Study On Synthesis And Properties Of PH,Oxidation And Reduction Triple Responsive Block Copolymers And Reduction,Enzyme Dual Responsive Linear Dendritic Block Copolymers

The differences in p H,glutathione（GSH）concentration,and enzyme expression between tumor cells and normal cells can be used to design stimulation-responsive targeted drug delivery systems in order to achieve controlled release and targeted release of drugs.Because diselenide bonds（Se-Se）or disulfide bonds（S-S）are relatively active and sensitive to external oxidation and reduction environments,many amphiphilic block copolymers based on diselenide bonds or disulfide bonds on the main chain have been reported,but most of these block copolymers are symmetrical.However,there are few reports of asymmetric p H and redox responsive block copolymers with a diselenide bond on the main chain,and linear dendritic block copolymers（LDBCs）containing disulfide bonds with enzyme and redox dual responsiveness have not been reported in the literature.In this thesis,we introduced p H responsive segments into block copolymers containing a diselenide bond,and enzyme responsive segments into LDBCs containing a disulfide bond to synthesize asymmetric p H and redox responsive block copolymers with a diselenide bond on the main chain and enzyme and redox responsive LDBCs with a disulfide bond linking a hydrophilic linear chain and a hydrophobic dendron.The properties of these copolymers have been investigated.Two amphiphilic block copolymers PNVP₄₃-Se Se-b-PIMPHMAM_m（m=11,21）with a diselenide bond linking hydrophilic poly（N-vinylpyrrolidone）（PNVP）block andahydrophobicpoly（isopropylidene-2,2-Bis（methoxy）propionic hydroxyethylmethacrylate）（PIMPHMA）were synthesized by reversible addition-fragmentation chain transfer（RAFT）radical polymerization and atom transfer radical polymerization（ATRP）.Their structure and molecular weight were characterized by ¹H NMR spectra and gel permeation chromatography（GPC）.Then the self-assembly behavior in aqueous solution,p H/redox responsiveness,drug controlled release behavior,in vitro cytotoxicity and blood compatibility of these block copolymerswere studied.The results showed that PNVP₄₃-Se Se-b-PIMPHMAM_m（m=11,21）self-assembled into spherical micelles or nanovesicles in aqueous solution,and their critical aggregation concentration（CAC）and particle size decreased with the increase of the hydrophobic segment of the copolymers.In vitro drug release experiments showed that the loaded doxorubicin（DOX）could be released from the aggregates of copolymers in acidic environment（p H=5.0）or upon the addition of GSH or H₂O₂.The combination of GSH and p H dual stimuli results in significantly accelerated and more complete release of the loaded DOX.The longer the hydrophobic segment of the block copolymer was,the slower the release rate of the loaded DOX was.Blood compatibility evaluation and cytotoxicity test showed that PNVP₄₃-Se Se-b-PIMPHMAM_m（m=11,21）had good blood compatibility and biocompatibility.The first-and second-generation reduction and enzyme responsive amphiphilic linear-dendritic block copolymers PHEG-SS-b-G_n（n=1,2）with a disulfide bond linking hydrophilic linear poly[N-（2-hydroxyethyl-L-glutamine）]（PHEG）and hydrophobic dendritic aromatic polyamide have been synthesized.Their structure and molecular weight were characterized and analyzed by ¹H NMR spectra and GPC.The self-assembly behavior in aqueous solution,enzyme/reduction responsive properties and in vitro cytotoxicity of PHEG-SS-b-G_n（n=1,2）were studied.The results showed that the CAC values of the copolymers decreased with the increase of their generation.The two generations of copolymers can self-assemble into spherical micelles in aqueous solution and have good redox and enzyme responsiveness.The result of in vitro cytotoxicity test showed that the copolymer had good biocompatibility.