Synthesis And Properties Of Well-Defined Comblike Copolymers And Multicomponent H-shaped Copolymers

Nonlinear polymers have gained great attention over the past decades due to their unique structures and properties. The development of controlled/"living" polymerization such as atom transfer radical polymer (ATRP), reversible addition-fragmentation chain transfer (RAFT) polymerization, ring-opening polymerization (ROP), greatly facilitates the synthesis of well-defined nonlinear polymers. This research is aimed at synthesis and properties of comblike copolymers and H-shaped copolymers by controlled polymerization. Their relationships between structure and properties were investigated, and the potential applications were also studied. The main contents are listed as follows.(1) Symmetric reduction-responsive amphiphilic comblike copolymers S-CP(PEG-alt-PCL) with poly(St-alt-HEMI) backbones and alternating poly(ε-caprolactone)(PCL) and poly(ethylene glycol)(PEG) side chains were synthesized and used as nanocarriers for in vitro release of doxorubicin. The target copolymers with predetermined molecular weight and narrow molecular weight distribution (Mw/Mn=1.15-1.20) were synthesized by RAFT copolymerization of vinylbenzyl-terminated PEG (St-PEG) and N-(2-hydroxyethyl) maleimide (HEMI) mediated by a disulfide-functionalized RAFT agent S-CPDB, and followed by ring-opening polymerization of CL. As compared with linear PEG-b-PCL copolymers, comblike copolymers with similar PCL contents usually exhibited decreased crystallization temperature, melting temperature and degree of crystallinity, indicating the significant influence of copolymer architecture on physicochemical properties. Dynamic light scattering (DLS) measurements revealed that comblike copolymers were liable to self-assemble into aggregates involving vesicles and micelles with average diameter in the range of56-226nm and particle size distribution ranging between0.07and0.20. In contrast to linear copolymer aggregates, comblike copolymer aggregates with similar compositions were of improved storage stability and enhanced drug loading efficiency. In vitro drug release confirmed the disulfide-linked comblike copolymer aggregates could rapidly release the encapsulated drug when triggered by10mM DL-dithiothreitol. These reduction-sensitive, biocompatible and biodegradable aggregates have a potential as controlled delivery vehicles.(2) Well-defined H-shaped copolymers with five kinds of chemical compositions were synthesized by two paths, and their properties were investigated. The first one was based on "one pot" method, in which PEG-(PCL)-PSt miktoarm star polymers were obtained in a one-pot method by ATRP of St, ROP of caprolactone (CL), and the click reaction with PEG-N3, then converted-Br to-N3to obtained azide-functionalized3-arm miktoarm star. In addition, PtBA-b-PLLA block copolymer was also obtained in a one-pot strategy. At last, azide-functionalized star and alkyne-functionalized block copolymers were used as building units to construct multicomponent H-shaped copolymers. Another method is to combine ROP and ATRP to synthesize mid-alkyne-functionalized diblock copolymers BC and DE, and then successive click reactions using PEG-N3and BC as starting materials were performed to synthesize H-shaped polymers.1H NMR and GPC results revealed the above-mentioned methods could be efficiently used to synthesize the target H-shaped copolymers with well-defined structures and polydispersity indices in the range of1.19-1.21. The self-assembly behavior of H-shaped copolymer and its precursors were studied. The results showed that the critical aggregation concentration of these copolymers in aqueous solution is about1-3μg/mL, and their hydrodynamic size and Zeta potential were related to concentration and pH values. The sizes of DOX-loaded aggregates of H-shaped copolymer and three-arm star polymer were slightly smaller than those lack of DOX. On this basis, the drug release behaviors of DOX in pH5.3and7.4were investigated. The results showed the drug release rate and cumulative release in pH5.3is higher than those in pH7.4. Finally, MTT assay revealed that aggregates formed by H-shaped copolymers were of low cytotoxicity and cell survival increased with time.In summary, this study was primarily focused on continuous development of efficient approaches to the synthesis of well-defined multicomponent comblike and H-shaped copolymers (a) and detailed investigations on their physicochemical properties, self-assembly behaviors, cytotoxicity and drug loading and release properties (b). Our preliminary results confirmed the resultant comblike and H-shaped copolymers could self-assembled into micelles and vesicles in aqueous solution with low cytotoxicity, which could be efficiently used for loading and release of hydrophilic drugs such as DOX. Therefore, these copolymer have a potential in controlled delivery vehicles.