The Preparation Of Reduction And PH-responsive Polypeptide Nanogels As Antitumor Drug Carriers

Chemotherapy is one of the most commonly used and efficient means of cancertherapy. Despite remarkable progress in chemotherapy, some serious impediments arestill unresolved, such as severe side effects to normal tissues and low efficacy againstmulti-drug resistant cancer cells. In order to solve the above problems, the antitumordrugs have been combined with various nanocarriers to achieve an enhancedchemotherapy efficacy. In this thesis, we mainly focused on the design of reductionand pH dual-responsive nanogels for antitumor drug delivery.(1) The reduction and pH dual-responsive nanogels were prepared throughring-openingpolymerization (ROP)ofε-benzyloxycarbonyl-L-lysine-N-carboxyanhydride andL-cystine-N-carboxyanhydride with amino group terminated methoxy poly(ethyleneglycol)(mPEG-NH2) as macroinitiator, and the subsequent elimination of protectivegroups. Doxorubicin (DOX), as a model anticancer drug, was loaded into thenanogels. DOX-loaded nanogels exhibit faster release behavior in reductive andacidic solution. The DOX-loaded nanogels realized the enhanced intracellular DOXrelease and antitumor efficacies.(2) Three derivatives of DOX were prepared by modifying DOX with succinicanhydride, cis-aconitic anhydride and2,3-dimethylmaleic anhydride to respectivelygenerate acid-insensitive succinyl-DOX, and acid-sensitive cis-aconityl-DOX (CAD)and2,3-dimethylmaleyl-DOX (DAD). The DOX derivatives were loaded intonanogels through electrostatic interaction. The rapid drug release from nanogel can betriggered by external reduction and low pH. The cell experiments revealed that theacid-sensitive drug loaded nanogels exhibited improved antitumor efficacy.(3) The reduction and pH-responsive nanogels were prepared through throughone-step ROP of L-phenylalanine-N-carboxyanhydride andL-cystine-N-carboxyanhydride with a pH-responsive amino-terminated PEG asmacroinitiator. The preliminary experiments revealed that the amino-terminatedketalized PEG are pH-responsive. The in vitro Nile Red release profiles alsoconfirmed the responsiveness of nanogel.