Preparation And Characterization Of Anti-tumor Drug Carriers Bonded To Multidrug Resistance Reversal Agents

In terms of current medical technology development,there are many problems in chemotherapy.After a period of clinical application,the vast majority of anti-tumor drugs will bring many toxic side effects and reflect the defects of short blood circulation time and low bioavailability.Constructing drug carrier and using degradable polyethylene glycol to synthesize polymeric bonded drugs that can self-assemble into micelles can greatly prolong the drug circulation time in vivo and reduce the damage of toxic and side effects on normal cells.But drug carriers also tend to cause damage to normal cells.The biochemical characteristics of a range of tumor cells also determine that the physiological environment of tumor tissue is different from that of normal tissue,which can be used for targeted drug release.However,the multidrug resistance of tumor cells generated in chemotherapy drugs will lead to the reduction of the efficacy of drugs on tumor cells.In view of this problem,the selection and combination of chemotherapy drugs are particularly important.Chemical sensitizers can be rationally used to fight or even reverse the multidrug resistance of tumor cells.In this paper,a p H responsive amphiphilic drug carrier was designed and synthesized to promote the targeted release of drugs in tumor tissues.3-mercaptopropionyl hydrazine was bonded to biodegradable amphiphilic block polymer PEG-b-PLA by mercaptoene photoclick reaction.Levulinic acid,paclitaxel(PTX)and curcumin(CUR)condensation reaction to obtain functionalized small molecule drug PTX-LEV and CUR-LEV,and then through nucleophilic addition-elimination reaction modified small molecule drug PTX-LEV and cur-Lev,PEG-b-P(LA-g-PTX /CUR),a ph-responsive polymer PEG-b-P(LA-g-NH-NH2)bonded to a amphiphilic block polymer PEG-b-P(LA-g-NH-NH2)with hydrazide on its side substrate,was obtained.In addition,another polymer bonded double drug with redox response was synthesized in this paper.Firstly,the amphiphilic block polymer m-PEG-b-PLA was synthesized.Then,a amphiphilic block polymer PEG-b-P(LA-g-OH)with hydroxyl group was obtained by the reaction of mercapto-ene ethanol with nornbornene of synthetic amphiphilic block polymer PEG-b-PLA side group by mercapto-ene photoclick reaction.Then dithio-dipropionate was introduced into resveratrol(RES)and curcumin(CUR),and RES-SS-COOH and CUR-SS-COOH,drug-modified small molecules with carboxyl terminal and redox responsive disulfide bonds,were obtained.Finally,the Dieckmann condensation reaction between functionalized small molecules and amphiphilic block polymers with hydroxyl groups on the side groups was carried out by one-pot method,and the dedox responsive polymer-bonded double drug PEG-b-P(LA-g-RES/CUR)was obtained.The two stimulus-responsive polymer bonded double drugs were self-assembled to form nanomicelles in water.The micelle particle size and critical micelle concentration(CMC)were measured and characterized by potential particle size analyzer(DLS)and fluorescence spectrometer,and the drug loading was also characterized by UV spectrum.At the same time,low p H and high glutathione(GSH)values of tumor tissues were simulated to control the release of micelles in vitro,which was used to test the sustained release effect of polymer bonded drugs.