Preparation And Function Study Of Reduction And Hypoxia Responsive Nanomedicine

Chemotherapy is one of the most widely studied and most commonly used anti-tumor treatments.However,treatment with drug resistance and cancer cell metastasis induced proliferative bursts has become a major obstacle during chemotherapy.In addition to certain endogenous cell or genetic mechanisms and some microenvironment selection pressures,the intercellular connection and paracrine communication in the tumor microenvironment(TME)are also considered to be essential for drug resistance and proliferation bursts.Even though specific pathway inhibitors or specific cell silencing strategies can be used to avoid such connections,the complexity of TME and the limited knowledge of those harmful connections may greatly affect such pathway inhibition therapy.The responsive nano-drugs designed for TME provide an effective strategy for improving the delivery of chemotherapeutic drugs,achieving controlled release of drugs,and alleviating proliferation bursts induced by traditional chemotherapy.The first part of this study is based on the reduction and synthesis of HPMA,and the synthesis of reduction and hypoxia responsive polymer carrier.Using D-Aspartic acid as the core,the comb polymer PNIMA-g-PHPMA was synthesized by Atom Transfer Radical Polymerization(ATRP)technology and Click chemistry reaction,with disulfide bonds and nitroimidazole functional groups in the hydrophobic segment.The polymer carrier and the loaded drug form micelle nanoparticles through self-assembly.Dynamic light scattering measurements show that the micellar nanoparticles have the proper particle size required for passive targeting of the tumor,and also have good stability in the simulated blood circulation environment.Due to the presence of disulfide bonds in the polymer and the nitroimidazole functional group with hypoxic responsiveness,chain scission and hydrophobic transition can occur under high glutathione(GHS)levels and deep tumor hypoxic environment.Then the nanoparticles lose the hydrophobic structure and disintegrate to release the drug.The toxicity of nanoparticles and the endocytosis ability of MCF-7/PTX to micelles were studied through cell experiments.The results showed that the use of reduction and hypoxia responsive polymer carrier increased the cellular uptake of drugs and exhibited higher suppression of drug-resistant cell in hypoxic environment.The second part of this study is based on the research of reduction-responsive polymer carrier PEG-b-PMASSVE.It can form micelle nanoparticles carrying prodrugs of camptothecin derivatives.For overcoming drug resistance and selectively acting on malignantly proliferating cancer cells,in response to the high esterase levels and GSH levels of malignantly proliferating cancer cells,the reduction-responsive disulfide bonds were introduced into the polymer carrier,while ester bonds as the relatively stable bonds were introduced into the prodrug.Studies on cells and animals have shown that the prodrug nanoparticle system can selectively inhibit malignantly proliferating drug-resistant cancer cells,and has gentle inhibition effect on normal cells.The prodrug nanoparticles can be used in combination therapy with non-selective chemotherapy and show significant anti-cancer efficacy.The combination therapy can inhibit the proliferation of paracrine communication between cancer cells themselves or between cancer cells and fibroblasts induced by non-selective chemotherapy,and avoid therapy induced proliferative burst.