A Study On Long-circulating Polymers As Nucleic Acid And Drug Delivery System For Cancer Therapy

Polymers for gene and drug co-delivery are the novel delivery system for cancer therapy.However,it remains the biggest obstacle for development of traditional co-delivery vector to be the real clinic therapeutic application,due to poor stability in blood and low celluar uptake efficiency.In this study,we developed two kinds of long-circulating cationic carriers,which showed excellent protein resistance ability and enhanced cell uptake efficiency.This thesis consists of two parts as briefly introduced below:In the first part,chitosan-agmatine bioconjugates,termed as CS-DM-Agm,were prepared by dimethylmaleic anhydride modification and the nucleophilic reaction between tosyl of tosylated chitosan and primary amine of agmatine.In neutral pH environment,CS-DM-Agm/siRNA complexes with negative surfaces could avoid the adsorption of negatively charged proteins in blood.When pH decreased to 6.5,the charge reversal behavior would facilitate the cellular uptake,resulting in much higher gene expression efficiency or gene silencing efficiency than in the normal culture environment.Furthermore,CS-DM-Agm/VEGF siRNA complexes were applied to investigate the tumor remission effect on HeLa tumor-bearing BALB/c nude mice.In vivo application demonstrated that these charge conversional VEGF siRNA complexes could inhibit tumor growth significantly.Moreover,this siRNA delivery system could significantly prolong the survival time of mice without causing noticeable organ toxicity.Therefore,CS-DM-Agm would be a promising candidate for effective and safe siRNA delivery in cancer therapy.In the second part,we also provided a facile way to synthesize a kind of amphiphilic star-shaped block polymers via atomic transfer radical copolymerization(ATRP)from a POSS-based initiator,termed as POSS@PDMAEMA-b-PMPDSAH.These star-shaped polymers could condense DNA into stable complexes.Conjugating the zwitterionic PMPDSAH blocks onto the cationic polymer could partially shield positive charges,lessening the damage of vectors to the cell membrane,so the gene complexes exhibited better blood compatibility as well as low cytotoxicity.The introduction of antifouling zwitterionic PMPDSAH segments not only could improve the serum stability of the complexes,but also facilitate the cellular uptake,together resulting in high transfection efficiency both at high serum concentrations in vitro and in vivo.These star-shaped copolymers with low critical micelle concentration could self-assemble into core-shell-corona micelles for co-encapsulating tumor suppressing gene p53 and doxorubicin(DOX).Furthermore,based on the in vivo antitumor evaluation,this p53 gene and DOX-encapsulating system not only enhanced the antitumor efficacy but also reduced blood and organ toxicity.The effective and safe combination delivery strategy offers a promising method for cancer therapy and can be used for potential clinical applications.