Study On Polymeric Micelles Targeting Delivery Of Antitumor Agent

Chemotherapy is the main approach for cancer therapy at present as cancer threatens human health seriously,but it is often interrupted by serious poisonous side effect so that the patients often miss the optimal treatment opportunity. Nanomedicine carriers will be tile outstanding chemotherapy agent for tumor treatment since it owns many advantages:the high targeting property,controlled release,reducing the poisonous side effect,and the improvement of dissolving and absorbing capacity for drugs.9-nitro-20(s)-camptothecin(9-NC),an effective topoisomeraseâ… inhibitor,has achieved remarkable success in clinical trials and been given approval by FDA for pancreatic cancer treatment.In order to improve lactone stability and hydrophilic performance of 9-NC and avoid poisonous side effects such as nausea,diarrhea and marrow suppression,this research work will focus on 9-NC encapsulation by copolymer micelles and realize the drugs targeting and controlled release delivery.The primary coverage of this dissertation is as following:1^st,methoxy poly(ethylene glycol)-b-poly(D,L-lactide)(mPEG-b-PLA, PELA)with varied PLA block and constant mPEG block were synthesized by ring-opening polymerization of D,L-lactide(LA),initiating by mPEG and catalyzing with stannous octoate.Copolymer characterization was carded out with 1^H-NMR,GPC,FT-IR,DSC,and statistic contact angle apparatus.2^nd,trimethylene carbonate(TMC)was synthesized from 1,3-propanediol and diethyl carbonate.Copolymer mPEG-b-poly(LA-co-TMC)(PETLA)was synthesized by copolymerization of TMC,LA and mPEG with catalyst stannous octoate under the following conditions:160℃,[Monomer]/[Catalyst]=2000, t=12 h.Copolymers with different hydrophobic length and different hydrophobic components ratios(PTMC/PLA)were prepared and characterized by ¹H-NMR, GPC,FT-IR,DSC and static contact angle.3^rd,six member cyclic carbonate monomer 9-phenyl-2,4,8,10-tetraoxaspiro -[5,5]undecane-3-one(CC)was synthesized.Taking aluminium isopropoxide as catalyst,copolymers PECLA with different hydrophobic length and hydrophobic component ratios(PCC/PLA)were prepared by copolymerization of tri-components:D,L-lactide,mPEG and CC.Novel block copolymer FA-PECLA was obtained by deprotection of PECLA and conjugating with folic acid. Ultraviolet spectra detection illustrated that 1.52 folic acid molecule were coupled with each molecule of FA-PECLA8 averagely.4^th,micelles M,MT and FA-MC(corresponds separately to copolymer PELA,PETLA and FA-PECLA)were prepared by solvent evaporation method and 9-NC was used as model drug.Taking micelle M3 for studying,micellar preparation processes were optimized by evaluating the effect of bath temperature, tri-distilled water amount,the stirring speed,drug input weight,and copolymer composition on the drug loading content and the diameter of micelles.5^th,Characterization on the micellar properties in aspects of size, morphology,critical micelle concentration,structure and composition,drug distribution condition,micellar stability,lactone stability,drug release profile in vitro and tissue distribution in rats were carried out with DLS,TEM,fluorescence spectrophotometer,¹H-NMR,GPC,XPS,WAXD,UV,and HPLC apparatus.In this dissertation,three kinds of micellar delivery systems constructed from three kinds of well biodegradable polymer PELA,PETLA and PECLA were established.Comprehensive characterizations including the micellar properties, drug stability,drug release behaviors in vitro and distribution in vivo were carried out.Innovative achievements could be concluded in the following aspects:(1) Three kinds of 9-NC encapsulated drug delivery systems were constructed on the base of the varied amphiphilic biodegradable copolymers,and the drug release rates from the micelles were nearly in zero order.(2)The lactone stability of 9-NC was improved greatly after the encapsulation by micelles and the labile bioactivity of 9-NC in use could be conquered.(3)Novel controlled release system based on folic acid targeted micelles was established and this provided novel opportunity for active targeted delivery of anti-cancer drugs. The significance of this research work lies in:systemic performance studies of 9-NC loaded controlled release systems were performed by the construction of 9-NC loaded micelles based on well compatible and biodegradable copolymer polyester-poly(ethylene glycol)and 9-NC,this work offered the foundational data for further study or further clinical research.On the other hand,micellar carriers could decrease the poisonous side effect to the patient and provided a more safe and effective chemotherapy approach for cancer treatment.