Studies On The Preparation And Drug Controllled Release Of Redox/pH-responsive Zwitterionic Nanoparticles

Stimuli-responsive nanoparticles have potential applications in cancer therapy. More and more attention has been paid to release drugs triggered by tumor intracellular pH and redox stimuli. The zwitterionic polymers have received considerable attention for good hydrophilic performance, high non-fouling ability and excellent "stealth" effect in synthesis nanoparticles. In order to promote accumulation of drug-loading nanoparticles in tumor cells, rapid uptake and targeted drug release, and eliminate the residual of polymer carrier, the research work on the synthesis of a series of biodegradable zwitterionic polymer nanoparticles. The product contain abundant of charged ions, such as amino and carboxyl, sulfonic group etc. The use of reversible protonation/deprotonation systems provides an alternate strategy that features high tenability. The surface charges of nanoparticles are adjusted through ratio of synthetic materials. The surface ions of nanoparticles are protoned or deprotoned in different pH conditions, which ensure nanoparticles are stable in the blood vessels and realize rapidly reversal of surface charge once in tumor extracellular, and to be uptaken by tumor cells. The polymer backbone or crosslinking structure of nanoparticles contains disulfide bonds. The disulfide bonds can be reductively degraded in presence of high concentration of GSH in tumor cell(2 ~ 10 mM), which promote the rapidly and effiectively released drug into the nucleus to realize specific drug delivery in sites within cells.This work chose natural polymers such as poly glutamic acid and dextran as raw material and chose cystamine as reducing components. The zwitterionic nanoparticles were prepared through modification and crosslinking reaction, which endowed p H and reduction responsiveness and biodegradable properties. In order to realize controllable molecular weight and completely degradation in reducible environment of polymer and increasing drug released rate of carrier, and avoid polymer residues, this work also took taurine, lysine, dodecylamine and N, N-Bis(acryloyl) cystamine as small molecules raw materials. Several categories biodegradable nanoparticles with pH/reduction-responsive were synthesized by Michael addition reaction.This thesis explored and optimized the synthesis conditions, characterized and researched nanoparticles structure and properties. Doxorubicin as model drug was used in controlled release and intracellular drug release studies. The cytotoxicity of nanoparticles experiment were carried on to evaluate nanocarrier safety. The results showed that the research work achieved the desired nanoparticles with size at 60 nm to 212 nm(differences in different system).The nanoparticles in protein solution had excellent resistance to non-specific adsorption performance. Above 90% of DOX were released in 10 mM GSH and pH 5.0 PBS solution. The nanoparticles could be biodegraded completely. The cell toxicity studies showed that blank nanoparticles were non-cytotoxic. Drug-loading nanoparticles could effectively be internalized by cell and inhibit cell proliferation by laser confocal microscope(CLSM) observation of doxorubicin in human cervical cancer cells(Hela) distribution, which have broad application prospects for cancer treatment.