Fabrication Of Intelligent Nanoparticles As Drug Carriers Via RAFT Dispersion Polymerization Induced Self-assembly

In recent years,responsive polymer nanomaterials have been widely used in the field of biomedicine.Responsive polymer nanocarriers with different morphologies have attracted more and more attention due to their excellent drug delivery and drug release properties.Meanwhile,polymerization-induced self-assembly(PISA),which combines polymerization and self-assembly in one-pot with a relatively high polymer concentration,has attracted more and more attention on polymer nanomaterials.In this dissertation,we fabricate intelligent nanocarriers with different morphologies based on RAFT dispersion polymerization in PISA,and study their drug release behaviors.Firstly,we prepare a dual-responsive polymeric prodrug nanoparticles by PISA method,and study its application in the controlled drugs release.In addition,we prepare a dual-responsive vesicles with robust membrane crosslinked structures by in-situ cross-linking PISA method,and study the polymerization kinetics and the stability of cross-linked vesicles,as well as its application in the controlled drugs release.The main results are as follows:1.Dual stimulus-responsive prodrug nanoparticles are successfully fabricated via a highly efficient strategy,PISA.Polymerization,self-assembly and drug encapsulation are simultaneously fulfilled via RAFT dispersion polymerization of BzMA using the prodrug diblock copolymer PHPMA-P(DIPEMA-co-CPTM)as the macro RAFT agent.The prodrug nanoparticles with three layers,well biocompatible PHPMA shell,drug-anchored P(DIPEMA-co-CPTM)middle layer,and solvophobic PBzMA core,are fabricated at a relatively high concentration(250 mg/g).Moreover,almost complete monomer conversion is achieved in PISA,which allows for direct application of the obtained prodrug nanoparticles without further purification.Reductive-triggered and pH-accelerated CPT release is realized in a synergistic manner that GSH actively reduce the disulfide bond in the prodrug nanoparticles to release CPT,and GSH diffuse faster into the prodrug nanoparticles due to the hydrophilic state of PDIPEMA chains in mildly acidic microenvironment.Cell viability assays show that the prodrug nanoparticles encompass excellent intracellular drug delivery properties and effective anticancer activity.Therefore,this study provides a highly efficient approach for fabrication of intelligent drug delivery systems.2.In situ cross-linking in PISA to fabricate pH and reductive dual stimulus-responsive polymersomes with robust membrane crosslinking structures is realized via RAFT dispersion copolymerization of DIPEMA and CBMA(disulfide crosslinker)using PEG-CPDB as the macro RAFT agent.The methacrylamide group in CBMA has a lower reactivity than the methacylate groups in DIPEMA,thus the morphology transition to form higher order nano-objects(vesicles)is not hindered by the slight crosslinking at the early stage of the polymerization and the crosslinking reaction is mainly delayed to the late stage of the polymerization after the formation of polymersomes,which is supported by 1H NMR and TEM analyses.Successful fabrication of robust membrane crosslinked polymersomes via in situ cross-linking strategy is demonstrated by the challenge of THF,which is a good solvent for all the blocks in PEG-P(DIPEMA-co-CBMA).The polymersomes exhibit pH and reductive dual stimulus-responsive regulated release of cargoes.pH-regulated membrane permeability of the polymersomes is due to the pH-responsive hydrophobic-to-hydrophilic transitions of the membrane-forming PDIPEMA blocks.Reductive-responsive disaggregation of the polymersomes is due to the reductive-cleavable disulfide-based crosslinker(CBMA).The pH and reductive dual stimulus-responsive behaviors may endow the vesicles superior performance to meet the strict requirements of drug delivery in a synergistic manner.In consideration of the dual stimulus-responsive(pH and reductive)tunable membrane properties of the polymersomes,and the high efficiency of the in situ cross-linking strategy,as well as the inherent high efficiency of PISA,this work reported herein might be of great interest for nanomedicine.