Design And Synthesis Of Anticancer Drug Deliveries Based On Dextran/Polylactide

Cancer is one of the major causes of morbidity and mortality in the word. Inrecent years, the incidence of cancer continues to increase, and it has seriouslyaffected the lives of patients. Nowdays, the main means for treatment of cancer ischemotherapy. However, most of the clinical chemotherapy drugs exist lots of defect，such as severe side effects to normal tissues and low efficacy against multi-drugresistant cancer cells. In order to better improve the effect of chemotherapy,tremendous effort has been centered on the development of various nanocarrierswhich can offer an opportunity to alter the pharmacokinetic profile of drugs, reduceoff-target toxicity, and improve the therapeutic index. In this thesis, biocompatibleamphiphilic nanomicelles based on dextran and polylactide were developed. Thethesis includes following two parts:1. Biodegradable stereocomplex micelles (SCMs) based on amphiphilicdextran-block-polylactide (Dex-b-PLA) were designed and used for efficientintracellular drug deliveries. The Dex-b-PLA copolymers were successfullysynthesized by click reaction. The structures of the resultant copolymers were verifiedby1H NMR and FT-IR spectra. The formation of stable micelles throughself-assembly driven by the stereocomplexation between enantiomericL-andD-PLAblocks were characterized by transmission electron microscope (TEM), dynamic laserscattering (DLS) and fluorescence techniques. It was interesting to observe that theSCMs showed lower critical micelle concentration values (CMCs) because of thestereocomplex interaction between PLLA and PDLA. Differential scanningcalorimetry (DSC) and X-ray diffraction (XRD) analysis provided information on thethermal and crystal properties of the copolymers and SCMs. The improved stability ofSCMs should be attractive for intracellular drug delivery. Thus, a model anticancerdrug doxorubicin (DOX) was loaded into micelles and the in vitro drug release wasalso studied. The release kinetics of DOX showed DOX-loaded SCMs exhibitedslower DOX release. Confocal laser scanning microscope (CLSM) and flowcytometry studies also showed that the DOX-loaded SCMs exhibited a slower drugrelease behavior. Meanwhile, the MTT assay demonstrated that DOX-loaded SCMsshow lower cellular proliferation inhibition against HepG2. In sum, the micellesthrough self-assembly driven by stereocomplex interaction would have great potentialto be used as stable delivery vehicles for pharmaceutical and biomedical applications.2. Stimuli-responsive drug carriers have great potential to deliver drug ondemand and to a specific location. Acid-responsive drug carriers can specificallyrelease their payload in the acidic microenvironments of tumors within a cell. Herein,3-carboxy-5-nitrophenylboronic acid (CNPBA) shell-cross-linked micelles based on amphiphilic dextran-block-polylactide (Dex-b-PLA) were designed and used for theefficient intracellular drug deliveries. Due to the reversible pH-depended binding withdiols to form boronate esters, CNPBA modified Dex-b-PLA showed excellentpH-sensitivity. At neutral aqueous, CNPBA-Dex-b-PLA could form theshell-cross-linked micelles to realize the loading of DOX, while boronate esters wouldhydrolysis at acid condition and the micelles de-crosslink resulting in the release ofthe payload. In vitro release studies indicated that the release of DOX cargoes wasminimized at physiological conditions, while there was a burst release in response tolow pH value. The cell viability of CNPBA-Dex-b-PLA investigated by MTT assaywas more than90%, indicating that as drug delivery CNPBA-Dex-b-PLA had goodcytocompatibility. These features suggest that the pH-responsive biodegradableCNPBA-Dex-b-PLA can efficiently load and deliver DOX into tumor cells andenhance the inhibition of cellular proliferation in vitro, providing a favorable platformas drug delivery system for cancer therapy.