Synthesis and self-assembly of amphiphilic thermoresponsive PNIPAAm-b-PHBHV-b-PNIPAAm triblock copolymers via RAFT polymerization

The design of amphiphilic thermoresponsive block copolymers enables the development of nanostructured systems for controlled drug delivery. In this context, we report the synthesis of a well-defined triblock copolymer, poly( N -isopropylacrylamide)- b -poly(3-hydroxybutyrate- co -3-hydroxyvalerate)- b -poly( N -isopropylacrylamide) (PNIPAAm- b -PHBHV- b -PNIPAAm), via reversible addition–fragmentation chain-transfer (RAFT) polymerization and its self-assembly into thermoresponsive micellar structures, with potential application in drug delivery. Hydroxyl-terminated PHBHV was prepared by transesterification with ethylene glycol, followed by bromination and xanthate substitution to yield a PHBHV-based macro-RAFT agent (EX-PHBHV-EX). Subsequent RAFT polymerization of N -isopropylacrylamide (NIPAAm) afforded the target PNIPAAm- b -PHBHV- b -PNIPAAm triblock copolymers. The copolymers were thoroughly characterized by Fourier-Transform Infrared (FTIR) spectroscopy, Proton Nuclear Magnetic Resonance ( 1 H NMR) spectroscopy, Size Exclusion Chromatography (SEC), Differential Scanning Calorimetry (DSC), and X-ray Diffraction (XRD), confirming the structural integrity and tunable segment composition. The critical micelle concentration (cmc) of the block copolymers increased with longer PNIPAAm chains and decreased with longer PHBHV segments. Dynamic Light Scattering (DLS) revealed that micellar size increased with increasing hydrophobic PHBHV block length and decreased with increasing hydrophilic PNIPAAm block length. Additionally, temperature-dependent DLS experiments confirmed the thermoresponsive behavior of the micelles, showing a reduction in the hydrodynamic diameter at physiological temperature (37 °C) due to the collapse of the PNIPAAm chains.