Controlled Synthesis And Properties Of Stimuli-responsive Multicomponent Miktoarm Stars

Controlled synthesis and properties of complex macromolecular architectures have been an enduring topic in current polymer science. The latest advance in living/controlled polymerization techniques and highly efficient linking reactions enables precise synthesis of various types of functional polymers. In polymer family, multicomponent miktoarm star copolymer(MMS) with at least three kinds of chemical compositions can be regarded as a special type of miktoarm star copolymer with inner core and different arm segments in the outer layer. As compared with their linear analogue, MMS is liable to exhibit more interesting morphologies and increasingly special functional regions originating from branching effect related complex microphase-separation behaviors, and thus it holds a great promise in functional materials. Meanwhile, the introduction of stimuli-cleavable linkages and stimulisensitive segments can further enhance the functions and applications of polymers. Owing to the great challenge in controlled synthesis, the examples of stimuli-liable MMSs are very scarce, and the research on construction of miktoarm star quintopolymers remains in the early stage. Therefore, much emphasis should be paid on developing novel general methodologies to synthesize functional MMSs, studying their self-assembly behaviors, and exploring the potential applications in various fields involving biomedical materials and interfacial materials.In this context, this research aims at facile synthesis of some multicomponent miktoarm stars involving 3-arm ABC terpolymers, 4-arm ABCD quaterpolymers and 5-arm ABCDE star quintopolymers, in which controlled polymerizations(i.e. reversible addition-fragmentation chain transfer(RAFT) polymerization, atom transfer radical polymerization(ATRP) and ring-opening polymerization(ROP)) and click reactions such as copper(I)-catalyzed azide-alkyne cycloaddition(Cu AAC) and Diels-Alder(DA) reactions are usually combined during macromolecular design. On this basis, their self-assembly behaviors and potential in smart drug delivery systems are investigated as well. Main contents and research progresses are listed below.In Part 1, the research is focused on synthesis and properties of multi-stimuli- responsive ABC star terpolymers with a reduction-labile arm. Among MMS family, ABC-type star copolymer has been extensively investigated, and their precise synthesis and properties can promote the development of polymer chemistry and physics and multifunctional materials. Thus far, the examples of stimuli-liable star terpolymers are very scarce. This study aims at versatile synthesis of 3-arm ABC-type(A = PCL, B = PNIPAM, C = Pt BA or PAA) miktoarm stars with a reducible disulfide linkage via “core first” approach. To this end, a heterotrifunctional initiator 2-((2-((2-hydroxymethyl-2-((2-bromo-2-methyl)propionyloxy)methyl)propionyloxy)ethyl)disulfanyl)ethyl 4-cyano-4-(phenylcarbonothioylthio)pentane(HBCP) was used for consecutive ROP of ε-caprolactone(CL), RAFT polymerization of N-isopropylacrylamide(NIPAM) and ATRP of tert-butyl acrylate(t BA) to generate ABC1 star, and followed by a selective hydrolysis to give ABC2 star. 1H NMR and GPC analyses revealed the desired structures and their precursors showed well-controlled molecular weight and relatively low polydispersity(PDI ≤ 1.12). As confirmed by GPC analysis, the disulfide linkage in ABC star could be efficiently cleaved upon reductive stimulus, during which the topology was converted from star terpolymer to mixtures of homopolymer(B) and diblock copolymer(AC). The star terpolymer could self-assemble into micelles, and the particle size and distribution were significantly affected by external stimuli. Moreover, the release kinetics of doxorubicin(DOX) loaded ABC2 aggregates could be efficiently adjusted via control over addition of single, dual or triple stimuli. Owing to the presence of terminal bromide, dithiobenzoate and hydroxyl functionalities, ABC stars are expected to form other reduction-cleavable multicomponent copolymers such as linear and dendritic graft copolymers and dendrimer-like copolymers via postpolymerization modification. Our research affords a straightforward “core first” method to construct multifunctional star terpolymers with stimuli-responsive arms and reduction-labile linkage, and they may hold a great promise in smart materials.In Part 2, the research aims at synthesis and properties of a p H/reduction dual-sensitive ABCD star quaterpolymer with a reduction-labile arm. Thus far, some modular methods involving “2+2” and “3+1” strategies have been developed to synthesize 4-arm star quaterpolymers, however, the examples of such miktoarm stars and stimuli-liable MMSs obtained via controlled polymerization are very scarce. In this study, the “2+2” modular synthesis was adopted to construct monocleavable ABCD stars. First, 2-azidomethyl-2-bromomethyl-3-hydroxypropyl 4-(benzodithioyl)-4-cyano pentanoate(ABCP) was synthesized and used to generate in-chain-azide- functionalized AB diblock copolymer comprising polystyrene(PSt, A) and poly(ethylene glycol)(PEG, B) segments via consecutive esterification and RAFT process. Second, ROP and RAFT processes starting from 2-((2-((2-hydroxymethyl-2-(pent-4-ynoyloxy)methyl)propionyl oxy)ethyl)disulfanyl)ethyl 4-cyano-4-(phenylcarbonothioylthio)pentanoate(HCP) gave in-chain-alkyne-functionalized CD1(C = PCL, D1 = Pt BA) diblock copolymer. Last, ABCD1 star was obtained by Cu AAC, and followed by selective hydrolysis to achieve PSt-PEG-PCL-PAA(ABCD2) star. The results given by 1H NMR, GPC-MALLS and DSC revealed that the resultant star copolymers had well-defined topology, controlled molecular weight and composition, and partial compatibility among different arms. ABCD2 star could self-assemble into vesicles with uniform size in aqueous solution. As p H and/or reduction stimuli were applied, obvious changes in the shape and size of vesicles were noted, which could be ascribed to reassembly originating from the variable parameters involving topology, molecular weight and end group. The remaining alkyl bromide in the core and reactive dithiobenzoate and hydroxyl functionalities in the chain end of arm segments allows for multiple topological transformations and formation of functional MMSs with enhanced compositions via postpolymerization modifications.In Part 3, the research lies in modular synthesis and self-assembly of an amphiphilic PEG-PCL-PSt-PLLA-PAA star quintopolymer for p H-sensitive drug delivery. At present, precise synthesis of ABCDE stars is still challenging, and almost no systematic researches on their properties are available. In this study, an amphiphilic star bearing PAA segment was generated by combination of modular synthesis via Cu AAC-based “1+2+2” strategy and selective hydrolysis of Pt BA segment, and drug delivery of DOX-loaded copolymer aggregates was investigated as well. Terminal diazide functionalized PEG(PEG-(N3)2, A) and alkyne-mid- functionalized PCL-b-PSt(BC) and PLLA-b-Pt BA(DE’, D = poly(L-lactide), E’ = Pt BA) diblock copolymers acted as building blocks for the modular synthesis. The target star had controlled molecular weight and precise composition, as evidenced from 1H NMR and GPC-MALLS analyses. DSC analyses revealed star copolymers usually exhibited complex chain relaxation and melting behaviors although arm segments were partly compatible, and the presence of branching structure and other segments could disturb the crystallization of PCL and PLLA segments. Various copolymers could self-assemble into vesicles(for ABC and ABCDE stars) and micelles(for DE copolymer) in aqueous solution, and the copolymer vesicles were of stability. The drug loading property and release kinetics of copolymer aggregates were affected by some factors such as topology, chemical composition and p H. The release rate of DOX from various aggregates at p H 7.4 was decreased in the order DE > ABCDE star > ABC star. At p H 5.3, the deformation and reassembly of aggregates happened, and the solubility of DOX was improved, resulting in remarkably accelerated release kinetics under acidic conditions. The ABCDE vesicles had a great potential as smart delivery vehicles due to their excellent stability, satisfactory drug loading efficiency, and p H-responsive drug release properties.The research in Part 4 aims at synthesis and properties of couplable ABCDE star copolymers by orthogonal Cu AAC and DA click reactions. Modular synthesis and orthogonal reaction are important strategies in organic and polymer syntheses, and their combination has enabled one-pot synthesis of complex topological polymers. For the traditional “1+2+2” strategy using the same type of click reaction, the selectivity during linking reaction may be poor in some cases, and such limitation can be addressed by the high selectivity bearing orthogonal chemistry. This study aims to develop modular and orthogonal approaches to synthesize multicomponent stars via one-pot strategy using distinct building blocks A, BC and DE. Tandem Cu AAC and DA reactions were utilized to generate ABCDE star comprising PCL(A), Pt BA(B), PLLA(C), PNIPAM(D) and poly(5-methyl-5-allyloxycarbonyl-1,3-dioxane-2-one)(PMAC, E) arms, and a subsequent hydrolysis afforded PAA(B’) bearing AB’CDE star with clickable and dual-sensitive segments. The results revealed that the desired star had controlled molecular weight and precise composition, and various segments could be partly compatible. The star copolymers were liable to self-assemble into some intriguing morphologies involving vesicles, spherical micelles and large compound micelles which could be tuned by adopting thermo and p H stimuli. Owing to the presence of allyl moieties in PMAC segment, some reactive functionalities can be introduced via postmodification reactions such as epoxidation and thiol-ene click reaction. Consequently, it is possible to convert a single ABCDE star into many examples of star copolymers with richer compositions and enhanced properties. The modular synthesis using orthogonal chemistry allows us to prepare ABCDE-type stars with well-controlled molecular weight, tunable composition, and versatile functions, and this straightforward approach may act as a general method to construct functional MMSs. The success of this study further paves the way for facile synthesis of multifunctional star quintopolymers and their derivatives with multipurpose applications involving multiphase functional materials.In summary, with the aid of controlled polymerization and click reaction, some functional MMSs such as ABC, ABCD and ACBDE stars with controlled composition have been successfully synthesized via modular and orthogonal strategies. The introduction of disulfide linkage and stimuli-sensitive segments can further enhance the functions and applications of multicomponent copolymers. Upon external stimuli, the miktoarm stars are liable to perform topological transformation and/or change the hydrophobic/hydrophilic balance, and thus the self-assembly behaviors and drug delivery properties can be efficiently adjusted in a wide range. As a result, they can hold a great promise in functional materials such as smart interfacial and biomedical materials. Our research has close relationship with some disciplines such as polymer chemistry and physics, functional materials and biomedical materials. The modular and orthogonal methods may act as general routes to generate various types of MMSs, and the research progress can strongly promote the development of synthetic methodology on multicomponent copolymers and pave way for systematic researches on unique properties and applications of functional MMSs.