Facile Synthesis of Hyperbranched Copolymers via an [A₂ + B₃] Click Polymerization Synthesized Reducible Hyperbranched Template

Synthesis of multifunctional hyperbranched polymers (HPs) with simultaneously precisely modulated degrees of branch (DBs) and multibiorelevant signal-triggered sensitivities generally suffers from multistep preparation and purification procedures and uncontrolled DB. To develop a facile yet robust approach toward multifunctional HPs with a precisely modulated DB, we reported herein the synthesis of a reducible hyperbranched polymer template (HPT) with a fixed DB via an [A2 + B3]-based click polymerization and its further mediation of reversible addition–fragmentation chain transfer (RAFT) polymerization for the facile preparation of well-defined multifunctional HPs with a uniform DB, predetermined polymer compositions, and well-modulated molecular weights (MWs) and low dispersity (Đ) indexes. The breakthrough of this study is the design of a bioreducible HPT-based multimacro chain transfer agent (multimacro-CTA) with a fixed DB of 0.45 via click polymerization between an A2 unit containing a central trithiocarbonate group for further conduction of RAFT polymerization of any vinyl-based monomers, two disulfide links for reduction sensitivity, and two azide groups and a branched B3 unit with three highly reactive alkynyl functions. The resulting HPT was further adopted as a multimacro-CTA to mediate RAFT polymerization of a previously reported acidic pH cleavable oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) monomer, α-OEGMA, affording reduction and acidic pH dual sensitive HPT-P(α-OEGMA). Notably, the resulting polymer panel of HPT-P(α-OEGMA)s could self-assemble into stabilized unimolecular micelles with MW-dependent mean hydrodynamic size in a range from 18.9 to 27.0 nm. The drug-loaded HPT-P(α-OEGMA) micelles incubated in a reducing or an acidic pH condition showed accelerated drug release due to the reduction-triggered cleavage of the disulfide links or an acidic pH induced breakage of the acetal links for polymer degradation. Therefore, the universal HPT platform provides a facile yet robust approach toward well-defined multifunctional HPs with a uniform DB, well-controlled MWs, and low Đ indexes for biomedical applications.