Synthesis And Properties Of Stimuli-responsive Heterografted Comblike-linear Block Copolymers

Synthesis and properties of graft polymers and their derivatives have attracted much attention in current polymer science. Precise architecture and multifunction play crucial roles in polymer materials, in which precise microstructure can endow materials with novel physicochemical properties, and the function integration can allow rich multipurpose applications. In the family of sequence-regulated polymers, the researches on graft polymers are relatively scarce although linear polymers have been widely investigated. To further reveal the relationships between structure and properties, it is necessary to develop general methodology for the synthesis and explore the properties and applications of well-defined graft copolymers and their derivatives. As well documented, styrene and maleimide are liable to form alternating copolymer when they are subjected to copolymerization using equimolar ratio. In this study, alternating copolymerization via reversible addition-fragmentation chain transfer(RAFT) process was adopted to form alternating microstructure of polymer backbone of comblike block, and some stimuli-responsive comblike-linear diblock and triblock copolymers with a heterografted block were prepared. The resultant copolymers combined the topological features of comblike block with alternating side chains and linear block and exhibited asymmetric or symmetric architecture in molecular level, and thus they may possess some unique properties. On this basis, their self-assembly behaviors, drug loading and release properties and the influence of external stimuli on properties were systematically investigated. Main contents are listed below.The study in Part one aimed at synthesis and properties of stimuli-sensitive heterografted toothbrushlike terpolymers with a linear handle and two types of V-shaped grafts. The target polymer was controllably synthesized by combination of RAFT process, atom transfer radical polymerization(ATRP), ring-opening polymerization(ROP) and hydrolysis. RAFT polymerization of NIPAM mediated by 2-(2-cyanopropyl) dithiobenzoate(CPDB), and followed by RAFT copolymerization of 4-vinylbenzyl 2,2-di((2-bromopropanoyloxy)methyl)propanoate(St(Br)2), and 2-maleimidoethyl 2,2-di(hydroxymethyl)propanoate(MI(OH)2) to afford PNIPAM-b-P(St(Br)2-coMI(OH)2)(PNSM) macroinitiator with multiple bromine and hydroxyl functionalities. Then, successive ATRP, ROP and hydrolysis were performed to synthesize PNIPAM(PAA)2m(PCL)2m copolymers. As evidenced by 1H NMR and GPC-MALLS, the resultant copolymers had well-controlled molecular weights, low polydispersity indices(PDI = 1.14-1.35). The toothbrushlike terpolymer could self-assemble into versatile morphologies involving spherical and sea cucumber-like micelles and vesicles upon external stimuli. In the presence of thermo/p H stimuli and additives such as β-CD and GSH, the in vitro release kinetics and cumulative release from DOX-loaded aggregates could be efficiently adjusted. As compared with copolymer aggregates formed from its linear analogue PNIPAM-b-PCL-b-PAA, the aggregates formed from the toothbrushlike copolymer could exhibit higher DLE, faster release kinetics and enhanced storage stability. The stimuli-sensitive aggregates had a great potential in smart drug delivery system(SDDS) due to their relatively high drug loading efficiency and multi-triggered release properties.The study in Part two aimed at synthesis and properties of multi-stimuli-responsive heterografted comblike-linear triblock copolymers. Acetal-functionalized styrenic poly(ethylene glycol)(St-a PEG) and maleimidic poly(ε-caprolactone)(MI-PCL) were synthesized and subjected to RAFT copolymerization mediated by a disulfide-linked RAFT agent S-CPDB, and followed by RAFT chain extension polymerization of NIPAM to synthesize PNIPAM-b-s Pa SM-b-PNIPAM(TB). The straightforward method enabled facile synthesis of the target copolymers with controlled molecular weight and polydispersity less than 1.35. The comblike-linear triblock terpolymer could self-assemble into versatile morphologies involving spherical and vesicles, and the aggregates with monomodal distribution in DLS plots could be stably stood for a long period of time. To reveal the potential of multi-stimuli-responsive comblike-linear triblock terpolymers in biomedical materials, in vitro release of DOX-loaded TB aggregates was investigated. The cumulative releases at 24 h were 49.6%(37 oC, p H 5.3 + DTT), 44.8%(37 oC, p H 5.3), 42.2%(37 oC, DTT), 36.8%(37 oC, p H 7.4) and 24.3%,(25 oC, p H 7.4), respectively. These results revealed that fast and efficient drug releases could be performed as single, dual and triple stimuli were applied, and thus the polymeric aggregates have a great potential in smart drug delivery systems.In the last part, the study aimed at synthesis and properties of multi-stimuli- responsive normal and quaternized heterografted comblike-linear triblock copolymers. PDMA-b-PSM-b-PDMA(B1) was synthesized by two step reactions involving RAFT copolymerization of St-PEG and MI-PCL mediated by S-CPDB and a subsequent chain extension polymerization of DMA. Then, Menschutkin reaction between PDMA-b-PSM-b-PDMA and bromide-functionalized small molecules such as benzyl bromide, 3-bromopropanol and 3-bromopropionic acid gave ion-bearing quaternized heterografted triblock copolymers QB1-QB3. As evidenced by 1H NMR and GPC-MALLS, the resultant copolymers had well-controlled molecular weights, low polydispersity indices(PDI = 1.22-1.28). The results revealed molecular weight and chemical composition played an important role in thermoresponsive properties. The cloud point of reduction-cleaved polymers was lower than that of the origianl triblock copolymers, and the Tc difference was ranged between 3.5 and 14.8 oC. Although all the reduced samples exhibited LCST in aqueous solution, the original quaternized block copolymers bearing OH and COOH moieties showed UCST behaviors. The comblike-linear triblock terpolymer with PDMA segments could self-assemble into versatile morphologies involving spherical micelles, large compound micelles and vesicles.In summary, the acid and reduction-cleavable linkages and stimuli-sensitive segments were introduced into amphiphilic comblike-linear diblock and triblock copolymers via controlled polymerization and postmodification reaction, and multi-stimuli-responsive systems were constructed by self-assembly. Upon single, dual and multiple stimuli, the morphology of aggregates and drug release kinetics could be efficiently adjusted. The heterografted block copolymers may have a great potential as nanocarriers and antibacterial materials. Therefore, facile methods to synthesis graft copolymers and their derivatives with regular side chains were developed in this study, the types of nonlinear topological polymers were further enriched, and the novel block copolymers obtained may act as multifunctional smart materials.