Reduction And PH Dual-sensitive Core Cross-linked Doxorubicin Nanomicelle Drugs

Recently,polymeric nanomicelles have attracted great attention in oncotherapy,and have been applied in drug delivery system for improving drug stability and solubility,decreasing system side effects,controlling drug release and achieving passive targeting ability.The research content of this dissertation is mainly divided into three parts.Part I:Poly?beta-amino esters??PBAE?with disulfides and modifiable amino groups was synthesized by the Michael addition polymerization,and was grafted with PEG-2000and 3,4-dihydroxyphenylacetic acid to generate reduction degradable graft copolymers,termed as methoxypoly?ethylene glycol?-g-poly?N,N'-cystamine bisacrylamide-N-Boc-1,2-diaminoethane?-g-3,4-dihydroxyphenylaceticacid?mPEG-g-SS-PCD-DA?.The chemical structure of mPEG-g-SS-PCD-DA was characterized by nuclear magnetic resonance hydrogen spectrum in detail.Part II:Self-assemble nanomicelles of graft copolymer mPEG-g-SS-PCD-DA were obtained by dialysis method.After addition of Fe³⁺to the polymer solution,the core cross-linked micelles?CCLMs/SS?were obtained due to the formation of polycoordinate complex between Fe³⁺and catechol.The reduction sensitivity and pH responsivity of mPEG-g-SS-PCD-DA micelles were studied further,respectively.Part III:DOX-loaded core cross-linked micelles?DOX-CCLMs/SS?were prepared through the dialysis method.The DOX release profiles and cytotoxicity against A549cells of DOX-CCLMs/SS were studied in vitro.Besides,the cellular uptake of DOX-CCLMs/SS against A549 cells was studied in vitro.It was found that the copolymer micelles showed good reduction sensitivity and pH responsivity.In simulated blood conditions,DOX-CCLMs/SS could keep stable and protect the loaded drugs from drug leakage before reaching targeting sites.The charge conversion happened with Zeta potentials changing from-1.75 mV to+3.09mV,when the condition changing from pH 7.4 to pH 6.5 due to the protonation of tertiary amines in PBAE,which improved the cellular uptake of DOX-CCLMs/SS.After DOX-CCLMs/SS entered into endosomes/lysosomes of tumor cells,high concentration of glutathione?GSH?led to the breakage of disulfide bonds and the coordination of catechol-Fe³⁺complex change from polycoordinate-compex to monocoordinate-complex under low pH values,which made micelles disassemble to release the loaded drugs.