Design Of Stimuli-responsive Nanodrug Carriers And Its Tumor Combination Therapy Research

Cancer has become the second leading cause of human death in the world.However,most conventional chemotherapy still have serious side effects.In recent decades,the development and application of engineered nanotherapeutics have made significant progress in cancer treatment.With the deep understanding of the tumor microenvironment and materials science,the stimuli-responsive nano-drug carriers capable of releasing the payload on demand according to various internal and external stimuli has become a new engineering strategy for the new generation of nano-drug transportation system.Based on the superiority of the intelligent nano drug system,this paper focuses on improving the design of functionalized nanocarriers,improving the therapeutic effect of tumors and reducing the side effects,our selects biomacromolecule bovine serum albumin,erythrocyte membrane and natural glucose oxidase(GOx)with good biocompatibility as nanocarriers,designed three nano-drug delivery systems with p H and GSH dual response,light triggered release,and enzyme catalyzed response for site-specific and sequential release of drugs at the tumor site,enabling tumor targeting,real-time tracking,and multifunctional therapy.The main research work of this thesis as follows.(1)First,the development of the stimuli-responsive nanodrug delivery system in tumor therapy was summarized.In Chapter 2,in order to improve the efficient delivery of nanomedicine,we prepared a "dynamic-covalent targeting" nanosystem for responsive drug release at the target.After the nanosystems achieve internalization under receptor-mediated endocytosis,the nanocluster can be dissociated into cationic albumin under intracellular reduction and acid environment,achieving stimuliresponsively triggered drug release.As a result,the nanocluster for DOX and VEGFsi RNA codelivery exhibits high efficient gene silence capacity and apoptosis-inducing ability,and also markedly suppresses the migration and invasion of cancer cells,it showed significant combination effects against tumor growth.Although the albumin intelligent nanosystems have achieved good therapeutic results in tumor therapy,drugloaded nanoparticles will inevitably leak during transportation.(2)In order to solve this problem,in chapter 3,we introduced the erythrocyte membrane to camouflage the carrier,reserving the intact cell membrane structure and membrane protein,can gain excellent cell-specific functions such as long blood circulation and immune escape,providing a promising therapy nanoplatform for drug delivery.A novel RBC membrane biomimetic combination therapeutic system with tumor targeting ability was constructed by embedding bovine serum albumin(BSA)encapsulated with 1,2-diaminocyclohexane-platinum(II)(DACHPt)and indocyanine green(ICG)in the targeting peptide modified erythrocyte membrane(R-RBC@BPt I)for prolonging blood circulation time of drug,enhancing tumor internalization and synergetic chemo-phototherapy.R-RBC@BPt I with tumor-specific targeting ability accomplished complete ablation of tumor and suppress of lung metastasis in vivo by photothermal and chemotherapy combined damage under photo-triggering.Although in chapter 3 of the study,we have achieved better tumor treatment effects,but chemotherapy drugs and photothermal therapy will inevitably bring some adverse effects.(3)Therefore,we have further designed a “two-enzyme in one” tumor-targeted biomimetic cascade delivery system,hoping to release nanozymes in situ for chemical kinetic treatment to improve cancer treatment efficiency and reduce side effects.The ultra-small iron nanoparticles were anchored within the interior cavity of glucose oxidase and then embedding them with photosensitizer indocyanine green in the tumor targeting ligand Angiopep-2 functionalized erythrocyte membrane.Our biomimetic nanocatalytic system could preferentially accumulate at the target tumor site via targeted ligand-mediated endocytosis.Based on the high glucose uptake and weakly acidic environment in tumor site,the GOx effectively catalyzes conversion of glucose at the tumor site to H2O2 for inducing Fe NPs to initiate in situ Fenton reaction.The hydroxyl radicals produced after sequential catalysis could kill tumor cells by causing oxidative damage to tumor cells.In Chapter 4,the work in the whole thesis was summarized,and the future work were discussed and prospected.Our work provides a solution for targeted therapy of tumors,construction of stimuli-responsive erythrocyte membrane nanoparticles,and reduction of drug side effects.