Biocompatible Polymer-Grafted TiO₂ Nanoparticle Sonosensitizers Prepared Using Phosphonic Acid-Functionalized RAFT Agent

Sonodynamic therapy is widely used in clinical studies including cancer therapy. The development of sonosensitizers is important for enhancing the generation of reactive oxygen species (ROS) under sonication. Herein, we have developed poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)-modified TiO₂ nanoparticles as new biocompatible sonosensitizers with high colloidal stability under physiological conditions. To fabricate biocompatible sonosensitizers, a grafting-to approach was adopted with phosphonic-acid-functionalized PMPC, which was prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization of 2-methacryloyloxyethyl phosphorylcholine (MPC) using a newly designed water-soluble RAFT agent possessing a phosphonic acid group. The phosphonic acid group can conjugate with the OH groups on the TiO₂ nanoparticles. We have clarified that the phosphonic acid end group is more crucial for creating colloidally stable PMPC-modified TiO₂ nanoparticles under physiological conditions than carboxylic-acid-functionalized PMPC-modified ones. Furthermore, the enhanced generation of singlet oxygen (¹O₂), an ROS, in the presence of PMPC-modified TiO₂ nanoparticles was confirmed using a ¹O₂-reactive fluorescent probe. We believe that the PMPC-modified TiO₂ nanoparticles prepared herein have potential utility as novel biocompatible sonosensitizers for cancer therapy.