Aggreagation-induced Assembly And Emission Of Polymer And Their Tumor Microenvironment-responsive Drug Delivery

In recent years,drug delivery system(DDS)has attracted widely attention for cancer therapy.Among drug delivery systems,polymer-based drug delivery system is of importance because of their good biocompatibility,biodegradability,and functionality.In general,hydrophobic chains can induce the selfassembly of amphiphilic copolymer to form polymer-based nanostructures in an aqueous phase.However,the application of polymer-based nanostructures has been prevented due to the insufficient functionality of hydrophobic chains.To address these critical issues,the unique tetraphenylethene(TPE)moiety with aggregation-induced emission(AIE)is employed as functional hydrophobic chains to induce copolymer self-assembly and form polymeric micelles that can show strong fluorescence and a low critical micelle concentration(CMC)in aqueous solution.Accordingly,a series of drug delivery systems were designed and further explore their application in cancer treatment.The specific research contents are as follows:Firstly,taking advantage of TPE-based AIE and block copolymer self-assembly,we designed and prepared fluorescent polymeric micelles with AIE characteristics through the self-assembly of the amphiphilic block copolymer[polyethylene glycol-block-poly(acrylic acid-g-tetraphenylethene acrylate)(CH3O-PEG43-b-P(AA-g-TPE)].By introducing the carboxyl groups into the backbone and incorporating the TPE moiety into the side chain,the amphiphilic block copolymer can encapsulate the drug during the self-assembly process and emit fluorescence in its aggregated state.In addition,putting the TPE moiety in the skeleton of the amphiphilic block copolymer through the ester linkage endows the polymeric micelles with enzyme-responsiveness.In this design,its structure stability in physiological medium and enzyme-responsive cleavage in the presence of esterase not only avoid the premature leakage of DOX during blood circulation,but also enhance drug release at the target sites.As the disintegration of polymeric micelles occurs,the incorporated TPE moiety is detached from the skeleton of the amphiphilic block copolymer to quench the fluorescence,which serves as a crucial marker to monitor the delivery task of these polymeric micelles.Therefore,through the combination of AIE and block copolymer self-assembly,polymeric micelles with fluorescence and stability are fabricated to effectively deliver anticancer drugs,holding great promise for cancer therapy.Secondly,we prepared a novel natural polymer-based drug delivery system based on hyaluronic acid-tetraphenyl ethylene conjugate(HA-SS-TPE)with redox-responsiveness and fluorescence for targeted drug delivery.In the self-assembly process,the aggregation of TPE moieties not only induce the self-assembly of the HA-SS-TPE conjugates in the selective solvent,but also load the hydrophobic anti-cancer drug of doxorubicin(DOX)to form the DOX-loaded polymeric spheres(DOX@HA-SS-TPE).The DOX-loaded polymeric spheres exhibit a high drug loading capacity,and fast glutathione-triggered dissociation to further unload active drugs by responding to tumor microenvironment.Moreover,the intracellular distribution of HA-SS-TPE can be visualized depending on the strong fluorescence of TPE.Through the in-vitro investigations,the DOX-loaded polymeric spheres presented a high intracellular release ratio in the CD44-positive cells,when compared to that of the CD44-negative cells.Such redox-responsive natural polymer-based drug delivery system with AIE features provided a potential treatment for CD44-overexpressing cancers.