Chain-Transfer Agent Functionalization Combines ROP and RAFT Polymerizations to Direct Amphiphilic and Thermoresponsive Polymer Self-Assembly

In a reversible addition–fragmentation chain transfer (RAFT) polymerization, the chain-transfer agent (CTA) is selected to regulate the radical polymerization, although the specific functional group retained in an amphiphilic macromolecule may influence its self-assembly and colloidal behavior. This feature can be advantageously exploited to engineer polymer nanoparticles with programmable behavior. Here, the carboxylic group of a dodecyl trithiocarbonate CTA was linked to ethanolamine to introduce a hydroxyl functionality while converting the ionizable terminus into a neutral amide. The resulting dual-purpose CTA was used as an initiator in the ring-opening polymerization (ROP) of D,l-lactide and subsequently to mediate the RAFT copolymerization of di(ethylene glycol) methyl ether methacrylate (EG2MA) and N-isopropylacrylamide (NIPAM). The result is an amphiphilic macromolecule capable of self-assemblying forming nanoparticles (NPs) with a poly(lactic acid) (PLA) core and a thermoresponsive shell. Eight copolymers were synthesized by varying PLA length, EG2MA fraction, and overall thermoresponsive block length in a 23 factorial design. These same properties were benchmarked against a similar polymer library in which the biodegradable portion was obtained from a 2-hydroxyethyl methacrylate-g-PLA macromonomer copolymerized with the aforementioned thermoresponsive monomers in a two-step RAFT polymerization. The reference copolymers followed the size scaling expected for micelle-like core–shell assemblies, whereas CTA-directed nanoparticles exhibited a nonconventional dependence of size on polymer composition, lower dispersity, and near-neutral to weakly positive surface charge. These findings establish CTA functionalization as a molecular design strategy that transfers information from the polymerization junction to nanoparticle self-assembly, interfacial properties, and thermoresponsive behavior.