The Preparation Of Degradable Antitumor Polymer Prodrug With Multi-drug Effect

In view of the high heterogeneity and complexity of tumors,the efficacy of monotherapy is not satisfactory during clinical treatment.In recent years,Immunotherapy,Vascular occlusion therapy and Chemotherapy have attracted the attention of many researchers.These monotherapy have their own unique advantages and also have fatal defects.The emergence of multimodal combination drug which combines the advantages of monotherapy and enhances drug efficacy by multi-drug synergy breaks the boundaries between the various therapies.The combination of immunotherapy and vascular occlusion therapy,chemotherapy and vascular occlusion therapy can solve the problems of multi-drug resistance,cancer recurrence and drug infiltration in clinical aspects from different angles and could improve the efficacy of drugs.However,these types of drugs all have problems such as poor water solubility,and short circulation time in the body.It is a good strategy to use nano drug carriers for drug delivery.The physical packaging is easy to drug burst release and the polymer-drug conjugates has the ability to avoid drug burst release in drug-loading method of nano drug carriers,so we use the dual drug conjugated system to form a polymer bonding system that combines multiple drug.In this study,the polylactide block polymer containing the side polyethylene glycol hydrophilic chain was firstly used to obtain the amphiphilic block polymer and the side azide group was contained by thiol-ene and DIC condensation.Then combretastatinsA4 as the blood vessels and imiquimod as the immunomodulator was dibenzocyclooctyne functionalized to obtain DBCO-CA4 and DBCO-R837.Finally the amphiphilic block polymer with side azide group conjugate with the drug which have been dibenzocyclooctyne functionalized to get therapeutic synergistic polymer bonding drug P(LA-g-mOEG)-b-P(LA-g-CA4/R837)by SPAAC.In addition,a stimuli-responsive polymer bond based on the synergistic effect of vascular blockers and chemotherapy was prepared by the differences of physiological pH and glutathione concentration between tumor tissue and normal tissue cells.Firstly,the biodegradable amphiphilic block polymer mPEG-b-PLA was synthesized,and then the side group hydroxyl group was functionalized by the mercapto-ene reaction.And doxorubicin was modified to the carboxyl group doxorubicin with Schiff base(DOX-N=C-R-COOH),combretastatinsA4 was modified to the carboxyl group combretastatinsA4 with a disulfide-bonded(CA4-S-S-R-COOH).Finally the hydroxyl group of block polymer conjugate with double drug which have been carboxylated to obtained a polymer bonding drug mPEG-b-P(LA-g-DOX/CA4)by DIC condensation reaction.The two polymer-drug conjugates we have synthesized could self-assemble to form nanomicelles in water,and we used DLS,fluorescence spectroscopy to obtain particle size,zeta potential characterization and CMC determination.Two kinds of polymer-drug conjugates was also tested by drug release experiments in vitro to evaluate the drug release ability.The results showed that two polymer-drug conjugates have a good nano-particle size distribution,could maintain the stability of the polymer bonding and have excellent drug release properties in simulated tumor microenvironment.