Synthesis And Application Of Stimulus-responsive Nanodrug Capsules In Tumor Combination Therapy

Cancer is one of the world's top five terminal illnesses.People are eager to find effective treatments to eliminate malignant tumors.Currently,chemotherapy is still the main means of clinical cancer treatment.In view of the low bioavailability of traditional chemotherapy drugs,the toxic side effects are large,new targeted chemotherapeutic drugs are exploding.Targeted nanodrug delivery systems have been used as therapeutic tools,and targeted nanodrug capsules loaded with anti-tumor drugs can passively target tumor tissues by means of high permeability and retention of tumor tissues(EPR effect).The nanodrug capsules can enrich in tumor tissues,and then be taken up by the tumor cells and release intracellularly.Moreover,by modifying the targeting molecule to the nanodrug capsule,it can also have active targeting to the tumor.Therefore,due to the extremely excellent antitumor activity of nanodrug capsules,it is increasingly favored in cancer treatment.To realize intelligent drug release in tumor microenvironment,functional polymers loaded with anti-tumor drugs were designed to construct stimuli-responsive nanodrug capsules.Under the action of internal and external source stimulation factors(light,redox and enzymes,etc.),nanodrug capsules achieve precise assembly and disassembly by destroying the polymer structure to achieve the effect of precise drug controlled release.Further,anti-tumor drugs can be combined with other therapeutic drugs with different action mechanisms and can be loaded into the nanodrug capsules to establish a combined drug preparation to improve the therapeutic effect of the cancer.In this thesis,two kinds of environmental stimuli-responsive nanodrug capsules were designed and synthesized,and it is applied in the targeted combination therapy of oral squamous cell carcinoma and triple-negative breast cancer.The specific research contents are as follows:(1)Liquid anti-solvent precipitation method combined with Polyethylene glycol grafted polysulfide copolymer(PEG-PPS-cRGD)design,a targeted nanodrug capsule loaded with a combined anti-tumor drug was prepared,and the chemotherapeutic drug doxorubicin(DOX)and photosensitizer indocyanine green(ICG)were loaded into the nanodrug capsules(DINCs).The endogenous or exogenous stimuli including redox substrates and near-infrared lasers was used to drug controlled release effect of nanodrug capsules in the tumor microenvironment.Further,the targeting and anti-tumor effects of nanodrug capsules for oral squamous cell carcinoma were evaluated comprehensively and systematicly by in vitro cell and in vivo animal experiments.(2)Liquid anti-solvent precipitation method combined with functional pentaerythritol tetrakis(mercaptoacetate)grafted polysulfide copolymer design(PTM-g-PPS-PDT),a targeted nanodrug capsule loaded with a combined anti-tumor drug was prepared,and the chemotherapeutic drug DOX and anti-vascular drug Sunitinib were loaded into the nanodrug capsules(DSNCs).The endogenous stimuli including enzyme and redox substrates was used to drug controlled release effect of nanodrug capsules in the tumor microenvironment.Further,the targeting and anti-tumor effect of nanodrug capsules for triple-negative breast cancer were evaluated systematically by in vitro cell and in vivo animal experiments.