imaging agent, and the imaging agent comprises a radiopharmaceutical, a radiological contrast agent, an optical imaging agent or a precursor thereof, a quantum dot, or a combination thereof.

[0254] Aspect 45: The radiopharmaceutical is 11 CL-methyl-methionine, 18 F-fluorodeoxyglucose, 18 F - sodium fluoride, 18 F fluorocholine, 18 F desmethoxyfalipride, 67 Ga-Ga 3+ , 68 Ga-dotatoc, 68 Ga-PSMA, 111 In-diethylenetriaminepentaacetic acid, 111 In-white blood cells, 111 In-platelets, 111 In-Penetreotide, 111 In-octreotide, 123 I-iodide, 123 Io-iodine hiprate, 123 Im-iodobenzylguanidine, 123 I-FP-CIT, 125 I-fibrinogen, 131 I-iodide, 131 Im-iodobenzylguanidine, 81 Kr m -gas, 81 Kr m -aqueous solution, 13 N-ammonia, 15 O-water, 75 Se-selenolcholesterol, 75 Se-seleno-25-homo-tauro-cholate, 120 Tl-Tl + , 133 Xe-gas, 133 Xe (in isotonic sodium chloride solution), 99 Tc m -Pertechnetate, containing macroaggregates or microspheres 99 Tc m human albumin, 99 Tc m phosphonates and / or phosphates, 99 Tc m -diethylenetriaminepentaacetic acid, 99 Tc m -dimercaptosuccinic acid, 99 Tcm -colloid, 99 Tc m -hepatic iminodiacetic acid, 99 Tc m whole red blood cells, 99 Tc m -Mercaptoacetyltriglycine, containing examethasone-labeled leukocytes 99 Tc m Examethadime, 99 Tc m sester-methoxyisobutylisonitrile, 99 Tc m IMMU-MN3 mouse Fab'-SH anti-granulocyte monoclonal antibody fragment, 99 Tc m -Technegas, 99 Tc m human immunoglobulin, 99 Tc m - tetrofosmin, 99 Tc m 45. The stereocomplex according to embodiment 44, comprising -ethyl cysteine ​​dimer, or another radiopharmaceutical.

[0255] Embodiment 46: The stereocomplex of embodiment 44, wherein the radiological imaging agent comprises diatrizoate, metrizoate, iothalamate, ioxaglate, iopamidol, iohexol, ioxilan, iopromide, iodixanol, ioversol, another iodocontrast agent, barium sulfate, gadoterate, gadodiamide, gadobenate, gadopentetate, gadoteridol, gadofosveset, gadoversetamide, gadoxetate, gadobutrol, or another gadolinium chelator.

[0256] Embodiment 47: The stereocomplex of embodiment 44, wherein the optical imaging agent, or precursor thereof, comprises methylene blue, indigo carmine, another non-specific dye, fluorescein isothiocyanate, indocyanine green, rosamine, a BODIPY (boron-dipyrromethane) derivative, a chalcone, a xanthone, oxazole yellow, thiazole orange, fluorescein, luciferin, Texas red, squaraine, a porphyrin, a phthalocyanine, a polymethine cyanine dye, including Cy3, Cy5, Cy5.5, or Cy7, Alexa fluor, 5-aminolevulinic acid, a metal chelator, or another optical imaging agent.

[0257] Embodiment 48: A stereocomplex according to any one of embodiments 1 to 47, further comprising an adjuvant.

[0258] Embodiment 49: A stereocomplex according to embodiment 48, wherein the adjuvant comprises a stroma disrupting agent, an anti-fibrotic agent, an aromatase inhibitor, an immunosuppressant, an estrogen blocker, a gonadotropin-releasing hormone agonist, an estrogen modulator, a progestin therapeutic agent, an LHRH agonist, an androgen-lowering agent, an antiandrogen, an immunosuppressant, or any combination thereof.

[0259] Embodiment 50: A stereocomplex according to embodiment 48, wherein the adjuvant comprises a stroma-rupturing agent, wherein the stroma-rupturing agent comprises losartan, azilsartan, candesartan, eprosartan, irbesartan, olmesartan, telmisartan, valsartan, luteolin, quercetin, genistein, catechin, cyaniding, naringenin, delphinidin, malvidin, petunidin, peonidin, pelargonidin, gallocatechin, catechin-3-gallate, epicatechin, epigallocatechin, daidzein, glycitein, equol, kaempferol, myricetin, eriodictyol, hesperitin, taxifolin, or any combination thereof.

[0260] Embodiment 51: A stereocomplex according to embodiment 48, wherein the adjuvant comprises an antifibrotic agent, and the antifibrotic agent comprises pirfenidone, mimosine, ciclopirox, geodon, bemeglide, deferiprone, etanercept, bosentan, sildenafil, nintedanib, colchicine, or a combination thereof.

[0261] Aspect 52: Component I has the following structure: [ka] (In the formula, n 1 is 45 to 90, m 1 is 15 to 60, o is 1 to 4; C a wherein the stereochemistry is R or S; Component II has the following structure: [ka] (In the formula, n 2 is 45 to 90, m 2 is 15 to 60, each p is independently 0 to 7; q is 1 to 7; C a The stereochemistry in is R or S) and The ratio of the total number of D-lactic acid units in the stereocomplex to the total number of L-lactic acid units in the stereocomplex is 0.9:1.1 to 1.1:0.9. A stereocomplex according to embodiment 1.

[0262] Embodiment 53: A stereocomplex according to embodiment 52, wherein o is 2, each p is 2 and q is 3.

[0263] Embodiment 54: A stereocomplex according to any one of embodiments 1 to 53, having an average diameter of 50 nm to 200 nm.

[0264] Embodiment 55: A pharmaceutical composition comprising a stereocomplex according to any one of embodiments 1 to 54, and a pharmaceutically acceptable carrier.

[0265] Embodiment 56: A method for treating cancer in a subject, the method comprising administering to the subject a stereocomplex according to any one of embodiments 1 to 54.

[0266] Aspect 57: The method of aspect 50, wherein the cancer is pancreatic cancer, non-small cell lung cancer, small cell lung cancer, ovarian cancer, nasopharyngeal cancer, breast cancer, ovarian cancer, prostate cancer, colon cancer, gastric adenocarcinoma, head cancer, neck cancer, brain cancer, oral cancer, pharyngeal cancer, thyroid cancer, esophageal cancer, gallbladder cancer, liver cancer, rectal cancer, kidney cancer, uterine cancer, bladder cancer, testicular cancer, lymphoma, myeloma, melanoma, leukemia, or non-specific solid tumor.

[0267] Embodiment 58: A method for reducing a tumor in a subject, the method comprising administering to the subject a stereocomplex according to any one of embodiments 1 to 54.

[0268] Embodiment 59: A method according to any one of embodiments 56 to 58, wherein the stereocomplex is administered to the subject by intravenous injection.

[0269] Aspect 60: Component I has the following structure: [ka] (In the formula, n 1 is 45 to 90, m 1 is 15 to 60, o is 1 to 4; C a The stereochemistry in is R or S) and Component II has the following structure: [ka] (In the formula, n 2 is 45 to 90, m 2 is 15 to 60, each p is independently 0 to 7; q is 1 to 7; C a The stereochemistry in is R or S) and The ratio of the total number of D-lactic acid units in the stereocomplex to the total number of L-lactic acid units in the stereocomplex is 0.9:1.1 to 1.1:0.9. 60. The method of any one of embodiments 56 to 59.

[0270] Embodiment 61: The method of embodiment 60, wherein o is 2, each p is 2, and q is 3. [Example]

[0271] The following examples are presented so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, and methods described and claimed herein are made and evaluated; they are intended to be purely illustrative and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), but some error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, temperatures are in ° C. or are at ambient temperature, and pressures are at or near atmospheric pressure. Numerous variations and combinations of reaction conditions (e.g., concentrations of components, desired solvents, solvent mixtures, temperatures, pressures, and other reaction ranges and conditions) can be used to optimize product purity and yields obtained from the described processes. No more than reasonable and routine experimentation will be required to optimize such process conditions. Example 1 Synthesis of polymer-conjugated drugs Synthesis of mPEG-PD / LLA:

[0272] mPEG-PD / LLA copolymer was synthesized by ring-opening polymerization using mPEG-OH as an initiator. Briefly, in a flame-dried and nitrogen-purged flask, distilled mPEG (M n = 2000) and recrystallized D / L-lactide were added. Stannous octoate (in toluene) and toluene were added sequentially to the flask, and the sealed flask was then maintained at 120 °C for 24 hours. The synthesized polymer was recovered by precipitation in ice-cold diethyl ether. The resulting precipitate was filtered and dried under vacuum at room temperature, and the yield was calculated to be 90%. Synthesis of DM1-SS-COOH:

[0273] Mertansine (DM1) and 3-(pyridin-2-yldisulfanyl)propanoic acid were dissolved in N,N-dimethylacetamide (the stoichiometric molar ratio of DM1 to 3-(pyridin-2-yldisulfanyl)propanoic acid was 1:2), and then acetic acid was added (10 μL / mL of reaction solution). After stirring at 35 °C for 24 h under a nitrogen atmosphere, the reaction solution was cooled to room temperature and then dialyzed against deionized water. After lyophilization, the resulting product was obtained and used in the next step without further purification, with a calculated yield of 88%. A schematic diagram of the synthesis is shown in Figure 4. Synthesis of mPEG-PDLA-SS-DM1:

[0274] mPEG-PDLA copolymer, DM1-SS-COOH, DCC, and DMAP were dissolved in dry dichloromethane and cooled in an ice bath (the stoichiometric molar ratio of mPEG-PDLA:DM1-SS-COOH:DCC:DMAP was 1:1:2:2). The reaction was stirred under a nitrogen atmosphere at 0°C for 48 hours, then filtered and concentrated under reduced pressure. The DM1-conjugated mPEG-PDLA was recovered by precipitation in cold diethyl ether and dried under vacuum. Gel permeation chromatography (GPC) using THF as the mobile phase was used to remove free DM1-SS-COOH, and the yield was calculated to be 64%. A schematic diagram of the synthesis is shown in Figure 4. Figure 5 shows the structure of the purified product. 1 H NMR is shown. Synthesis of DTX-LEV:

[0275] Docetaxel (DTX) was esterified to the 2'-hydroxyl of DTX with LEV to give the respective ester derivatives. Briefly, EDC·HCl and LEV were dissolved in dichloromethane under stirring at 4 °C for 30 min. Then, a dichloromethane solution of DTX and DMAP was added to the reaction mixture (the stoichiometric molar ratio of DTX:EDC·HCl:DMAP:LEV was 1:2:2:2). The reaction mixture was stirred overnight at 4 °C under a nitrogen atmosphere. After washing twice with 0.05 N HCl and once with saturated NaCl, the organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the product in 77% yield. A schematic diagram of the synthesis is shown in Figure 6. Synthesis of DTX-hydrazone-OH:

[0276] Hydrazone-containing DTX derivatives were obtained by the reaction of DTX-LEV and 4-hydroxybutanehydrazide. Briefly, DTX-LEV and 4-hydroxybutanehydrazide were dissolved in anhydrous methanol under stirring at 45 °C (the stoichiometric molar ratio of DTX-LEV to 4-hydroxybutanehydrazide was 1:10). After the addition of acetic acid (10 μL / mL of the reaction solution), the reaction was carried out for 2 h. The reaction solution was then cooled to room temperature and washed with saturated NaHCO to remove acetic acid and unreacted 4-hydroxybutanehydrazide, followed by extraction with acetyl acetate, dehydration with anhydrous NaSO, and concentration under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography using CHCl:MeOH (90:10) as the mobile phase in 72% yield. A schematic diagram of the synthesis is shown in Figure 6. Synthesis of mPEG-PLLA-COOH:

[0277] Succinic anhydride, DMAP, and mPEG-PLLA were dissolved in dichloromethane, and then TEA (the stoichiometric molar ratio of mPEG-PLLA: succinic anhydride: DMAP: TEA was 1:2:2:2) was added. After 24 hours at room temperature, the reaction solution was diluted to 0.1 M The product was washed twice with HCl and deionized water to remove DMAP and unreacted succinic anhydride, then dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting mPEG-PLLA-COOH was recovered by precipitation in cold diethyl ether in 78% yield. A schematic diagram of the synthesis is shown in Figure 6. Synthesis of mPEG-PLLA-hydrazone-DTX:

[0278] Distilled mPEG-PLLA-COOH, DTX-hydrazone-OH, DCC, and DMAP were dissolved in dry dichloromethane and cooled in an ice bath (the stoichiometric molar ratio of mPEG-PLLA-COOH:DTX-hydrazone-OH:DCC:DMAP was 1:1.2:2:2). The reaction was stirred under a nitrogen atmosphere at 0°C for 48 hours, then filtered and concentrated under reduced pressure. The DTX-conjugated mPEG-PLLA was recovered by precipitation in cold diethyl ether and dried under vacuum. The final product was purified by preparative gel permeation chromatography using THF as the mobile phase. The yield was calculated to be 60%. A schematic diagram of the synthesis is shown in Figure 6. Figure 7 shows the structure of the purified product. 1 H NMR is shown. Synthesis of mPEG-PLLA-ester-DTX:

[0279] Distilled mPEG-PLLA-COOH (previously described), DTX, DCC, and DMAP were dissolved in dry dichloromethane and cooled in an ice bath (the stoichiometric molar ratio of mPEG-PLLA-COOH:DTX:DCC:DMAP was 1:2:2:2). The reaction was stirred under a nitrogen atmosphere at 0°C for 48 hours, then filtered and concentrated under reduced pressure. The DTX-conjugated mPEG-PLLA was recovered by precipitation in cold diethyl ether and dried under vacuum. GPC using THF as the mobile phase was used to remove free DTX. The yield was calculated to be 42%. Figure 8 shows the purified product. 1 H NMR is shown. Synthesis of DTX-SS-pyridine:

[0280] DTX was esterified to the 2'-hydroxyl of DTX with 3-(pyridin-2-yldisulfanyl)propanoic acid to give the respective ester derivatives. Briefly, DTX, 3-(pyridin-2-yldisulfanyl)propanoic acid, CMPI, and DMAP were dissolved in anhydrous CHCl (the stoichiometric molar ratio of DTX:3-(pyridin-2-yldisulfanyl)propanoic acid:CMPI:DMAP was 1:1:1.2:2.4). The reaction mixture was stirred at 40 °C for 1 h. The resulting reaction solution was concentrated under reduced pressure to give the crude product, which was purified in 80% yield by silica gel column chromatography using CHCl:acetyl acetate (50:50) as the mobile phase. A schematic diagram of the synthesis is shown in Figure 9. Synthesis of DTX-SS-COOH:

[0281] DTX-SS-pyridine and 3-mercaptopropanoic acid were dissolved in N,N-dimethylacetamide (the stoichiometric molar ratio of DTX-SS-pyridine to 3-mercaptopropanoic acid was 1:1.1), followed by the addition of acetic acid (10 μL / mL of the reaction solution). The reaction solution was stirred under a nitrogen atmosphere at 35 °C for 24 h, then cooled to room temperature and dialyzed against deionized water. The resulting product was obtained after lyophilization and used in the next step without further purification. The yield was estimated to be approximately 75%. A schematic diagram of the synthesis is shown in Figure 9. Synthesis of mPEG-PLLA-SS-DTX:

[0282] Distilled mPEG-PLLA copolymer, DTX-SS-COOH, DCC, and DMAP were dissolved in dry dichloromethane and cooled in an ice bath (the stoichiometric molar ratio of mPEG-PLLA:DTX-SS-COOH:DCC:DMAP was 1:1.2:2.4:2.4). The reaction mixture was stirred under a nitrogen atmosphere from 0°C to room temperature for 48 hours, then filtered and concentrated under reduced pressure. The resulting mPEG-PLLA-SS-DTX conjugate was recovered by precipitation in cold diethyl ether and dried under vacuum. GPC using THF as the mobile phase was used to remove free DTX-SS-COOH. A schematic diagram of the synthesis is shown in Figure 9. Synthesis of HOOC-PEG-PDLA:

[0283] HOOC-PEG-PDLA copolymer was synthesized by ring-opening polymerization using COOH-PEG-OH as the initiator. Briefly, in a flame-dried and nitrogen-purged flask, distilled HOOC-PEG (M n =3500) and recrystallized D-lactide were added. Stannous octoate (in toluene) and toluene were added sequentially to the flask, and the sealed flask was then maintained at 120°C for 24 hours. The synthesized polymer was recovered by precipitation in ice-cold diethyl ether. The resulting precipitate was filtered and dried under vacuum at room temperature, resulting in an 88% yield. Synthesis of cRGD-amide-PEG-PDLA:

[0284] HOOC-PEG-PDLA was dissolved in DMF and activated with HBTU for 1 hour under stirring at room temperature, after which a DMF solution of cRGD and DIEA was added (the stoichiometric molar ratio of HOOC-PEG-PLLA:cRGD:HBTU:DIEA was 1:1.1:3:3). After 24 hours at room temperature under a nitrogen atmosphere, the reaction mixture was filtered and recovered by precipitation in ice-cold diethyl ether. The resulting precipitate was redissolved in DMF and dialyzed against water. After lyophilization, the resulting cRGD-amide-PEG-PDLA was obtained in 75% yield. Figure 10 shows the structure of the purified product. 1 H NMR is shown. Synthesis of maleimide-PEG-PDLA:

[0285] Maleimide-PEG-PDLA copolymer was synthesized by ring-opening polymerization using maleimide-PEG-OH as the initiator. Briefly, in a flame-dried and nitrogen-purged flask, distilled maleimide-PEG (M n =3500) and recrystallized D-lactide were added. Stannous octoate (in toluene) and toluene were added sequentially to the flask, and the sealed flask was then maintained at 120°C for 24 hours. The synthesized polymer was recovered by precipitation in ice-cold diethyl ether. The resulting precipitate was filtered and dried under vacuum at room temperature. The yield was calculated to be 67%. Synthesis of cRGD-S-PEG-PDLA:

[0286] Maleimide-PEG-PDLA and cRGDfc were dissolved in DMF (the stoichiometric molar ratio of maleimide-PEG-PDLA to cRGDfc was 1:1.2). The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. The final mixture was dialyzed against deionized water. After lyophilization, the resulting cRGD-maleimide-PEG-PDLA was obtained. Synthesis of Folate-NH2:

[0287] Folate was dissolved in DMSO, followed by the addition of NHS and DCC. After activation at 50°C in the dark under a nitrogen atmosphere for 6 hours, a DMSO solution of ethane-1,2-diamine and pyridine was added to the reaction mixture (stoichiometric molar ratio of folate:ethane-1,2-diamine:NHS:DCC:pyridine = 1:2:2:2:1). The reaction was then allowed to proceed at room temperature for 24 hours. The mixture was filtered, precipitated in ACN, and placed at 4°C overnight, followed by centrifugation (4000 rpm, 5 minutes). The solid was washed twice with ethanol, dried under vacuum, and then used in the next step without further purification. The yield was estimated to be 58%. Synthesis of folate-amide-PEG-PL / DLA:

[0288] Distilled HOOC-PEG-PL / DLA (previously described), NHS, and EDC·HCl were dissolved in DMSO. The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. Then, a DMSO solution of folate-NH2 was added to the mixture, which was then kept in the dark at room temperature for 24 hours (the stoichiometric molar ratio of HOOC-PEG-PL / DLA:folate-NH2:NHS:EDC·HCl:pyridine was 1:2:1.5:1.5). The final mixture was dialyzed sequentially against DMSO and water. After lyophilization, the resulting folate-amide-PEG-PL / DLA was obtained in 53% yield. Figure 11 shows the purified product. 1 H NMR is shown. Synthesis of Glu-PEG-PDLA:

[0289] HOOC-PEG-PDLA, methyl α-D-glucopyranoside, and lipase 435 were suspended in acetonitrile. The mixture was homogenized at 50°C for 5 days. The enzyme was filtered off, followed by evaporation of the solvent. The residue was dissolved in CHCl and washed with deionized water. The organic phase was dried over anhydrous NaSO and concentrated. The resulting Glu-PEG-PDLA conjugate was recovered in 80% yield by precipitation in cold diethyl ether. Figure 12 shows the structure of the purified product. 1 H NMR is shown. Example 2 Preparation of stereocomplexes Preparation of D-DM1 formulations

[0290] mPEG-PDLA-SS-DM1 was dissolved at a concentration of 20 mg / mL in 0.5 mL DMF and 0.5 mL DMSO. The solution was added dropwise to Di-PBS. After stirring for 1 hour at room temperature, the mixture was transferred to a dialysis membrane (cutoff 3.5K) and the solvent was removed by dialysis against PBS for 2 days. After filtration using a 450 nm filter, the size of the D-DM1 formulation was characterized by dynamic light scattering (Zetasizer, Malvern Instruments, Malvern, UK). The concentration of DM1 was tested by HPLC utilizing DTT. Briefly, 100 μl of the D-DM1 solution was lyophilized to a powder. The powder was then dissolved using 1 mL of DMF solution containing 40 mM DTT and sonicated for 30 minutes. The DM1 content was evaluated using an RP-HPLC system with UV detection at 254 nm using a mixture of acetonitrile and water (v / v, 60 / 40) as the mobile phase. The standard curve for DM1 was calculated as Y = 14.51448X - 15.43867 (Y = peak area; X = DM1 concentration; r 2 =0.99709; 1-50ug / ml). Preparation of L-DTX formulations

[0291] mPEG-PLLA-hydrazone-DTX was dissolved in 1 mL of DMSO to a final concentration of 30 mg / mL. The DMSO solution was added dropwise to Di-PBS. After stirring for 1 h at room temperature, the mixture was transferred to a dialysis membrane (cutoff 3.5 K) and the solvent was removed by dialysis against PBS for 2 days. After filtration using a 450 nm filter, the size of the L-DTX formulation was characterized by dynamic light scattering (Zetasizer, Malvern Instruments, Malvern, UK). The DTX concentration was tested by HPLC after alkaline degradation. Briefly, the L-DTX sample solution (80 μL), 6 M NaOH (200 μL), and water (220 μL) were sequentially added to a 15 mL centrifuge tube. The mixture was incubated overnight at 60 °C in a water bath. Next, 6 M formic acid (250 μL) was added, and the volume of the solution was adjusted to 3 mL with water. A solution containing benzoic acid derived from the decomposition of DTX in alkaline solution was used for HPLC. The mobile phase consisted of ammonium acetate (20 mM) and methanol in a 90:10 ratio. The column effluent was detected at 230 nm. A calibration curve was prepared using standards of benzoic acid dissolved in methanol. The mass conversion ratio of DTX:benzoic acid is 6.62:1. The calibration curve for benzoic acid is Y = 5.8601X - 3.9858 (Y = peak area, X = DTX concentration; r2 = 0.99871; 6.62 - 132.4 μg / mL). Preparation of complex formulations

[0292] mPEG-PLLA-hydrazone-DTX was dissolved in 2 mL of THF at a concentration of 17 mmol. mPEG-PDLA-SS-DM1 was dissolved in 2 mL of DMF with or without mPEG-PDLA at concentrations of 2.3 mmol for mPEG-PDLA-SS-DM1 and 13.5 mmol for mPEG-PDLA, respectively. After mixing the THF and DMF solutions, the mixture was stirred at room temperature for 4 hours and then added dropwise to Di-PBS. After stirring at room temperature in a fume hood for 1 hour to evaporate as much THF as possible, the mixture was transferred to a dialysis membrane (cutoff 3.5 K) and the solvent was removed by dialysis against PBS for 2 days. After filtration using a 450 nm filter, the size of the complex was characterized by dynamic light scattering (Zetasizer, Malvern Instruments, Malvern, UK). The method used to concentrate DM1 and DTX in the complex was the same as that used for the prodrug formulation. The lyophilized powder was successfully reconstituted from the complex solution without the use of any lyoprotectant, and the concentrations of DTX and DM1 in the complex formulation were 6.63 mmol and 0.95 mmol, respectively.

[0293] In the second step, mPEG-PLLA-hydrazone-DTX was dissolved in 2 mL of THF at a concentration of 17 mmol. mPEG-PDLA-SS-DM1 was dissolved in 2 mL of acetonitrile at concentrations of 2.3 mmol for mPEG-PDLA-DM1 and 10.5 mmol for mPEG-PDLA, respectively, with or without mPEG-PDLA. After mixing the THF and acetonitrile solutions, the mixture was stirred at room temperature for 4 hours and then added dropwise to Di-PBS. After stirring at room temperature for 1 hour, the organic solvent was rotary evaporated under vacuum. After lyophilization and reconstitution, the concentrations of DTX and DM1 in the complex were 7.79 mmol and 1.08 mmol, respectively. Preparation of glucose preparations containing complexes

[0294] mPEG-PLLA-hydrazone-DTX was dissolved in 2 mL of THF at a concentration of 17 mmol. mPEG-PDLA-SS-DM1 and Glu-PEG-PDLA were dissolved in 2 mL of DMF at concentrations of 2.3 mmol for mPEG-PDLA-DM1 and 25 mmol for Glu-PEG-PDLA, respectively. After mixing the THF and DMF solutions, the mixture was stirred at room temperature for 4 h and then added dropwise to Di-PBS. After stirring at room temperature for 1 h and rotary evaporation under vacuum at room temperature to remove as much solvent as possible, the mixture was transferred to a dialysis membrane (cutoff 3.5 K) and dialyzed against PBS for 2 days to remove residual organic solvents. After filtration using a 450 nm filter, the size of the complexes was characterized by dynamic light scattering (Zetasizer, Malvern Instruments, Malvern, UK). The lyophilized powder was successfully reconstituted from the glucose-containing complex solution without the use of any cryoprotectant, and the concentrations of DTX and DM1 in the complex formulation were 5.37 mmol and 0.745 mmol, respectively. Example 3 In vitro release test

[0295] Poly-DTX release was performed by dialysis in phosphate-buffered saline (pH 7.4 and 5.5, containing 0.2% w / v polysorbate 80). Briefly, 1 mL of poly-DTX formulation with a docetaxel concentration adjusted to 3 mg / mL with PBS was placed in a dialysis bag (MWCO = 3.5 kDa) and sealed. After immediate immersion in 10 mL of release medium, the sample was incubated at 37°C. At designated time intervals (4, 8, 24, and 48 hours), 1 mL of the external release medium was withdrawn and replenished with an equal volume of fresh medium.

[0296] The cumulative release of DTX was indirectly measured by quantifying the content of benzoic acid (one of the stable end-degradation products of DTX) by HPLC. Briefly, the solution extracted from the release medium was lyophilized, dissolved in 6 M NaOH (0.25 mL), and incubated overnight at 60 °C in a water bath. Finally, 6 M formic acid (0.25 mL) was added, and the mixture was filtered through a 0.45 μm PTFE filter for HPLC detection. The mobile phase consisted of ammonium acetate (20 mM) and methanol in a 90:10 ratio. The column effluent was detected at 230 nm. A calibration curve was prepared using benzoic acid standards dissolved in methanol. The mass conversion ratio of DTX to benzoic acid was 6.62:1. The calibration curve for benzoic acid was calculated for concentrations ranging from 6.62 to 132.4 μg / mL using the equation Y = 4.92334X - 3.53882 (Y = peak area, X = DTX concentration; r 2 =0.99976).

[0297] Poly-DM1 release was performed by dialysis in phosphate-buffered saline (pH 7.4, containing 0.2% w / v polysorbate 80) with or without 10 mM glutathione (GSH). Briefly, 1 mL of poly-DM1 formulation, with a DM1 concentration adjusted to 0.5 mg / mL with PBS, was placed in a sealed dialysis bag (MWCO = 3.5 kDa). After immediate immersion in 10 mL of release medium, the sample was incubated at 37 °C. At designated time intervals (4, 8, 24, and 48 h), 1 mL of external release medium was withdrawn and replenished with an equal volume of fresh medium. All released samples were lyophilized, and the amount of released DM1 was determined using HPLC analysis as previously described. Example 4 DM1 and DTX combination index

[0298] Combination indices were calculated for free DM1 and DTX in various cell lines at various ratios of DM1 to DTX. As used herein, "combination index" or "CI" refers to the quantitative determination of drug combinations. Results are classified as synergism (condition CI<1), additive effect (condition CI=1), and antagonism (condition CI>1). Tests were performed on human alveolar basal adenocarcinoma cells (A549), non-small cell lung cancer cells (NCI-H460), pancreatic cancer cells (MiA PaCa-2), gastric cancer cells (SGC-7901), and liver cancer cells (Hep3B2.1-7). The combination index results for these five cell lines are shown in Figure 13, with various drug ratios on the horizontal axis and combination index on the vertical axis. Example 5 Dynamic Light Scattering to Determine Particle Size

[0299] The particle sizes of the stereocomplex and the individual component molecules were determined using dynamic light scattering. Figure 14A shows the particle sizes of the prodrugs mPEG-PDLA-SS-DM1 and mPEG-PLLA-hydrazone-DTX. Figure 14B shows the particle sizes of the complexes produced by dialysis (left panel) and after lyophilization and reconstitution (right panel). The size of the complexes is approximately 80 nm. Figure 14C shows the particle sizes of the complexes produced by rotary evaporation (left panel) and after lyophilization and reconstitution (right panel). The size of the complexes is approximately 50 nm. Example 6 Differential scanning calorimetry to determine melting temperatures

[0300] Differential scanning calorimetry (DSC) was used to determine the melting temperatures of the prodrug, precursor molecule, and stereocomplex. The DSC results are shown in Figures 15A-15B. Figure 15A shows the DSC profiles of free DM1 powder (blue line), lyophilized powder of mPEG-PDLA (black line), and the mPEG-PDLA-DM1 prodrug (red line). DM1 has a melting temperature of 177 °C, while PDLA has a melting temperature of approximately 120 °C. Figure 15B shows the melting temperature profiles for the prodrug mPEG-PLLA-DTX (black line), mPEG-PDLA-DM1 (red line), and the stereocomplex formed between the two (blue line). A new melting temperature of 186 °C is observed in the DSC profile of the stereocomplex, indicating a strong interaction between PDLA and PLLA during stereocomplex formation. Example 7 Release of DTX and DM1 over time

[0301] The release of DTX from the stereocomplex over time was measured at pH 7.4 (squares) and pH 5.5 (circles). The results are presented in Figure 16A. Conjugation of DTX with a pH-sensitive hydrazone linker results in faster release of DTX at pH 5.5 than at the near-neutral pH of 7.4.

[0302] The release of DM1 over time from the stereocomplex with and without glutathione (GSH) was measured at pH 7.4. The results are presented in Figure 16B. DM1 is released most rapidly from the isolated prodrug in the presence of GSH (squares) and more slowly from the stereocomplex (circles). In the absence of glutathione, essentially no DM1 is released from either the isolated prodrug or the complex (triangles and inverted triangles at 0% cumulative release). Thus, conjugation of DM1 with a redox-sensitive disulfide linker prevents premature release of DM1 without GSH. Example 8 Tolerance of the formulation in tumor-free mice

[0303] Healthy mice (n = 5 per treatment group) were injected via the tail vein with either 4 mg / kg of the DM1-containing prodrug, 4 mg / kg of the DM1-containing prodrug and mPEG-PLLA, or a stereocomplex containing 4 mg / kg DM1 and 27 mg / kg DTX per injection on days 1, 8, 15, and 22 of the 28-day study. Body weight was monitored to determine treatment tolerance. Body weight increased slightly on average in the DM1-containing prodrug group, but two mice showed tail swelling and ulceration on days 8–14 (squares). One mouse in the prodrug and PLLA treatment group died on day 4, and treatment in this group was discontinued (circles). Body weight decreased slightly on average with the stereocomplex treatment, but remained within 5% of the normal range. No tail swelling or ulceration was observed in the stereocomplex-treated group (triangles). The results are shown in Figure 17A. Healthy mice (n=5 for each treatment group) were injected with the complex at 3.6 mg / kg DM1 once a week for a total of three injections, at 5 mg / kg DM1 once every two weeks for a total of two injections, and at 7 mg / kg DM1 once a day, respectively. As shown in Figure 17B, no obvious weight loss was observed in any treatment group over the course of 21 days. Example 9 Tumor size in treated and control groups

[0304] A human gastric cancer cell suspension (BGC-823) was injected subcutaneously into the back of mice to establish a tumor model. The tumor volume was approximately 60 mm. 3Upon reaching 10 days, groups of tumor-bearing mice (n=5) were injected with the stereocomplex via the tail vein on the days indicated by the arrows in panel (a) (i.e., days 1, 8, and 15, at doses of 4 mg / kg DM1 and 36 mg / kg DTX per injection). Figure 18A shows tumor size measurements for the control group (squares) and the treated group (circles). No significant weight loss was observed in either the treated or control groups (Figure 18B). Significant tumor reduction was achieved in the complex group (resected tumors are shown in Figure 18C), with a greater overall reduction in tumor weight achieved in the stereocomplex-treated group (Figure 18D). Example 10 Antitumor efficacy and toxicity in pancreatic tumor models

[0305] The in vivo antitumor efficacy of the complex was evaluated in a subcutaneous MiA PaCa-2 pancreatic tumor model. The MiA PaCa-2 cell suspension was injected subcutaneously into the back of mice to establish the tumor model. The tumor volume was approximately 140 mm 3 Upon reaching 100 mg / kg / day, groups of tumor-bearing mice (n=5) were injected via the tail vein on days 1 and 14 of the approximately 40-day study. After 24 days, one treated mouse was tumor-free, and a total of three mice were tumor-free after 38 days. After tumor regression, no recurrence was observed during the study period. The change in tumor size is presented in Figure 19A, and Figure 19B shows photographs of mice in the control group (top row) and the treated group (bottom row) on day 29. Example 11 Comparison of antitumor efficacy in pancreatic tumor models

[0306] The antitumor efficacy and toxicity of the stereocomplexes and DM1-containing prodrugs were evaluated in a subcutaneous MiaPaCa-2 pancreatic tumor model. MiAPaCa-2 cell suspensions were injected subcutaneously into the backs of mice to establish the tumor model. Tumor volumes of approximately 140 mm were obtained. 3Once tumor size reached 100 mg / kg, groups of tumor-bearing mice (n = 5) were injected with the treatment via the tail vein. Nearly identical antitumor effects were observed after four injections of the DM1-containing prodrug (D-DM1) and two injections of the stereocomplex. However, D-DM1 treatment induced mouse death and significant weight loss, and this treatment group was terminated after the fourth injection for humane reasons. In contrast, the stereocomplex-treated group showed weight gain throughout the entire treatment period, indicating the general safety of the treatment. The results are presented in Figures 20A-20B. Figure 20A shows tumor volumes for the control group (squares), the D-DM1 prodrug group (circles), and the stereocomplex-treated group (triangles). Figure 20B shows body weights for the control group (squares), the D-DM1 prodrug group (circles), and the stereocomplex-treated group (triangles). Example 12 Antitumor efficacy and toxicity in liver tumor models

[0307] The antitumor efficacy and toxicity of the stereocomplex was evaluated in a subcutaneous Hep 3B2.1-7 liver tumor model. The tumor model was established by subcutaneous injection of Hep 3B2.1-7 cell suspension into the back of mice. The tumor volume was approximately 130 mm 3 Once tumor size reached 100 mg / kg, groups of tumor-bearing mice (n=5) were injected with treatment via the tail vein. In this model, the body weight of the control group decreased with increasing tumor size. The body weight of the stereocomplex-treated group remained normal throughout the study period. After treatment, one mouse from the stereocomplex-treated group was tumor-free, and the average tumor weight of the stereocomplex-treated group (n=5) was only 4.5% of the average tumor weight of the control group (n=3) (two mice died before the end of the study due to the formation of very large tumors).

[0308] The results are presented in Figures 21A-21D. Figure 21A shows the tumor volumes of the control group (squares) and the stereocomplex-treated group (circles), and the arrows indicate the injection dates for the treatment groups at doses of 4 mg / kg DM1 and 28 mg / kg DTX per injection. Figure 21B shows the body weights of the control group (squares) and the stereocomplex-treated group (circles). Figure 21C shows the excised tumors of the control group (top row) and the stereocomplex-treated group (bottom row). Figure 21D shows a comparison of tumor weights between the control group (left) and the stereocomplex-treated group (right). Example 13 Antitumor efficacy and toxicity in colon tumor models

[0309] The antitumor efficacy and toxicity of the stereocomplexes were evaluated in a subcutaneous HT-29 colon tumor model. The cell suspension was injected subcutaneously into the back of mice to establish the tumor model, and tumors grew to approximately 100 mm. 3 Once tumor-bearing mice were treated, groups of mice (n=5) were injected with the composition via the tail vein. Figure 22A shows that untreated mice (squares) experienced a more significant increase in tumor volume, while mice treated with the complex (circles) exhibited smaller final tumor volumes (arrows indicate the injection date at a dose of 4 mg / kg DM1 and 32 mg / kg DTX per injection). Figure 22B shows the weight changes in the control and treatment groups. Figure 22C shows excised tumors from the control group (top row) and the stereocomplex-treated group (bottom row). Figure 22D shows a comparison of tumor weights between the control group (left) and the stereocomplex-treated group (right). Example 14 Comparison of antitumor efficacy in nasopharyngeal tumor models

[0310] The antitumor efficacy and toxicity of the stereocomplexes and DM1-containing prodrugs were evaluated in a subcutaneous CNE nasopharyngeal tumor model when the treatment was delivered by intravenous injection. The cell suspension was injected subcutaneously into the back of the mice to establish the tumor model. Tumors with a volume of approximately 100 mm 3Upon reaching 100 μg / day, groups of tumor-bearing mice (n=5) were injected with the complex via the tail vein. Figure 23 shows that tumor volume increased significantly in the D-DM1 prodrug-treated group after four injections of 4 mg / kg DM1 once per week, while mice treated with the complex showed smaller final tumor volumes after four injections of 4 mg / kg DM1 and 26 mg / kg DTX once per week. Example 15 Antitumor efficacy and toxicity in small cell lung tumor models

[0311] The in vivo antitumor efficacy of the complex was evaluated in a subcutaneous NCI-H526 small cell lung tumor model. The tumor model was established by subcutaneous injection of NCI-H526 cell suspension into the back of mice. The tumor volume was approximately 100 mm 3 Upon reaching 18 days, groups of tumor-bearing mice (n=5) were injected via the tail vein once a week. After three injections of 3.8 mg / kg DM1 and 32 mg / kg DTX once a week, one mouse was tumor-free on day 18, and all mice were tumor-free from day 32. Figure 24A shows the tumor size change for the group treated with the complex (red line) versus the control group (black line). Figure 24B shows the control mice (top row of photographs) and the treated mice (bottom row of photographs) on day 18 of the study. Example 16 Antitumor efficacy and toxicity in non-small cell lung tumor models

[0312] The in vivo antitumor efficacy of the complex was evaluated in a subcutaneous NCI-H1975 non-small cell lung tumor model. The cell suspension was injected subcutaneously into the back of mice to establish the tumor model, and tumors grew to approximately 130 mm. 3Once the composition was administered, groups of tumor-bearing mice (n=5) were injected via the tail vein. Figure 25A shows that untreated mice (black line) experienced a more significant increase in tumor volume, while mice treated with the complex (red line) exhibited a smaller final tumor volume after only a single injection of 5 mg / kg DM1 and 33 mg / kg DTX. Figure 25B shows the weight changes in the control and treatment groups. Figure 25C shows the excised tumors in the control group (top row) and the stereocomplex-treated group (bottom row). Note that in the treatment group, one mouse was tumor-free at the end of the study. Figure 25D shows a comparison of tumor weights in the control group (left) and the stereocomplex-treated group (right). Example 17 Antitumor efficacy and toxicity in a triple-negative breast tumor model

[0313] The in vivo antitumor efficacy of the complex was evaluated in a subcutaneous MDA-MB-231 triple-negative breast tumor model. The cell suspension was injected subcutaneously into the back of mice to establish the tumor model, and tumors grew to approximately 100 mm. 3 Once the tumor-bearing mice were in the 20-well plate, groups of mice (n=6) were injected with the composition via the tail vein. Figure 26A shows that untreated mice (squares) experienced a more significant increase in tumor volume, while mice treated with the complex (circles) exhibited a smaller final tumor volume after only a single injection of 2.5 mg / kg DM1 and 18 mg / kg DTX. Figure 26B shows the weight changes in the control and treatment groups. Figure 26C shows the excised tumors in the control group (top row) and the stereocomplex-treated group (bottom row); notably, one mouse remained tumor-free from day 23 until the end of the study. Figure 26D shows a comparison of tumor weights in the control group (left) and the stereocomplex-treated group (right). Example 18 Antitumor efficacy and toxicity in breast tumor models

[0314] The in vivo antitumor efficacy of the complex in large tumors was evaluated in a subcutaneous MX-1 breast tumor model. The tumor model was established by subcutaneous injection of a cell suspension into the back of mice. The tumor volume was approximately 530 mm 3 Upon reaching 100 mg / kg, a group of tumor-bearing mice (n=5) was injected with the complex via the tail vein. After just one injection of 6 mg / kg DM1 and 42 mg / kg DTX, tumor size continuously decreased over the following 20 days, as shown in Figure 27A, demonstrating the efficacy of the complex even in large tumors. No weight loss was observed with this treatment (Figure 27B). Example 19 Antitumor efficacy and toxicity in breast tumor models

[0315] The in vivo antitumor efficacy of the complex was evaluated in a subcutaneous MCF-7 breast tumor model. The cell suspension was injected subcutaneously into the back of the mice to establish the tumor model, and the tumors grew to approximately 100 mm 3 Once the composition was administered, groups of tumor-bearing mice (n=8) were injected via the tail vein. Figure 28A shows the tumor volume change in the untreated group (black line) and the group treated with the complex (red line) after two injections (arrows indicate the injection date for each injection at 5 mg / kg DM1 and 30 mg / kg DTX). Figure 28B shows no difference in body weight change between the control and treatment groups. Figure 28C shows the excised tumors in the control group (top row) and the stereocomplex-treated group (bottom row). Note that one mouse was tumor-free by day 25, and three mice were tumor-free at the end of the study. Figure 28D shows a comparison of tumor weights in the control group (left) and the stereocomplex-treated group (right). Example 20 Antitumor efficacy and toxicity in bladder tumor models

[0316] The in vivo antitumor efficacy of the complex was evaluated in a subcutaneous RT112 bladder tumor model. The cell suspension was injected subcutaneously into the back of the mice to establish the tumor model, and the tumors grew to approximately 100 mm. 3Once tumor-bearing mice were treated, groups of mice (n=5) were injected with the composition via the tail vein. Figure 29A shows that untreated mice (squares) experienced a more significant increase in tumor volume, while mice treated with the complex (circles) exhibited a smaller final tumor volume after three weekly injections of 3.6 mg / kg DM1 and 30 mg / kg DTX. Figure 29B shows the weight changes in the control and treatment groups. Figure 29C shows excised tumors from the control group (top row) and the stereocomplex-treated group (bottom row). Figure 29D shows a comparison of tumor weights between the control group (left) and the stereocomplex-treated group (right). Example 21 Antitumor efficacy and toxicity in esophageal tumor models

[0317] The in vivo antitumor efficacy of the complex was evaluated in a subcutaneous TT esophageal tumor model. The cell suspension was injected subcutaneously into the back of the mouse to establish the tumor model, and the tumor grew to approximately 110 mm. 3 Once the composition was administered, groups of tumor-bearing mice (n=5) were injected via the tail vein. Figure 30A shows that untreated mice (squares) experienced a significant increase in tumor volume, while mice treated with the complex experienced rapid tumor shrinkage after three weekly injections of 4 mg / kg DM1 and 40 mg / kg DTX. Figure 30B shows the weight changes in the control and treatment groups. Figure 30C shows the excised tumors in the control group (top row) and the stereocomplex-treated group (bottom row). Note that one mouse remained tumor-free by day 27. Figure 30D shows a comparison of tumor weights in the control group (left) and the stereocomplex-treated group (right). Example 22 Antitumor efficacy and toxicity in glioblastoma tumor models

[0318] The in vivo antitumor efficacy of the complex was evaluated in a subcutaneous U251 glioblastoma tumor model. The cell suspension was injected subcutaneously into the back of mice to establish the tumor model, and the tumor grew to approximately 150 mm. 3Once tumor-bearing mice were treated, groups of mice (n=5) were injected with the composition via the tail vein. Figure 31A shows that untreated mice (squares) experienced a significant increase in tumor volume, while mice treated with the complex (circles) exhibited smaller final tumor volumes after two weekly injections of 3 mg / kg DM1 and 30 mg / kg DTX. Figure 31B shows the weight changes in the control and treatment groups. Figure 31C shows excised tumors from the control group (top row) and the stereocomplex-treated group (bottom row). Figure 31D shows a comparison of tumor weights between the control group (left) and the stereocomplex-treated group (right). Example 23 Antitumor efficacy and toxicity in kidney tumor models

[0319] The in vivo antitumor efficacy of the complex was evaluated in a subcutaneous Caki-1 kidney tumor model. The cell suspension was injected subcutaneously into the back of mice to establish the tumor model, and tumors grew to approximately 170 mm 3 Once tumor-bearing mice were treated, groups of mice (n=5) were injected with the composition via the tail vein. Figure 32A shows that untreated mice (squares) experienced a more significant increase in tumor volume, while mice treated with the complex (circles) exhibited a smaller final tumor volume after three weekly injections of 3.2 mg / kg DM1 and 32 mg / kg DTX. Figure 32B shows the weight changes in the control and treatment groups. Figure 32C shows excised tumors from the control group (top row) and the stereocomplex-treated group (bottom row). Figure 32D shows a comparison of tumor weights between the control group (left) and the stereocomplex-treated group (right). Example 24 Antitumor efficacy and toxicity in non-small cell lung tumor models

[0320] The in vivo antitumor efficacy of the complex was evaluated in a subcutaneous NCI-H522 non-small cell lung tumor model. The cell suspension was injected subcutaneously into the back of mice to establish the tumor model, and tumors grew to approximately 130 mm. 3Once the composition was administered, groups of tumor-bearing mice (n=5) were injected via the tail vein. Figure 33A shows that tumor volume increased significantly in untreated mice (squares), whereas tumor volume rapidly decreased in mice treated with the complex after two injections of 5 mg / kg DM1 and 50 mg / kg DTX once per week. Figure 33B shows the weight changes in the control and treatment groups. Figure 33C shows the excised tumors in the control group (top row) and the stereocomplex-treated group (bottom row). Note that three mice were tumor-free at the end of the study. Figure 33D shows a comparison of tumor weights in the control group (left) and the stereocomplex-treated group (right). Example 25 Antitumor efficacy and toxicity in non-small cell lung tumor models

[0321] The in vivo antitumor efficacy of the complex was evaluated in a subcutaneous NCI-H226 non-small cell lung tumor model. The cell suspension was injected subcutaneously into the back of the mice to establish the tumor model, and the tumors grew to approximately 120 mm. 3 Once tumor-bearing mice were treated, groups of mice (n=4) were injected with the composition via the tail vein. Figure 34A shows that untreated mice (squares) experienced a more significant increase in tumor volume, while mice treated with the complex (circles) exhibited a smaller final tumor volume after two injections of 4 mg / kg DM1 and 32 mg / kg DTX once every two weeks. Figure 34B shows the weight changes in the control and treatment groups. Figure 34C shows excised tumors from the control group (top row) and the stereocomplex-treated group (bottom row). Figure 34D shows a comparison of tumor weights between the control group (left) and the stereocomplex-treated group (right). Example 26 Antitumor efficacy and toxicity in ovarian tumor models

[0322] The in vivo antitumor efficacy of the complex was evaluated in a subcutaneous ovarian tumor model. The cell suspension was injected subcutaneously into the back of the mice to establish the tumor model, and the tumors grew to approximately 150 mm. 3Once tumor-bearing mice were treated, groups of mice (n=5) were injected with the composition via the tail vein. Figure 35A shows that untreated mice (squares) experienced a significant increase in tumor volume, while mice treated with the complex (circles) exhibited a small final tumor volume after only a single injection of 6 mg / kg DM1 and 39 mg / kg DTX. Figure 35B shows the weight changes in the control and treatment groups. Figure 35C shows the excised tumors in the control group (top row) and the stereocomplex-treated group (bottom row). Figure 35D shows a comparison of tumor weights in the control group (left) and the stereocomplex-treated group (right). Example 27 Antitumor efficacy and toxicity in prostate tumor models

[0323] The in vivo antitumor efficacy of the complex was evaluated in a subcutaneous PC-3 prostate tumor model. The cell suspension was injected subcutaneously into the back of the mice to establish the tumor model, and the tumor grew to approximately 130 mm. 3 Once tumor-bearing mice were treated, groups of mice (n=5) were injected with the composition via the tail vein. Figure 36A shows that untreated mice (squares) experienced a significant increase in tumor volume, while mice treated with the complex (circles) exhibited a smaller final tumor volume after three weekly injections of 3.8 mg / kg DM1 and 38 mg / kg DTX. Figure 36B shows that mice in the control group lost weight, while those in the treated group maintained normal weight. Figure 36C shows excised tumors from the control group (top row) and the stereocomplex-treated group (bottom row). Figure 36D shows a comparison of tumor weights between the control group (left) and the stereocomplex-treated group (right). Example 28 Antitumor efficacy and toxicity in lymphoma tumor models

[0324] The in vivo antitumor efficacy of the complex was evaluated in a subcutaneous Raji lymphoma tumor model by intravenous injection. The cell suspension was injected subcutaneously into the back of the mice to establish the tumor model. The tumor volume was approximately 130 mm 3Upon reaching 30 days, groups of tumor-bearing mice (n=4) were injected with the complex via the tail vein. After only one injection of 5 mg / kg DM1 and 40 mg / kg DTX, three mice were tumor-free on day 15, and all mice were tumor-free from day 22 onwards. Figure 37A shows the change in tumor size for the complex-treated group (circles) versus the control group (squares). Figure 37B shows photographs of control mice (top row) and treated mice (bottom row) on day 25 of the study. Example 29 Blood parameters and clinical chemistry tests after a single injection of the complex

[0325] Mice (4 per group) were injected with the complex at a single iv dose of 5 mg / kg DM1 and 32.5 mg / kg DTX, and then sacrificed on days 3, 7, and 14. Blood samples were collected and analyzed for the following general parameters: white blood cell count (WBC); red blood cell count (RBC); hemoglobin concentration (HGB) and platelet count (PLT). Compared with the control (no injection) labeled day 0, RBC and HGB showed no statistical difference in all tests. Even though lower WBC and PLT counts were observed on day 3, they all recovered on day 7 and remained normal on day 14, as shown in Figure 38.

[0326] Figure 39 shows clinical chemistry in nude mice after a single iv injection of the complex. Mice (4 per group) were injected with the complex at a single iv dose of 5 mg / kg DM1 and 32.5 mg / kg DTX, and then sacrificed on days 3, 7, and 14. Blood samples were collected and analyzed for the following parameters: alanine aminotransferase (ALT); aspartate aminotransferase (AST); alkaline phosphatase (ALP), creatinine (CREA), and urea (UREA). Compared with the control (no injection) labeled day 0, ALT and AST increased after injection but returned to normal on day 14. There was no obvious difference in UREA and CREA, indicating the absence of any nephrotoxicity. Example 30 Histopathological analysis of organs after multiple injections of the complex

[0327] A CNE (nasopharyngeal) tumor cell suspension was injected subcutaneously into the back of the mice to establish a tumor model, and the tumors grew to approximately 100 mm 3 Groups of tumor-bearing mice (n=5) were then injected weekly via the tail vein for 4 consecutive weeks with the composition at a dose of 4 mg / kg DM1 for the D-DM1 group and 4 mg / kg DM1 with 26 mg / kg DTX for the complex group. After harvesting the heart, kidneys, spleen, lungs, and liver, sections were stained with hematoxylin and eosin for observation. As shown in Figures 40 and 41, compared with the control and D-DM1 treatments, complex treatment did not induce any damage to the organs. Example 31 Antitumor efficacy and toxicity of glucose-containing complexes in lymphoma tumor models

[0328] The in vivo antitumor efficacy of the glucose-containing complex was evaluated in a subcutaneous Raji lymphoma tumor model by intravenous injection. The cell suspension was injected subcutaneously into the back of the mouse to establish the tumor model. The tumor volume was approximately 130 mm 3 Upon reaching 4 days, groups of tumor-bearing mice (n=4) were injected with the complex via the tail vein. After just one injection of 5 mg / kg DM1 and 40 mg / kg DTX, three mice were tumor-free on day 15, and all mice were tumor-free from day 18 onwards. Figure 42A shows the change in tumor size for the complex-treated group (red line) versus the control group (black line). Figure 42B shows photographs of control mice (top row) and mice treated with the glucose-containing complex (bottom row) on day 25 of the study. Example 32 patient research Preparation and administration of stereocomplexes

[0329] mPEG-PLLA-hydrazone-DTX was dissolved in 2 mL of THF, and mPEG-PDLA-SS-DM1 was dissolved in 2 mL of acetonitrile along with mPEG-PDLA. The two solutions were mixed together, and the mixture was stirred at room temperature for 4 hours and then added dropwise to Di-PBS. After stirring at room temperature for 1 hour, the organic solvent was evaporated under vacuum by rotary evaporation. After evaporation, the stereocomplex was lyophilized, and the powder was reconstituted with water and filtered through a 200 nm filter for sterilization. The weight percentage of DM1 was approximately 0.8%, and the weight percentage of DTX was approximately 6%, meaning that the weight ratio of DTX to DM1 was 7-9.

[0330] Aqueous solutions of the stereocomplex were mixed with saline (500 mL) for intravenous injection. The stereocomplex was administered intravenously to each patient over approximately 1 hour. The stereocomplex was administered approximately every 2 weeks after the first treatment. The amounts of DM1 and DTX administered to each patient varied as follows: total amount of DM1 was measured and expressed in mg / m 2 is the body surface area calculated for height and weight. As noted below, patient 1 received 4 mg / m 2 DM1 was administered. 2 For a subject with a body surface area (BSA) of 1000 mg, the total amount of DM1 administered is 4.8 mg. As presented above, the weight percentage of DM1 in the stereocomplex is about 0.8% by weight of the stereocomplex, which means that the total weight of the stereocomplex administered to the subject is about 600 mg (4.8 / 0.8). patient 1

[0331] The first patient was a 71-year-old man with squamous cell lung cancer. Based on the AJCC cancer staging classification from the PET-CT study, the lung cancer was classified as stage 3 with a hypermetabolic subtracheal nodule in the right lower lobe. Based on the PET-CT study, four treatments (4 mg DM1 / m per treatment) were administered. 2After CT scan, the intensity of the subcarinal lymph nodes decreased significantly, as shown in Figure 43. The patient underwent right total lobectomy. The 38 adjacent lymph nodes that were removed were normal, there was no evidence of tumor in the pathology report, and the cancer was pathologically classified as stage 1. No further treatment was performed after surgery, and the patient was normal after 4 months of follow-up based on PET-CT scans. patient 2

[0332] The second patient was a 70-year-old man with pancreatic cancer. At the start of the study, the size of the pancreatic head mass was 3.68 cm x 3.77 cm x 4.26 cm, as confirmed by MR imaging (axial and coronal planes), and biopsy revealed adenocarcinoma of the pancreas. Stereocomplex (4 mg DM1 / m 2 After treatment with DM1 / m2, the size of the pancreatic mass was 3.19 cm x 3.27 cm as confirmed by contrast-enhanced CT (axial plane), which is a 25% reduction in cross-sectional area. 2 After five procedures with MRI, the patient underwent a Whipple procedure. The surgical specimen revealed a 2 cm x 1.5 cm pancreatic head tumor, representing an approximately 80% reduction in cross-sectional area compared with the initial MR imaging. patient 3

[0333] The third patient was a 6-year-old boy with diffuse pontine glioma (DIPG). Initially, the boy was treated with hyperfractionated radiotherapy at a total dose of 54 Gray (Gy) in 30 daily fractions. Leptomeningeal metastases were subsequently noted by MR, and grade 4 diffuse pontine glioma was confirmed by stereotactic biopsy. Prior to treatment with stereocomplex, sagittal MR of the spine showed multiple large, irregularly shaped masses occupying most of the spinal canal from L1 to S1, with minimal visible CSF space. Stereocomplex (10 mg DM1 / m per treatment) was administered. 2After five treatments with MRI, MR revealed significant tumor mass reduction in the spinal canal between L1 and S1, representing an approximately 93% reduction in tumor volume in this region. Only a small residual mass was observed behind L4 and L5, and the CSF space and cauda equina nerve fibers were easily identified (Figure 44). patient 4

[0334] The fourth patient was a 70-year-old man with non-small cell lung cancer. At the beginning of the study, the tumor size was 3.3 cm x 2.9 cm as confirmed by PET / CT. Immediately after the first treatment, the tumor size increased to 3.5 cm x 2.8 cm as confirmed by PET / CT. Stereocomplex (12 mg DM1 / m per treatment) was administered. 2 After two treatments with EGFR-1000, PET / CT scans confirmed that the tumor's long diameter decreased from 3.5 cm to 2.2 cm in 15 days, as shown in Figure 45. The uptake of mediastinal, hilar, and abdominal aortic lymph nodes changed to normal (Figure 46). Notably, before treatment, the tumor was found to have invaded the parietal pleura, but after treatment, the tumor size decreased, and the tumor and parietal pleura were found to be completely separated (Figure 47).

[0335] Throughout this publication, various publications are referenced, the entire disclosures of which are hereby incorporated by reference into this application in order to more fully describe the methods, compositions, and compounds herein.

[0336] Various modifications and variations can be made to the materials, methods, and articles described herein. Other aspects of the materials, methods, and articles described herein will be apparent from consideration of the specification and practice of the materials, methods, and articles disclosed herein. It is intended that the specification and examples be considered as illustrative. The present invention provides, for example, the following items. (Item 1) Components X 1 -Y 1 -L 1-Z 1 (I) X 2 -Y 2 -L 2 -Z 2 (II) (In the formula, each X 1 and X 2 is a hydrophilic group, Each Y 1 and Y 2 is PDLA or PLLA, Each L 1 and L 2 is a cleavable linker, Z 1 is an anticancer drug, Z 2 is an anti-cancer agent or imaging agent, where Z 2 If is an anticancer drug, Z 1 and Z 2 are different anticancer drugs, and Here, (1)Y 1 If is PDLA, then Y 2 is PLLA, and Y 1 If is PLLA, Y 2 is PDLA, and (2) the ratio of the total number of D-lactic acid units in the stereocomplex to the total number of L-lactic acid units in the stereocomplex is 0.9:1.1 to 1.1:0.9. Stereo complex including. (Item 2) X 1 and X 2 are different hydrophilic groups. (Item 3) X 1 and X 2 are the same hydrophilic group. (Item 4) X 1 and X 2 and each are a polyalkylene glycol. (Item 5) X1 and X 2 and each are a polyalkylene glycol having a molecular weight of 1,000 Da to 5,000 Da. (Item 6) X 1 and X 2 and each are polyethylene glycol having a molecular weight of 1,000 Da to 5,000 Da. (Item 7) X 1 and X 2 and each are monomethoxypolyethylene glycol having a molecular weight of 1,000 Da to 5,000 Da. (Item 8) 8. The stereocomplex according to any one of items 1 to 7, wherein PDLA and PLLA have a molecular weight of 700 Da to 5,000 Da. (Item 9) L 1 and L 2 are different linkers. (Item 10) L 1 and L 2 and are the same linker. (Item 11) L 1 and L 2 independently contain a disulfide group, an ester group, a hydrazone group, an acetal group, an imine group, a β-thiopropionate group or an amide group. (Item 12) Z 1 and Z 2are independently paclitaxel, doxorubicin, gemcitabine, cisplatin, methotrexate, 5-fluorouracil, betulinic acid, amphotericin B, diazepam, nystatin, propofol, testosterone, estrogen, prednisolone, prednisone, 2,3 mercaptopropanol, progesterone, docetaxel, maytansinoid, PD-1 inhibitor, PD-L1 inhibitor, protein kinase inhibitor, P-glycoprotein inhibitor, autophagy inhibitor, PARP inhibitor, aromatase inhibitor, monoclonal antibody, photosensitizer, radiosensitizer, interleukin, antiandrogen, or any combination thereof. (Item 13) 13. The stereocomplex according to item 12, wherein the maytansinoid is ansamitocin, mertansine (DM1) or ravtansine. (Item 14) Z 1 and Z 2 14. The stereocomplex according to any one of items 1 to 13, wherein the molar ratio of (Item 15) Z 1 is mertansine, and Z 2 15. The stereocomplex according to any one of items 1 to 14, wherein is docetaxel. (Item 16) Regarding component I, X 1 is a monomethoxypolyethylene glycol having a molecular weight of 2,000 Da to 4,000 Da, the number of L-lactic acid units or D-lactic acid units is 15 to 60, and L 1 contains a disulfide group, and Z 1 16. The stereocomplex according to any one of items 1 to 15, wherein is mertansine (DM1). (Item 17) Component I has the following structure: [ka] (In the formula, n 1is 45 to 90, m 1 is 15 to 60, o is 1 to 4, and C a The stereochemistry in is R or S) Item 17. The stereocomplex according to item 16, having the formula: (Item 18) 18. The stereocomplex according to item 17, wherein o is 2. (Item 19) Regarding component II, X 2 is a monomethoxypolyethylene glycol having a molecular weight of 2,000 Da to 4,000 Da, the number of L-lactic acid units or D-lactic acid units is 15 to 60, and L 2 contains an ester, hydrazone, or disulfide group, and Z 2 19. The stereocomplex according to any one of items 16 to 18, wherein is docetaxel. (Item 20) Item 20. The stereocomplex according to item 19, wherein the molar ratio of mertansine to docetaxel is 4:1 to 1:10. (Item 21) Component II has the following structure: [ka] (In the formula, n 2 is 45 to 90, m 2 is 15 to 60, p is 0 to 7, and C a The stereochemistry in is R or S) 20. The stereocomplex according to item 19, having the formula: (Item 22) 22. The stereocomplex according to item 21, wherein p is 2. (Item 23) Component II has the following structure: [ka] (In the formula, n 2 is 45 to 90, m 2 is 15 to 60, each p is independently 0 to 7; q is 1 to 7; C a The stereochemistry in is R or S) 20. The stereocomplex according to item 19, having the formula: (Item 24) 24. The stereocomplex according to item 23, wherein each p is 2 and q is 3. (Item 25) Component II has the following structure: [ka] (In the formula, n 2 is 45 to 90, m 2 is 15 to 60, each p is independently 0 to 7; C a The stereochemistry in is R or S) 20. The stereocomplex according to item 19, having the formula: (Item 26) 26. The stereocomplex according to item 25, wherein each p is 2. (Item 27) The stereocomplex is formed by the reaction of component VII X 3 -Y 3 (VII) (In the formula, X 3 is a hydrophilic group, and Y 3 is PDLA or PLLA) 27. The stereocomplex according to any one of items 1 to 26, further comprising: (Item 28) X 3Item 28. The stereocomplex according to item 27, wherein is a polyalkylene glycol having a molecular weight of 1,000 Da to 5,000 Da. (Item 29) X 3 is a polyethylene glycol having a molecular weight of 1,000 Da to 5,000 Da. (Item 30) X 3 28. The stereocomplex according to item 27, wherein is monomethoxypolyethylene glycol having a molecular weight of 1,000 Da to 5,000 Da. (Item 31) X 3 is monomethoxypolyethylene glycol having a molecular weight of 2,000 Da to 4,000 Da, and the number of L-lactic acid units or D-lactic acid units present in PDLA or PLLA is 15 to 60. (Item 32) The stereocomplex is represented by component VIII TA-X 4 -Y 4 (VIII) (In the formula, X 4 is a hydrophilic group, Y 4 is PDLA or PLLA, and TA is a targeting group 32. The stereocomplex according to any one of items 1 to 31, further comprising: (Item 33) X 4 is a polyalkylene glycol having a molecular weight of 1,000 Da to 5,000 Da, wherein X 4 The molecular weight of X 1 and X 2 33. The stereocomplex according to item 32, having a molecular weight greater than (Item 34) X 4 is polyethylene glycol having a molecular weight of 1,000 Da to 5,000 Da, where X 4 The molecular weight of X1 and X 2 33. The stereocomplex according to item 32, having a molecular weight greater than (Item 35) X 4 is a polyethylene glycol having a molecular weight of 2,000 Da to 4,000 Da, and the number of L-lactic acid units or D-lactic acid units present in PDLA or PLLA is 15 to 60. (Item 36) 33. The stereocomplex according to item 32, wherein TA is a ligand. (Item 37) Component VIII has the structure: [ka] (In the formula, n 3 is 45 to 90, m 3 is between 15 and 60, and C a The stereochemistry in is R or S) 33. The stereocomplex according to item 32, having the formula: (Item 38) 33. The stereocomplex according to item 32, wherein TA is an unsubstituted or substituted sugar. (Item 39) 39. The stereocomplex according to item 38, wherein the sugar is ribose, galactose, mannose, fructose, fuculose, glucosamine or fucoidan. (Item 40) 33. The stereocomplex according to item 32, wherein TA is glucose or a substituted glucose. (Item 41) 41. The stereocomplex according to item 40, wherein TA is an alkyl-substituted glucose. (Item 42) 41. The stereocomplex according to item 40, wherein TA is methyl-α-glucose or methyl-β-glucose. (Item 43) The stereocomplex is represented by formula IX X 5 -Y 5 -L 5 -Z 5 (IX) (In the formula, X 5 is a hydrophilic group, Y 5 is PDLA or PLLA, L 5 is a cleavable linker, and Z 5 is an anticancer drug, where Z 5 is Z 1 and Z 2 (different from 43. The stereocomplex according to any one of the preceding items, further comprising one or more components of (Item 44) Z 2 is an imaging agent, and said imaging agent comprises a radiopharmaceutical, a radiological contrast agent, an optical imaging agent or a precursor thereof, a quantum dot, or a combination thereof. (Item 45) The radiopharmaceutical is 11 CL-methyl-methionine, 18 F-fluorodeoxyglucose, 18 F - sodium fluoride, 18 F fluorocholine, 18 F desmethoxyfalipride, 67 Ga-Ga 3+ , 68 Ga-dotatoc, 68 Ga-PSMA, 111 In-diethylenetriaminepentaacetic acid, 111 In-white blood cells, 111 In-platelets, 111 In-Penetreotide, 111 In-octreotide, 123 I-iodide, 123 Io-iodine hiprate, 123 Im-iodobenzylguanidine,123 I-FP-CIT, 125 I-fibrinogen, 131 I-iodide, 131 Im-iodobenzylguanidine, 81 Kr m -gas, 81 Kr m -aqueous solution, 13 N-ammonia, 15 O-water, 75 Se-selenolcholesterol, 75 Se-seleno-25-homo-tauro-cholate, 120 Tl-Tl + , 133 Xe-gas, 133 Xe (in isotonic sodium chloride solution), 99 Tc m -Pertechnetate, containing macroaggregates or microspheres 99 Tc m human albumin, 99 Tc m phosphonates and / or phosphates, 99 Tc m -diethylenetriaminepentaacetic acid, 99 Tc m -dimercaptosuccinic acid, 99 Tc m -colloid, 99 Tc m -hepatic iminodiacetic acid, 99 Tc m whole red blood cells, 99 Tc m -Mercaptoacetyltriglycine, containing examethasone-labeled leukocytes 99 Tc m Examethadime, 99 Tc m sester-methoxyisobutylisonitrile, 99 Tc m IMMU-MN3 mouse Fab'-SH anti-granulocyte monoclonal antibody fragment, 99 Tc m -Technegas, 99 Tc m human immunoglobulin, 99 Tc m - tetrofosmin, 99Tc m - A stereocomplex according to item 44, comprising ethyl cysteinate dimer, or another radiopharmaceutical. (Item 46) 45. The stereocomplex of item 44, wherein the radiocontrast agent comprises diatrizoate, metrizoate, iothalamate, ioxaglate, iopamidol, iohexol, ioxilan, iopromide, iodixanol, ioversol, another iodocontrast agent, barium sulfate, gadoterate, gadodiamide, gadobenate, gadopentetate, gadoteridol, gadofosveset, gadoversetamide, gadoxetate, gadobutrol, or another gadolinium chelator. (Item 47) Item 48. The stereocomplex of item 44, wherein the optical imaging agent or precursor thereof comprises methylene blue, indigo carmine, another non-specific dye, fluorescein isothiocyanate, indocyanine green, rosamine, a BODIPY (boron-dipyrromethane) derivative, a chalcone, a xanthone, oxazole yellow, thiazole orange, fluorescein, luciferin, Texas red, squaraine, a porphyrin, a phthalocyanine, a polymethine cyanine dye including Cy3, Cy5, Cy5.5, or Cy7, Alexa fluor, 5-aminolevulinic acid, a metal chelator, or another optical imaging agent. 48. The stereocomplex according to any one of items 1 to 47, wherein the stereocomplex further comprises an adjuvant. (Item 49) 49. The stereocomplex according to item 48, wherein the adjuvant comprises an interstitial disrupting agent, an antifibrotic agent, an aromatase inhibitor, an immunosuppressant, an estrogen blocker, a gonadotropin-releasing hormone agonist, an estrogen modulator, a progestin therapeutic agent, an LHRH agonist, an androgen-lowering agent, an antiandrogen, an immunosuppressant, or any combination thereof. (Item 50) 49. The stereocomplex according to item 48, wherein the adjuvant comprises a stroma-rupting agent, wherein the stroma-rupting agent comprises losartan, azilsartan, candesartan, eprosartan, irbesartan, olmesartan, telmisartan, valsartan, luteolin, quercetin, genistein, catechin, cyaniding, naringenin, delphinidin, malvidin, petunidin, peonidin, pelargonidin, gallocatechin, catechin-3-gallate, epicatechin, epigallocatechin, daidzein, glycitein, equol, kaempferol, myricetin, eriodictyol, hesperitin, taxifolin, or any combination thereof. (Item 51) 49. The stereocomplex according to item 48, wherein the adjuvant comprises an antifibrotic agent, wherein the antifibrotic agent comprises pirfenidone, mimosine, ciclopirox, geodon, bemeglide, deferiprone, etanercept, bosentan, sildenafil, nintedanib, colchicine or a combination thereof. (Item 52) Component I has the following structure: [ka] (In the formula, n 1 is 45 to 90, m 1 is 15 to 60, o is 1 to 4, and C a is R or S), and Component II has the following structure: [ka] (In the formula, n 2 is 45 to 90, m 2 is 15 to 60, each p is independently 0 to 7; q is 1 to 7, and C aThe stereochemistry in is R or S) and wherein the ratio of the total number of D-lactic acid units in the stereocomplex to the total number of L-lactic acid units in the stereocomplex is 0.9:1.1 to 1.1:0.9. Item 1. A stereocomplex according to item 1. (Item 53) 53. The stereocomplex according to item 52, wherein o is 2, each p is 2, and q is 3. (Item 54) 54. The stereocomplex according to any one of items 1 to 53, wherein the stereocomplex has an average diameter of 50 nm to 200 nm. (Item 55) 55. A pharmaceutical composition comprising a stereocomplex according to any one of items 1 to 54 and a pharmaceutically acceptable carrier. (Item 56) 55. A method for treating cancer in a subject, comprising administering to the subject a stereocomplex according to any one of items 1 to 54. (Item 57) 57. The method of item 56, wherein the cancer is pancreatic cancer, non-small cell lung cancer, small cell lung cancer, ovarian cancer, nasopharyngeal cancer, breast cancer, ovarian cancer, prostate cancer, colon cancer, gastric adenocarcinoma, head cancer, neck cancer, brain cancer, oral cancer, pharyngeal cancer, thyroid cancer, esophageal cancer, gallbladder cancer, liver cancer, rectal cancer, kidney cancer, uterine cancer, bladder cancer, testicular cancer, lymphoma, myeloma, melanoma, leukemia, or nonspecific solid tumor. (Item 58) 55. A method for reducing a tumor in a subject, comprising administering to the subject a stereocomplex according to any one of items 1 to 54. (Item 59) 59. The method of any one of items 56 to 58, wherein the stereocomplex is administered to the subject by intravenous injection. (Item 60) Component I has the following structure: [ka] (In the formula, n 1 is 45 to 90, m 1 is 15 to 60, o is 1 to 4, and C a The stereochemistry in is R or S) and Component II has the following structure: [ka] (In the formula, n 2 is 45 to 90, m 2 is 15 to 60, each p is independently 0 to 7; q is 1 to 7; C a The stereochemistry in is R or S) and wherein the ratio of the total number of D-lactic acid units in the stereocomplex to the total number of L-lactic acid units in the stereocomplex is 0.9:1.1 to 1.1:0.9. 60. The method of any one of items 56 to 59. (Item 61) Item 61. The method according to item 60, wherein o is 2, each p is 2, and q is 3.

Claims

1. A stereo complex, Components X １ -Y １ -L １ -Z １ (I) 8 ２ -9 ２ -8 ２ - ２ (A) (In the formula, Each X １ and X ２ is a polyalkylene glycol, Each Y １ and Y ２ is PDLA or PLLA, Each L １ and L ２ is a cleavable linker independently selected from a disulfide group, an ester group, a hydrazone group, an acetal group, an imine group, a β-thiopropionate group, or an amide group; Z １ is an anticancer drug, Z ２ is an imaging agent, and Here, (1) Y １ If is PDLA, then Y ２ is PLLA, and Y １ When Y is PLLA, ２ is PDLA, and (2) the ratio of the total number of D-lactic acid units in the stereocomplex to the total number of L-lactic acid units in the stereocomplex is 0.9:1.1 to 1.1:0.

9. Stereo Complex, including.

2. X １ and X ２ 10. The stereocomplex as claimed in claim 1, wherein: are different polyalkylene glycols or are the same polyalkylene glycol.

3. 3. The stereocomplex as claimed in claim 1 or 2, wherein each of PDLA and PLLA has a molecular weight of 700 Da to 5,000 Da.

4. L １ and L ２ A stereocomplex as claimed in any one of claims 1 to 3, wherein are different linkers or are the same linker.

5. Z １ is paclitaxel, doxorubicin, gemcitabine, cisplatin, methotrexate, 5-fluorouracil, betulinic acid, amphotericin B, diazepam, nystatin, propofol, testosterone, estrogen, prednisolone, prednisone, 2,3 mercaptopropanol, progesterone, docetaxel, maytansinoid, PD-1 inhibitor, PD-L1 inhibitor, protein kinase inhibitor, P-glycoprotein inhibitor, autophagy inhibitor, PARP inhibitor, aromatase inhibitor, monoclonal antibody, photosensitizer, radiosensitizer, interleukin, antiandrogen, or any combination thereof; the PD-1 inhibitor is pembrolizumab, nivolumab, pidilizumab, AMP-224, AMP-514, or PDR001; the PD-L1 inhibitor is atezolizumab, avelumab, durvalumab or BMS0936559; the protein kinase inhibitor is afatanib, axitinib, bosutinib, cetuximab, cobimetinib, crizotinib, cabozanitinib, dasatinib, entrectinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, mubritinib, nilotinib, pazopanib, pegaptanib, ruxolitinib, sorafenib, sunitinib, SU6656, vandetanib or vemurafenib; The p-glycoprotein inhibitors include verapamil, cyclosporine, tamoxifen, calmodulin antagonists, dexverapamil, dexniguldipine, valspodar (PSC833), biriquidar (VX-710), tariquidar (XR9576), zosuquidar (LY335979), laniquidar (R101933), elacridar (GF120918), timcodar (VX-853), taxifolin, naringenin, dios amine, quercetin, diltiazem, bepridil, nicardipine, nifedipine, felodipine, isradipine, trifluoperazine, clopenthixol, trifluopromazine, flupenthixol, emopamil, gallopamil, Ro11-2933, amiodarone, clarithromycin, colchicine, erythromycin, lansoprazole, omeprazole, paroxetine, sertraline, quinidine or any combination thereof; the autophagy inhibitor is 3-methyladenine, wortmannin, LY294002, PT210, GSK-2126548, spautin-1, SAR405, VPS34-IN1, PIK-III, MRT68921, SBI-0206965, pepstatin A, E64d, bafilomycin A1, clomipramine, lucanthone, chloroquine, hydroxychloroquine, Lys05, or ARN5187; the PARP inhibitor is MK-4827, rucaparib, iniparib, talazoparib, olaparib, veliparib, CEP9722, E7016, BGB2-290 or 3-aminobenzamide; the aromatase inhibitor is aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, 1,4,6-androstatriene-3,17-dione or 4-androstene-3,6,17-trione; A stereocomplex as claimed in any one of claims 1 to 4.

6. Z １ and Z ２ A stereocomplex as claimed in any one of claims 1 to 5, wherein the molar ratio of is from 10:1 to 1:

10.

7. Regarding component I, X １ is monomethoxypolyethylene glycol having a molecular weight of 2,000 Da to 4,000 Da, the number of L-lactic acid units or D-lactic acid units is 15 to 60, and L １ contains a disulfide group, and Z １ However, mertansine (DM1) A stereocomplex as claimed in any one of claims 1 to 6.

8. Regarding component II, X ２ is monomethoxypolyethylene glycol having a molecular weight of 2,000 Da to 4,000 Da, the number of L-lactic acid units or D-lactic acid units is 15 to 60, and L ２ 8. The stereocomplex as claimed in claim 7, wherein comprises an ester, hydrazone, or disulfide group.

9. The stereocomplex is formed by the reaction of component VII ︸ ３  ３ (().) (In the formula, X ３ is a polyalkylene glycol, and Y ３ is PDLA or PLLA) further comprising: A stereocomplex as claimed in any one of claims 1 to 8.

10. The stereocomplex is represented by component VIII () ４  ４ (().|) (In the formula, X ４ is a polyalkylene glycol, Y ４ is PDLA or PLLA, and TA is a targeting group, said targeting group being an antibody, an antibody fragment, an aptamer, a sugar, a peptide, a lectin, folic acid, a folate, or a steroid hormone. further comprising: A stereocomplex as claimed in any one of claims 1 to 9.

11. Component VIII has the structure: 【Chemistry 27】 (In the formula, n ３ is 45 to 90, m ３ is between 15 and 60, and C ａ The stereochemistry at is R or S.

11. The stereocomplex as claimed in claim 10, having:

12. 11. The stereocomplex as claimed in claim 10, wherein TA is an unsubstituted or substituted sugar.

13. 13. The stereocomplex as claimed in any one of claims 1 to 12, wherein the imaging agent comprises a radiopharmaceutical, a radiological contrast agent, an optical imaging agent or precursor thereof, a quantum dot, or any combination thereof.

14. the stereocomplex further comprises an adjuvant, wherein the adjuvant comprises a stroma-rupting agent, an anti-fibrotic agent, an aromatase inhibitor, an immunosuppressant, an estrogen blocker, a gonadotropin-releasing hormone agonist, an estrogen modulator, a progestin therapeutic agent, an LHRH agonist, an androgen-lowering agent, an antiandrogen, an immunosuppressant, or any combination thereof; the antifibrotic agent is pirfenidone, mimosine, ciclopirox, geodon, bemeglide, deferiprone, N-acetylcysteine, etanercept, bosentan, sildenafil, nintedanib, colchicine, or any combination thereof; the aromatase inhibitor is anastrozole, letrozole, or exemestane; the immunosuppressant is a corticosteroid (hydrocortisone), methotrexate, or interferon; and The estrogen blocker is tamoxifen, toremifene, or fulvestrant. A stereocomplex as claimed in any one of claims 1 to 13.

15. 15. A stereocomplex as claimed in any one of claims 1 to 14, wherein said stereocomplex has an average diameter of 50 nm to 200 nm as measured by dynamic light scattering.

16. A pharmaceutical composition comprising a stereocomplex as claimed in any one of claims 1 to 15 and a pharmaceutically acceptable carrier thereof.

17. 16. A composition comprising a stereocomplex as claimed in any one of claims 1 to 15 for use in treating cancer in a subject.

18. A composition comprising a stereocomplex as claimed in any one of claims 1 to 15 for use in reducing a tumor in a subject.

19. 19. A composition for use as claimed in claim 17 or 18, wherein said composition is administered to said subject by intravenous injection.

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