Design And Synthesis Of Polysaccharide-based Reduction-responsive Carriers For Anti-cancer Drug

Nowadays, cancer is one of the major causes of morbidity and mortality in theworld, and the incidence of cancer continues to increase. Conventional chemotherapyhas proven partially successful in the treatment and prolonging the lives of patients.The limited clinical success is mostly due to the lack of tumor-selectivity ofanticancer drugs which resulted in the severe side effects to normal tissues and lowefficacy against multi-drug resistant cancer cells. Aiming to improve chemotherapy,tremendous effort has been centered on the development of various nanocarries thatare capable of the targeting controlled delivery of anticancer drugs. In this thesis，biocompatible amphiphilic nanomicelles based on natural polysaccharide weredeveloped, and then cross-linking nanomicelles were obtained by subsequentlyconjugated with disulfide bond group. The stability of these nanomicelles wasmarkedly enhanced through cross-linking. Because the cross linker can be reversedunder the reductive environments encountered in cancer cells or mildly acidic, whichhave redox-responsiveness and can efficiently release the loaded-drug. This thesisincludes following two parts:1. Reduction-responsive disulfide core-crosslinked micelles based on amphiphilicstarch-graft-poly(ethylene glycol)(starch-g-PEG) which can self-assemble intomicelles in water were prepared and used for efficient intracellular drug delivery. Bysubsequently conjugated with lipoic acid for disulfide crosslinking the crosslinkednanomicelles were more stable. In vitro release studies showed reduction responsiverelease of doxorubicin. The in vitro drug release profiles revealed that only35%ofthe loaded DOX was released at59.5h without GSH, while up to about90%of theloaded DOX can be quickly released in the presence of10.0mM GSH. Cellexperiment also proved that, the drug-loaded micelles system would release the drugrapidly in the reductive condition and inhibit the cell proliferation. These novelnanomicelles display unprecedented multi-functionalities, such as biocompatibility,degradability, high drug loading and efficient drug release inside cells, which mayprovide a favourable platform to construct intelligent drug delivery systems for cancertherapy.2. The amphiphilic block copolymers were successfully obtained by “click”coupling of dextran and poly(γ-benzyl-L-glutamate). The shell cross-linked redox-responsive micelles were prepared by cross-linking of dextran with3,3’-dithiodipropionic acid. The fast DOX release from the crosslinked micelles underthe reductive condition was most likely due to decreasing of the core cross-linkingdensity caused by cleavage of disulfide bonds. Cell experiment also proved that, thedrug-loaded micelles system would release the drug rapidly in the reductive conditionand inhibit the cell proliferation. Dextran is widely used as drug nanocarriers materialfor protein purification because of its definite biocompatibility. The block copolymersprepared by “click” chemistry have advantages of rapid reaction and clear structure.The obtained micelles have good biocompatibility, stimuli-responsiveness and clearstructure that have favorable applications as anticancer drug carrier.