Synthesis And Properties Of Multi-Responsive Heterografted Copolymers

Synthesis,properties and applications of stimuli-responsive polymers are important topics in polymer science.In the field of macromolecular self-assembly,traditional self-assembly and dispersion polymerization have gained important progress and become efficient bottom-up approach to preparation of nanomaterials,however,it remains challenging to conduct hierachical self-assembly to reversibly achieve two dimensional nanostructures involving nanosheets.Meanwhile,exploration and application of stimuli-responsive nanocarriers have attracted much attention in nanomedicine,and coassembly of polymer with drug affords facile route to perform targeted therapy on tumors and controlled drug delivery,whilst the research on the influence of architecture on properties is in the early stage.In this study,heterografted copolymers were designed as model polymers to address the aforementioned questions.To this end,heterografted copolymers with doubly thermoresponsive pendent chains were designed and subjected to temperature-induced self-assembly to achieve temperature-programmable hierachical self-assembly with reversible process,and multi-responsive heterografted copolymers with linear and V-shaped grafts were subjected to pH/T/redox-triggered aggregation to form potential nanocarriers for smart drug delivery systems.Main contents are listed below.In part 1,the research was focused on synthesis,thermoresponsivity and self-assembly of stimuli-responsive heterografted triblock copolymers.2-(2-Cyanopropyl)dithiobenzoate(CPDB)was used as an initial chain transfer agent,successive RAFT copolymerization and chain extension polymerization using 2-maleimidyl-4-thiobutyrolactone(MTL)and styrene-type inimers bearing hydroxyl and alkyl bromide functionalities,ATRP of N-isopropylacrylamide(NIPAM),end-capping reaction,one-pot aminolysis of thiolactone units and telomerization of 2-(dimethylamino)ethyl methacrylate(DMA),and ring-opening polymerization(ROP)of ?-caprolactone(CL)were performed to generate the desired graft copolymers G2 and G3 comprising poly(styrene-co-maleimide)backbone,where G2 had PNIPAM and PDMA grafts,and G3 had PNIPAM,PDMA and PCL grafts.Various copolymers were characterized by 1H NMR spectra,GPC and FT-IR spectra.Upon pH,CO2 and oxidation stimuli,LCST-type phase transition in H2O and D2O could be efficiently tuned,and rich self-assembled morphologies were obtained.Moreover,G2 was subjected to temperature-induced self-assembly(TISA)to achieve temperature-programmable hierachical self-assembly with reversible transitions among different morphologies,and the self-assembly mechanism was preliminarily investigated.It was found that the solvent isotope could play critical roles in affecting types of copolymer assemblies and the corresponding temperature window,thermo-induced stepwise hydration and dehydration favored to the formation of multiple morphologies.Although nanobowl(NB),vesicle(V),disk-like micelle(DM),nanosheet(NS),and nanoribbon(NR)could be successively formed in H2O and D2O,unimolecular micelle aggregates could only be available in H2O,and spindle-like micelle(SM)and hyperbranched micelle(HBM)could be formed in D2O.This phenomenon was possibly originated from some factors such as different strength of mutual interactions between polymer chain and solvent and dehydration rate.Heterografted copolymers with doubly thermoresponsive pendent chains can act as model polymers to prepare hierarchical nanomaterials,which affords an important platform to fabricate nanomaterials with tunable compositions and reversible morphologies and explore their potential applications.In part 2,the study was aimed at synthesis and properties of disulfide-linked multi-responsive heterografted copolymers.Starting from disulfide-functionalized chain transfer agent S-CPDB,successive RAFT copolymerization of 4-vinylbenzyl 3-(2-bromo-2-methylpropanoyloxy)methyl-2-hydroxymethylpropionate(VBHP)and MTL,ATRP of tert-butyl acrylate(tBA),end-capping reaction,ROP of CL,and hydrolysis of PtBA side chains were conducted to generate heterografted copolymers(H4-H6).The desired copolymers had poly(styrene-co-maleimide)backbone and two types of V-shaped grafts,and they were sensitive to pH,heat and redox responsiveness.1H NMR spectra,GPC and FT-IR spectra were used to characterize various copolymers.The cloud points could be tuned by control over the chain length of PCL grafts.Upon pH,heat,oxidation and reduction stimuli,the sizes and types of copolymer assemblies could be efficiently tuned,and different morphologies involving large compound micelles and vesicles with multiple pores were obtained.On this basis,the advantages using combinatorial therapy of cancer were investigated.To combine thermo-and chemo-therapy,multi-stimuli-responsive nanodrugs were prepared via coassembly of H5 with NIR photothermal agent indocyanine green(ICG)and chemotherapeutic compound doxorubicin(DOX).As ICG.DOX and copolymer were added with weight fraction of 2:1:7,the total drug loading capacity(DLC)and drug loading efficiency(DLE)of ICG/DOX-loaded aggregates were 73.3%and 22.1%,respectively.Near-infrared(NIR)light had good penetration to body tissues,the resultant heat could kill the tumor cells and lead to the collapse of PNIPAM chains,and the excessive singlet oxygen given by cells could result in oxidation of thioether groups.Consequently,the drug release process could be significantly accelerated.Cell viability of 4T1 cells,chemical and irradiation stability of encapsulated drugs and in vitro drug release behaviors were investigated,and the related parameters were compared with those of free drugs.The results fully conformed good biocompatibility of nanocarriers,relatively high DLC and stimuli-triggered fast drug release kinetics.As compared with a single stimulus,the combined stimuli such as pH 5.3,DTT and NIR irradiation could exhibit synergistic effect to result in accelerated release of encapsulated drugs.This study underlies the systematic research on in vivo cancer therapy using smart nanocarriers based on graft copolymers.In summary,this study is aimed at synthesis of multi-responsive heterografted copolymers with linear and V-shaped grafts,study on stimuli-dependent physical properties such as cloud points and self-assembly behaviors,and exploration on the influence of external stimuli on drug release properties.The results have confirmed that the doubly thermoresponsive graft copolymer can act as a model polymer to achieve temperature-induced hierachical self-assembly,which further underlies the systematic researches on the correlations among morphology,property and application of nanomaterials with same chemical compositions.Therefore,this study has enriched the types of graft polymers,partly addressed the challenges on facile preparation of nanosheet-bearing multiple nanostructures and reversible transitions among different morphologies,and preliminarily explored the dependence of material properties and bioapplications on architectures and chemical compositions.