Reversible Addition–Fragmentation Chain Transfer Synthesis of a Micelle-Forming, Structure Reversible Thermosensitive Diblock Copolymer Based on the <i>N</i>‑(2-Hydroxy propyl) Methacrylamide Backbone

A diblock copolymer composed of <i>N</i>-(2-hydroxy propyl) methacrylamide (HPMAm) as hydrophilic block and <i>N</i>-(2-hydroxy propyl) methacrylamide dilactate (HPMAm-Lac₂) as thermosensitive block was synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization. To this end, HPMAm was first polymerized with 4-cyano-4-[(dodecylsulfanylthiocarbonyl)-sulfanyl]­pentanoic acid as the chain transfer agent and azobisisobutyronitrile (AIBN) as the initiator. The polymerization showed a linear increase in <i>M</i>_n as a function of monomer conversion. The living p­(HPMAm) chain (7 kDa) was subsequently extended with HPMAm-Lac₂ yielding a diblock copolymer (total <i>M</i>_n of 22 kDa). The copolymer showed reversible thermosensitivity in aqueous solution and self-assembled into micelles with a size of 58 nm (PDI 0.13) above its critical micelle temperature (CMT, 2.1 °C) and concentration (CMC, 0.044 mg/mL) and was soluble below the CMT. Paclitaxel, a hydrophobic chemotherapeutic drug, was encapsulated in the micelles with a loading capacity of 16.1 ± 1.2%. Hydrolysis of the dilactate side groups of the p­(HPMAm-Lac₂) block converted the copolymer to the fully hydrophilic p­(HPMAm) homopolymer, resulting in dissociation of the micelles. In conclusion, the livingness and versatility of RAFT polymerization provide possibilities to synthesize block copolymers with HPMAm and derivatives thereof