Study On Polymeric Materials Containing Pluronic And Polylactic Acid As The Oral Carriers Of Anti-cancer Drugs

Cancer chemotherapy and the patient's life will be more convenient if oral administration of anti-cancer drugs can be achieved.For most anti-cancer drugs,their bioavailability and treatment efficiency will be decreased by oral administration,due to the gastrointestinal barrier.So it is important to find an effective drug carrier for oral administration of anticancer drug.The emergence of nanotechnology,led to the development of nanodrug carrier.Therefore a great breakthrough has been achieved for oral administration of anti-cancer drugs by using nanodrug carrier.The biodegradable block copolymers have shown great advantages as anticancer drug delivery carriers.Besides,the folate-modified nanocarriers can increase the targeting property of anti-cancer drugs,because,folate receptors are overexpressed on the intestinal epithelial cancer cells and cancer cells.At the same time,we prepared mixed nanoparticles by adding TPGS into folate-targeting polymeric nanoparticles in order to reduce multidrug resistance of cancer cells,inhibit the P-gp efflux transport and increase drug uptake in intestinal cells.In this thesis,we synthesized PLA-F127-PLA block copolymer with biodegradability and FA-F127-PLA block copolymer with folate targeting as carriers for then oral delivery of anticancer drug paclitaxel.In addition,we prepared mixed nanoparticles by adding TPGS as optimization agent into FA-F127-PLA micelles,and then study the feasibility of PLA-F127-PLA NPs,FA-F127-PLA NPs,and FA-F127-PLA/TPGS NPs as the oral delivery carrier for paclitaxel.The structure of PLA-F127-PLA and FA-F127-PLA block copolymers were confirmed by nuclear magnetic resonance spectroscopy(NMR).The diameter of nanoparticles were determined to be 30-100nm by dynamic light scattering instrument(DLS).The particles with this size could facilitate the targeting administration of the nanocarriers through enhanced permeability and retention effect(EPR)of solid tumors.At the same time,the morphology of the nanoparticles were determined to have core-shell vesicular structure so called polymersomes by transmission electron microscopy(TEM).In vitro studies of paclitaxel loaded in paclitaxel-loaded PLA-F127-PLA,FA-F127-PLA and FA-F127-PLA/TPGS polymersomes showed that encapsulating paclitaxel into polymersomes can achieve controlled-release behavior in simulated gastric and intestinal fluids,which benefits to increase the circulation time of drug in vivo and reduce the administration frequency.And the material cytotoxicity studies showed that both materials have good biocompatibility.Targeting studies in folate receptor overexpressed OVCAR-3 cells showed that paclitaxel loaded in folate-targeted nanocarriers exhibited higher cytotoxicity than non-targeted polymersomes.Furthermore,the absorption of the paclitaxel-loaded polymersomes in intestinal epithelial cells was further investigated in Caco-2 by using fluorescence spectrophotometer and fluorescence microscope.The results showed that polymersomes were mainly distributed in cytoplasm and more easily taken up by cells than free coumarin 6.In this research,TPGS was added to the folate targeted polymersomes as an optimization agent.Results showed that the drug encapsulation efficiency of FA-F127-PLA/TPGS mixed polymersomes was 10.04%,which was 1.63%and 4.89%higher than that of targeted and non-targeted polymersomes,respectively.The cellular uptake polymersome was found to incerease by using Caco-2 simulated intestinal epithelial cells.Besides,it increased cytotoxicity of drug-loaded targeted nanoparticles in OVCAR-3 cell.Finally,in vivo pharmacokinetic studies in rats showed that paclitaxel loaded in polymersome carriers had a higher area under concentration-time curve(AUC)and a longer sustainable treatment time than oral Taxol~?.This also indicates that paclitaxel nano-pharmaceuticals are more advantageous for oral administration than Taxol~?...