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CN-121971451-A - Combined medicine composition of supported-koji Bei Ti nano micelle and oxaliplatin and application thereof

CN121971451ACN 121971451 ACN121971451 ACN 121971451ACN-121971451-A

Abstract

The invention discloses a combined medicine composition of a supported yeast Bei Ti fixed nano micelle and oxaliplatin and application thereof, and relates to the technical field of delivery and medicine combination. Also discloses the application of the combination drug composition in preparing antitumor drugs. The pH sensitive amphiphilic biodegradable material (such as PCL-PEOz) is utilized to form stable micelle with chemical drugs through self-assembly so as to improve the bioavailability of the drugs, reduce the critical concentration of the micelle and realize in-vivo long-acting circulation; the system can be used in combination with oxaliplatin, promotes the sensitivity of tumor cells to oxaliplatin, exerts the synergistic effect of chemotherapy and immunotherapy, improves the treatment effect of malignant tumor and improves the tumor microenvironment.

Inventors

  • DU ZIXIU
  • Cui Xindie

Assignees

  • 上海交通大学

Dates

Publication Date
20260505
Application Date
20251231

Claims (10)

  1. 1. The combined drug combination of the supported troemia Bei Ti nano-micelle and the oxaliplatin is characterized by comprising the supported troemia Bei Ti nano-micelle and the oxaliplatin, wherein the drug administration molar ratio of the supported troemia to the oxaliplatin is 1:100-2000.
  2. 2. The combination pharmaceutical composition according to claim 1, wherein the trabectedin-carrying nano-micelle has a core-shell structure, the nano-micelle being formed from an amphiphilic block copolymer comprising a crystalline hydrophobic block and a hydrophilic block, the trabectedin co-crystallizing with the crystalline hydrophobic block to form an inner core of the core-shell structure, the hydrophilic block forming an outer shell of the core-shell structure.
  3. 3. The combination composition of claim 2, wherein the amphiphilic block copolymer is selected from any one of poly (epsilon-caprolactone) -polyethylene glycol, poly (epsilon-caprolactone) -poly (2-ethyl-2-oxazoline) and end-functionalized derivatives thereof, polylactic acid-glycolic acid copolymer-polyethylene glycol, polylactic acid-glycolic acid copolymer-poly (2-ethyl-2-oxazoline).
  4. 4. The combination pharmaceutical composition according to claim 3, wherein the amphiphilic block copolymer is poly (epsilon-caprolactone) -poly (2-ethyl-2-oxazoline) with carboxyl groups at the end, i.e. PCL-PEOz-COOH, wherein the molecular weight of PCL is 5000 da, the molecular weight of peoz is 2000 Da, the hydrophobic polycaprolactone PCL block and the trabectedin co-crystallize to form the inner core of the shell-core structure, and the hydrophilic poly (2-ethyl-2-oxazoline) PEOz block forms the outer shell of the shell-core structure.
  5. 5. The combination pharmaceutical composition of claim 1, wherein the trabectedin-carrying nano-micelle has a trabectedin-carrying amount of 3.0% -10.0%.
  6. 6. The combination pharmaceutical composition according to any one of claims 1 to 5, wherein the trabectedin-carrying nano-micelle is prepared from trabectedin and amphiphilic block copolymer by solvent evaporation method or dialysis method, and specifically comprises: S1, dissolving an amphiphilic block copolymer and trabectedin an organic solvent, slowly adding water to form a mixed solution of the organic solvent and water, and performing ultrasonic treatment until a uniform emulsion is formed; S2, removing the organic solvent in the emulsion or the uniform solution through reduced pressure rotary evaporation, ultrafiltration or dialysis to obtain the drug-loaded micelle.
  7. 7. The combination of claim 6, further comprising at least one of the following technical features: in the step S1, the organic solvent in the emulsion is at least one selected from chloroform, dichloromethane and toluene; and/or the organic solvent in the uniform solution is selected from at least one of tetrahydrofuran, acetonitrile and ethanol; In the step S1, the volume ratio of the organic solvent to the water is 1:1-20; In the step S2, the unencapsulated medicine is removed by microporous membrane filtration after the organic solvent is removed; In step S2, removing the unencapsulated drug further comprises removing the residual organic solvent by dialysis and centrifugation.
  8. 8. The combination of claim 1, wherein the mode of administration of the combination comprises intravenous or intraperitoneal administration.
  9. 9. Use of a combination according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment of a tumour.
  10. 10. The use according to claim 9, wherein the tumour comprises colorectal cancer.

Description

Combined medicine composition of supported-koji Bei Ti nano micelle and oxaliplatin and application thereof Technical Field The invention relates to the technical field of drug delivery and drug combination, in particular to a drug combination composition of a supported-koji Bei Ti nano micelle and oxaliplatin and application thereof. Background For colorectal cancer treatment, particularly under the condition that the action mechanisms of various chemotherapeutic drugs are obviously different, the release behaviors and action time windows of different drugs in vivo are difficult to match, and effective synergistic anti-tumor effects are often difficult to form in the same tumor cells or tumor tissues. In addition, some antitumor drugs, although exhibiting strong activity in vitro experiments or single drug therapy, are limited by in vivo delivery modes and exposure characteristics under the condition of combined administration, and the potential synergistic advantages are difficult to fully develop, and even damage to normal tissues may be aggravated due to nonspecific distribution. Trabectedin (Trabectedin, TBD) is a natural product of tetrahydroisoquinoline class which is isolated and extracted from the body of the mangrove octopus altaicus of Caribbean, is effective for various malignant tumors, and the tetrahydroisoquinoline ring can be embedded into and interacted with a DNA minor groove to induce DNA double strand break to cause cell death. As a novel potential anticancer drug, it shows strong anticancer activity at low concentrations (nM) compared to other conventional chemotherapeutic drugs. In addition, it has been demonstrated that it can also significantly reduce the number of tumor-associated macrophages in the tumor microenvironment by inducing apoptosis of monocytes and macrophages, while indirectly inhibiting the secretion of cytokines and inflammatory mediators by macrophages to affect the tumor microenvironment, increasing the number of cd8+, cd4+ tumor infiltrating T cells in the tumor, thereby restoring tumor immunity, and limiting tumor development and metastasis. In addition, the trabectedin not only has direct and strong cytotoxicity on tumor cells, but also can obviously reduce the number of tumor-related macrophages in a tumor microenvironment by inducing apoptosis of monocytes and macrophages, and indirectly inhibit products such as cytokines, inflammatory mediators and the like from secreting by the macrophages to influence the tumor microenvironment, so that the number of CD8+ and CD4+ tumor infiltrating T cells in the tumor is increased, thereby restoring tumor immunity and limiting tumor development and metastasis. At present, the clinical injection (Yondelis) of the Qu Bei Ti. Sup. 34. Sup. Dine is a mixture freeze-dried powder prepared from sucrose, monopotassium phosphate and trobenidine according to a mass ratio of 400:27.2:1, and the pH value of the mixture freeze-dried powder is 3.6-4.2. The preparation form only increases the solubility of the trabectedin water, does not shield the possibility of combining with other components in blood circulation, and Yondelis degrees celsius is completely separated from auxiliary materials such as sucrose and the like under physiological conditions (pH=7.4), so that the medicine is exposed prematurely in the systemic circulation, combined with the components in the blood, enters normal tissues in a non-specific way and the like to have local effects, the medicine concentration of tumor parts is greatly reduced, the side effect of the medicine is increased, the effectiveness is reduced, and the medicine is difficult to be deeply applied clinically. Oxaliplatin (Oxaliplatin, OXA) is a third generation platinum-based compound that blocks DNA replication and transcription by inducing cross-linked damage between and within DNA strands, ultimately leading to apoptosis. While oxaliplatin has proven to be an alkylating agent with minimal single drug activity compared to other chemotherapeutic agents, earlier cisplatin and carboplatin have lower nephrotoxicity and gastrointestinal response, but they still have significant limitations in clinical applications. Firstly, oxaliplatin is used as an alkylating agent, the anti-tumor activity of a single drug is limited, and the curative effect is easily reduced due to the influence of a tumor cell repair mechanism and a drug excretion system. Secondly, patients often experience acquired drug resistance after long-term or repeated administration, resulting in reduced therapeutic effects. The traditional clinical treatment scheme usually depends on simple mixed administration or sequential administration of chemotherapeutic drugs, and the traditional combined administration mode has the problems of large pharmacokinetic difference, uneven in-vivo distribution, difficult control of a synergistic action time window and the like, so that the actual curative effect of the combined treatment is limited. Dis