The Preparation And Tumor Therapy Of Stimuli-Responsive Polymeric Drug Carriers Based Natural Polysaccharide

The clinical applications of traditional anticancer drug molecules are limited by the poor water solubility,poor targeting efficiency,non-selective drug release,poor pharmacokinetic effect,low biosafety and many other issues.As an important member of intelligent drug delivery system,the stimuli-responsive polymers have gained widespread attention in tumor therapy due to their remarkable superiorities,including clear chemical structure,easy functionalization and selective release.In this dissertation,a series of responsive drug delivery system were synthesised by functional modification based natural polysaccharide compounds,and the anti-tumor effect of these drug delivery system were evaluated in different types of tumor cells and tumor models.Both in vitro and in vivo experiments show that such polymers have many impressive advantages including low production cost,adjustable drug loading rate,efficiency of drug delivery,long circulation time,safe and reliable,which provided a new method for the optimize development of anticancer drug delivery systems.The main contents and conclusions of this dissertation are summarized below:1.Atom transfer radical polymerization?ATRP?reaction was used to synthesize a kind of reductive responsive drug delivery system?DEX-PCPT-b-POEGMA,denoted as DCO?based on natural dextran for delivery of hydrophobic anticancer drug camptothecin?CPT?.The poly?ethylene glycol?methyl ether methacrylate?POEGMA?was served as hydrophilic block for enhancing hydrophilicity and prolonging blood circulation time.The CPT monomers containing disulfide bond?S-S?in hydrophobic block could realize the reduction responsive controllable drug release.This amphiphilic polymer could self-assemble into a spherical and uniform unimolecular micelle in water solution.The experiments proved that the DCO prodrug showed notable antitumor activity against human cervical cancer cells?HeLa?and human breast cancer cells?MCF-7?.Compared to non-stimulus-responsive produg containing double carbon bond?C-C?,the S-S conjugated DCO prodrug had an absolutely higher level of tumor cell apoptosis.The reductive responsive polymers in this investigated had obvious advantages in drug loading rate,micellar stability,cost and control release in contrast to traditional anticarcinogen.This study provided a promising approach for design of stimuli-responsive polymeric prodrug and proposed a new idea for mature development of polymeric drug carrier.2.In order to fully extert the advantages of high molecular polymer,we further constructed a series of supramolecular macrocyclic polymer PRs-poly?ethyl glycinate methacrylamide?-co-poly[?ethylene glycol?methyl ether methacrylate]?PR-PDOX-co-POEGMA,denoted as PRMO@DOX?based on cyclodextrin?CD?polyrotaxanes?PRs?to surpass the biological barriers.The anticancer drug doxorubicin?DOX?was then modified on the carrier molecular by hydrazone bond,forming the pH-responsive supramolecular macrocyclic polymer PRMO@DOX for intelligent delivery of anticancer drug DOX.Benefiting from its unique amphiphilic molecule structure,PRMO@DOX can form unimolecular micelles in water.The acid-responsive hydrazone bond in the polymer break rapidly and thus release drug molecules precisely and timely under an acidic tumor microenvironment,damaging the nuclei and mitochondria of tumor cells,and accelerating cell apoptosis.In this study,the PRMO@DOX show many advantages including good tumor penetration,surpass the biological barriers,high drug loading rate,rapid cell uptake,acid responsive drug controlled release,effictive antitumor activity and low systemic toxicity.Both in vitro and in vivo experiments clearly demonstrated a remarkable antitumor efficacy of this therapeutic platform,which provided a new strategy for the development of polyrotaxane-based nanomedicine for enhanced cancer therapy.3.On the basis of single-responsive polymer prodrug,we further designed dual redox response prodrug delivery system based on cyclodextrin?CD?to solve the problems of low delivery efficiency and poor tumor penetration.Choosing CPT as the model drug,two CPT monomers CPT_GSH and CPT_ROS containing S-S bond and oxalate bond were prepared for GSH-responsive and ROS-responsive drug release.Secondly,two functional hydrophobic CPT monomers and hydrophilic OEGMA were simultaneously polymerized to the cyclodextrin initiator?CD-Br?to form the dual redox responsive polymer precursor CD-b-P(CPT_GSH-co-CPT_ROS-co-OEGMA)(CP_GR)for tumor treatment.In tumor microenvironment,both high GSH concentration and high ROS levels can trigger micellar decomposition,and anticancer drugs are activated and released from the-cyclodextrin carrier.In addition,two corresponding single-responsive drug delivery systems,CD-b-P(CPT_GSH-co-OEGMA)?CP_G?and CD-b-P(CPT_ROS-co-OEGMA)?CP_R?,were further synthesized to fully demonstrate the advantages of the dual redox response mode.Both in vitro and in vivo experiments confirmed that the dual response delivery system(CP_GR)had stronger anticancer activity than the single responsive delivery system.This work has helped to design multiple responsive drug delivery systems for cancer therapy,showing promising potential for medical transformation.