Bottlebrush Polymer Excipients Enhance Drug Solubility: Influence of End-Group Hydrophilicity and Thermoresponsiveness.

Bottlebrush polymers have great potential as vehicles to noncovalently sequester, stabilize, and deliver hydrophobic small molecule actives. To this end, we synthesized a poly(N-isopropylacrylamide-stat-N,N-dimethylacrylamide) bottlebrush copolymer using ring-opening metathesis polymerization and developed a facile method to control the thermoresponsive properties using postpolymerization modification. Six increasingly hydrophilic end-groups were installed, yielding cloud point temperature control over a range of 22-42 °C. Solubility enhancement of the antiseizure medication, phenytoin, increased significantly with the hydrophilicity of the end-group moiety. Notably, carboxylated bottlebrush copolymers solubilized formulations with higher drug loadings than linear copolymers because they exist as unimolecular nanoparticles with a synthetically defined density of polymer chains that are more stable in solution. This work provides the first investigation of bottlebrush polymers for hydrophobic noncovalent sequestration and solubilization of pharmaceuticals.