Reversible Addition-Fragmentation Chain Transfer Synthesis of a Micelle-Forming, Structure Reversible Thermosensitive...

A diblock copolymer composed of N-(2-hydroxy propyl) methacrylamide (HPMAm) as hydrophilic block and N-(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 M_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 M_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.