Heterobifunctional RAFT Polymers for Simultaneous, Orthogonal Bioconjugations

In this work, we report the synthesis of an α-diethoxyphosphoryldithio, ω-alkynyl heterobifunctional chain transfer agent (CTA) that can engage in the reversible addition-fragmentation chain-transfer (RAFT) polymerization of (meth)acrylic monomers and subsequently engage in orthogonal Hetero–Diels-Alder (HDA) and copper-catalyzed azide-alkyne cycloadditions (CuAAC) at the resulting linear polymer end groups. A broad scope of monomers were polymerized with our CTA and the corresponding kinetics of RAFT polymerization were characterized. Efficient, orthogonal polymer end group transformations and kinetics were confirmed via polymer-dye, polymer-polymer, and polymer-protein conjugations. Finally, we employed the heterobifunctional CTA in the RAFT synthesis of amphiphilic triblock copolymers, fabricated micellular nanoparticles via self-assembly in aqueous buffer, and demonstrated stoichiometric control over nanoparticle surface chemistry via component polymer end groups. To our knowledge, this RAFT system is the first to report direct access to heterotelechelic, linear polymers capable of highly efficient, regioselective end group transformations immediately following polymerization without the need for post-polymerization end group modification/installation. We believe that the highly modular nature of this platform makes it amenable to applications in nanomedicine and bioconjugate chemistry, among others.