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CN-122005814-A - Drug-loaded polymer micelle, gel drug system, preparation method and application

CN122005814ACN 122005814 ACN122005814 ACN 122005814ACN-122005814-A

Abstract

The invention belongs to the technical field of polymer nano-drugs, and particularly relates to a polymer micelle and gel drug system for drug co-loading, and a preparation method and application thereof. According to the invention, the amphiphilic block polymer self-assembles and self-crosslinks, and simultaneously carries the anti-tumor drug, so that the polymer micelle double-drug nano-preparation is obtained. The polymer micelle for co-carrying the medicine has the advantages of simple and controllable preparation, adjustable medicine proportion, small size, easy storage, high stability, excellent biocompatibility, capability of rapidly releasing the medicine in cells in proportion, strong synergistic anti-tumor effect, high in vivo safety, capability of completely eradicating tumors and the like. In general, the polymer micelle loaded with two antitumor drugs has multiple advantages of simple preparation, safety, high-efficiency synergy and the like, can effectively inhibit postoperative recurrence of malignant tumors, and greatly improves postoperative survival rate.

Inventors

  • SUN HUANLI
  • TANG XUELING
  • ZHONG ZHIYUAN

Assignees

  • 苏州大学

Dates

Publication Date
20260512
Application Date
20260209

Claims (10)

  1. 1. The polymer micelle for co-carrying the medicine is characterized by comprising a polymer micelle, and a tubulin inhibitor and a PLK1 inhibitor loaded by the polymer micelle, wherein the preparation raw materials of the polymer micelle comprise amphiphilic block polymers, and the amphiphilic block polymers have a hydrophilic segment-hydrophobic segment structure.
  2. 2. The drug-loaded polymer micelle according to claim 1, wherein the tubulin inhibitor comprises one or more of paclitaxel, docetaxel, cabazitaxel, auristatin and maytansinol, the PLK1 inhibitor comprises one or more of volasertib, regetide, ON01910, BI2536, HMN-214 and GSK461364, the hydrophilic segment is a polyethylene glycol segment, the hydrophobic segment comprises a random copolymer P (A-DTC), A is an ester monomer or a carbonate monomer unit, and DTC is a disulfide five-membered cyclic carbonate unit.
  3. 3. The drug co-loaded polymer micelle of claim 2, wherein the hydrophobic segment further comprises mefenamic acid, the ester monomer is one or both of caprolactone and lactide, and the carbonate monomer is trimethylene carbonate.
  4. 4. A combination comprising a drug co-loaded polymeric micelle of claim 1 and an additional drug.
  5. 5. A gel drug system comprising a fibrin hydrogel and the combination of claim 4, or a fibrin hydrogel and the drug-loaded polymer micelle of claim 1.
  6. 6. The combination of claim 4 or the gel drug system of claim 5, wherein the additional agent comprises a TGF- β inhibitor.
  7. 7. The method for preparing the drug-loaded polymer micelle of claim 1, which comprises the step of mixing a tubulin inhibitor, a PLK1 inhibitor and an amphiphilic block polymer to prepare the drug-loaded polymer micelle.
  8. 8. The method for preparing the gel drug system according to claim 5, wherein the method comprises the steps of mixing a tubulin inhibitor, a PLK1 inhibitor and an amphiphilic block polymer to prepare polymer micelles carrying the drug together, and then loading the polymer micelles carrying the drug together or the polymer micelles carrying the drug together with other drugs into a fibrin hydrogel to prepare the gel drug system.
  9. 9. The method according to claim 7 or 8, wherein the mass ratio of the tubulin inhibitor to the PLK1 inhibitor is (0.1 to 5) to 1.
  10. 10. Use of a drug co-loaded polymer micelle according to claim 1, a combination according to claim 4 or a gel drug system according to claim 5 for the preparation of a therapeutic drug.

Description

Drug-loaded polymer micelle, gel drug system, preparation method and application Technical Field The invention belongs to the technical field of polymer nano-drugs, and particularly relates to a polymer micelle and gel drug system for drug co-loading, and a preparation method and application thereof. Background Surgical resection is a cornerstone for the treatment of solid tumors in clinical practice. However, even after maximal safe tumor resection and guideline-based adjuvant chemotherapy, targeted therapy, or radiotherapy, most patients eventually die from recurrence. This may be due to poor tumor selectivity, poor drug delivery, and serious side effects of the adjuvant treatment regimen, preventing complete clearance of residual tumor cells. In addition, surgical stress often causes the proliferation of anti-inflammatory cytokines such as transforming growth factor-beta (TGF-beta) and expansion of inhibitory immune cells, resulting in an immunosuppressive Tumor Microenvironment (TME), further increasing the difficulty of tumor clearance. Chemotherapeutic drugs capable of inducing Immunogenic Cell Death (ICD) can stimulate anti-tumor immunity while directly killing tumor cells, and are attracting great attention in tumor treatment. However, traditional ICD inducers such as anthracyclines and taxanes lack tumor selectivity and may have deleterious effects on the immune system. Recently, immunogenic nanomedicines carrying ICD inducers have been designed to improve delivery accuracy, mitigate toxic effects, and enhance ICD to improve therapeutic effects. However, ICD induced by existing nanomedicines alone is often deficient in postoperative treatment due to development of drug tolerance and tumor immunosuppression. TGF-beta acts as a key immunosuppressive molecule in TME, and can negatively regulate anti-tumor immunity, and is also associated with postoperative tumor recurrence and resistance to chemotherapy or immunotherapy. Thus, targeting TGF- β signaling pathways is an attractive strategy to alleviate immunosuppression and enhance anti-tumor efficacy. For example, TGF- β receptor kinase inhibitors such as galectin (Gal) show better anti-tumor activity against solid tumors when used in combination with chemotherapy or immune checkpoint blockade in multiple clinical trials. However, their non-specific distribution in normal tissues and insufficient enrichment at the tumor site trigger off-target toxicity and impair therapeutic efficacy. Therefore, a new drug system needs to be developed, so that not only is the efficient co-loading of different drugs realized, but also the enrichment of the drugs at tumor sites can be improved, the off-target toxicity is avoided, and the treatment effect can be improved through the co-delivery and the synergistic induction of tumor cell apoptosis and ICD generation. Disclosure of Invention The invention aims to provide a drug-loaded polymer micelle which is mainly prepared from amphiphilic block polymers and two anti-tumor drugs, and further delivered through fibrin hydrogel, so that the anti-tumor postoperative recurrence effect is synergistically improved. The invention adopts the following technical scheme. The polymer micelle for co-carrying the medicine comprises a polymer micelle, and a tubulin inhibitor and a PLK1 inhibitor loaded by the polymer micelle, wherein the preparation raw material of the polymer micelle comprises an amphiphilic block polymer, and the structure of the amphiphilic block polymer is a hydrophilic segment-a hydrophobic segment. A combination comprising a drug co-loaded polymeric micelle as described above together with other drugs. A gel drug system comprising a fibrin hydrogel and a combination as described above. In the invention, the microtubule inhibitor comprises one or more of paclitaxel, docetaxel, cabazitaxel, auristatin and maytansinol, and the PLK1 inhibitor comprises one or more of volasertib, regoratin, ON01910, BI2536, HMN-214 and GSK 461364. Other agents of the present invention include TGF-beta inhibitors such as DISITERTIDE (P44), galunisertib, A-83-011, and the like. In the invention, the hydrophilic segment is a polyethylene glycol chain segment, the hydrophobic segment comprises a random copolymer P (A-DTC), A is an ester monomer or a carbonate monomer unit, and DTC is a disulfide five-membered ring carbonate unit. Furthermore, the hydrophobic segment also comprises mefenamic acid, and specifically, the hydrophobic segment is a random copolymer P (A-DTC) -mefenamic acid. In the invention, the ester monomer is one or two of caprolactone and lactide, and the carbonate monomer is trimethylene carbonate. In the amphiphilic block polymer, the molecular weight of a hydrophilic segment is 1000-10000 Da, the molecular weight of a hydrophobic segment is 0.2-5 times of the molecular weight of the hydrophilic segment, and the molecular weight of PDTC is 30-70% of the total molecular weight of the hydrophobic segment. Preferably, in th