Design And Application Of Dextran Based Nanocarriers For Cancer Theropy

Cancer has increased to be the most serious thereaten for human health.Chemotherapy plays an important role in cancer therapy. However, commonly usedchemotherapy drugs always suffer from non-specific interaction, short half-life, lowdrug efficiency, severe toxicity and multi-drug resistance. To solve these problems, wedesigned novel biodegradable nanocarriers based on dextran for anticancer drugdelivery, and the effects on reducing toxicity, enhancing drug efficiency, targeteddelivery and multifunctionality were evaluated.(1) Dextran-b-poly (?-caprolactone)(Dex-PCL) diblock copolymers was preparedvia “click” reaction. The obtained Dex-PCL diblock copolymers were furtheremployed to assembly micelles for doxorubicin (DOX) delivery. The DOX-loadedDex-PCL nanoparticles were characterized by transmission electron microscopy(TEM) and dynamic light scattering (DLS). In vitro drug release and cytotoxicity ofthe DOX-loaded Dex-b-PCL micelles were examined. The cellular uptake andintracellular release behaviors of micelles were followed with CLSM and flowcytometry. The micelles provide a promising candidate to overcome the problems ofshort half-life and low drug efficiency for small molecule drugs.(2) To overcome the non-specific interaction and severe toxicity for normal tissue ofsmall molecule drugs, dextran-b-poly (?-caprolactone)(Dex-PCL) diblockcopolymers with folic acid or galactose were designed and prepared. In vitro drugrelease and cytotoxicity of targeted micelles were examined. The cellular uptake andintracellular release behaviors of targeted micelles were observes by CLSM and flowcytometry. All the results exhibited targeted Dex-PCL micelles can effectivelyenhance the cytotoxicity, cellular uptake and intracellular release behaviors forreceptor overexpressed cells.(3) Major challenge in chemotherapy is linked to multidrug resistance (MDR)against anticancer drugs. The stimuli responsive carriers are noted for theirsite-specific targeting release of payloads modulated by the specificmicroenvironments of intracellular space, leading to aggressive anticancer activityand maximal chemotherapeutic efficacy. So they are hopeful to overcoming multidrugresistance. Two pH-sensitive copolymers based on dextran were designed and furtheremployed to assembly micelles for doxorubicin (DOX) delivery. The pH-sensitive micelles were characterized by transmission electron microscopy (TEM) and dynamiclight scattering (DLS). Both the two DOX-loaded pH-sensitive micelles shownincreasing release in acid conditions mimicking the endosomal/lysosomalcompartments. The enhanced intracellular DOX release was observed in cells.DOX-loaded intracelluar pH-sensitive micelles showed higher cellular proliferationinhibition towards cancer cells than pH-insensitive micelles. Therefore, with the goodbiocompatibility and accelerated intracellular drug release, the two type of micellesprovide an efficient platform to build intelligent drug delivery systems.(4) The design and development of “multifunctional” nanoparticles intended toimprove delivery, therapeutic efficacy, and ultimately patient outcome.Multifunctional nanoparticles have been devised with targeting moieties to improvespecificity and tumor accumulation, imaging agents to assess delivery and dosing,endosome escape mechanisms, target-dependent assembly or disassembly to controldrug release, and so on. However, the cost/benefit ratio of these modifications inimproving the delivery of many small-molecule drugs is less certain. Each newfunctionality elevates complexity, cost and regulatory barriers arise. To solve thesebarriers, we design a kind of modular multifunctional nano delivery systems usinghost-guest recognition as the driving force for macromolecular self-assembly.Benzimidazole linked on dextran acts as backbone, while pre-synthesizedmultifunctional polymers with cyclodextrin act as changeable modules. For differenttumor therapeutic applications, different modules are chosen and inserted in the maincase to achive a multifunctional delivery system. These modular delivery systemsprovided a promising multifunctional carrier for cancer therapy.The above result would be expected to provide basic knowledge on theapplication of biodegradable polymers for anticancer drug delivery, and also providesome new strategies for nanocarrier of cancer therapy.