One-Pot/Simultaneous Synthesis of PHPMA-G-PLA Copolymers via Metal-Free Rop/Raft Polymerization and their Self-Assembly from Micelles to Thermoresponsive Vesicles

The present article reports a simple and straightforward approach to access thermoresponsive graft copolymers based on lactide (LA) and a methacrylic monomer, 2-hydroxypropyl methacrylate (HPMA), using a synthesized carboxy-functionalized trithiocarbonate-based chain transfer agent. One protocol involves a metal-free simultaneous synthesis through a combination of reversible addition-fragmentation chain transfer polymerization and organic acid-catalyzed ring-opening polymerization, which follows first-order kinetics. The resulting copolymers with a controlled structure exhibit remarkably narrow molecular weight distributions (Р< 1.10). Within this framework, the self-assembly of PHPMA-g-PLA graft copolymers (GCs) into nanoparticles (NPs) is demonstrated at concentrations of 0.2 and 0.5 wt.%, respectively. The displacement method, based on the rapid injection of the organic solvent (acetone) into an aqueous medium under vigorous stirring, produces spherical NPs such as micelles, vesicles, or non-spherical “lumpy rods”. The presence of a pseudo-thermoresponsive segment (PHPMA) in GCs facilitates stimulus-responsive self-assembly behavior. Well-defined spherical NPs—primarily vesicles of substantial size—develop upon heating above the glass transition temperature (T_g ≈35–36 °C) of the GCs in an acetone–water (80/20 wt.%) mixture. Last, specific interactions between the obtained PHPMA-g-PLA nano-objects and blood proteins in human plasma are studied using isothermal calorimetry.