Preparation And Application Of Intelligent Anticancer Nanomicelles Responsive To Tumor Microenvironmen

In recent years,cancer has become the biggest threat to human health,chemotherapy is currently the most commonly used means to treat cancer,but the traditional chemotherapy drugs generally have many shortcomings,such as poor water solubility,poor selectivity,large toxic and side effects.In order to solve these problems and improve the quality of life of patients,nano drug delivery system（DDS）came into being.As a common nano-drug delivery system,nano-polymer micelles can enhance the water-solubility and biocompatibility of traditional chemotherapy drugs,increase the circulation time of drugs in vivo,and realize the responsive release of drugs,reducing the toxic and side effects on the normal body.The purpose of this study was to construct nanopolymer micelles with both extracellular enzyme response and intracellular reduction response,and to characterize their properties in vitro and verify their anti-tumor activity in vivo.The main research contents are as follows:（1）In this paper,the peptide sequence PVGLIG with MMP2/9 response was first prepared by solid-phase synthesis,and the polymer TPGS₃₃₅₀-PVGLIG-SS-DOX was synthesized by multi-step amidation reaction,and it was characterized and verified.Successful synthesis of polymers.The polymer TPGS₃₃₅₀-PVGLIG-SS-DOX was self-assembled to form nanomicelles by thin film hydration method,and the free DOX was physically coated,which increased the drug load and the stability of nanomicelles.The particle size of the prepared nanomicelles is about 147 nm,and the TPGS in the outermost layer of the nanomicelles can effectively prevent the adsorption of BSA.The experiment verified that the average particle size of the adsorbed micelles only increased by 65nm,so it has good performance in blood circulation.The stability of the nanomicelle extends its half-cycle cycle,which is beneficial to the aggregation of nanomicelles at the tumor site.The highly expressed MMP2/9 enzyme in tumor tissue cleaves the PVGLIG polypeptide and removes the TPGS layer,which is beneficial to the internalization of the cell.The high concentration of glutathione（GSH）in the cell breaks the disulfide bond,dissociates the micelle,and releases the drug（56%can be released in 20 hours）,and its efficacy has been verified through cell and animal experiments.In cell experiments,the IC50 value of TPGS₃₃₅₀-PVGLIG-SS-DOX micelles was 2.08μg/m L,showing strong cytotoxicity.The internalization efficiency was analyzed by CLSM and flow cytometry,and its internalization was as high as 80%in 4 hours.In the antitumor activity experiment,by measuring the tumor volume and body weight of mice,TPGS₃₃₅₀-PVGLIG-SS-DOX micelles showed good antitumor effect and extremely low side effects;and the system we designed was verified by H&E section staining The strong toxicity of DOX to the heart is avoided.In conclusion,TPGS₃₃₅₀-PVGLIG-SS-DOX micelles have good antitumor application prospects.