Titanium dioxide nanoparticle-entrapped polyion complex micelles generate singlet oxygen in the cells by ultrasound irradiation for sonodynamic therapy

A new modality of using ultrasound irradiation instead of photoactivation, as in photodynamic therapy (PDT), sonodynamic therapy, has emerged as a promising treatment for various types of cancer. Titanium dioxide (TiO2) has the ability to generate reactive oxygen species (ROS) by not only photo-but also ultrasound-irradiation. Here, the formation of core-shell type polyion complex micelles from TiO2 nanoparticles with polyallylamine bearing poly(ethylene glycol) grafts effectively improves the dispersion stability of the TiO2 nanoparticles under physiological conditions for therapeutic application. The TiO2 nanoparticles in the micelles can generate ROS including singlet oxygen (O-1(2)) by sonication. Furthermore, the micelles are taken up into HeLa cells and the TiO2 nanoparticles generate O-1(2), which is widely believed to be the main cytotoxic agent in PDT, even in the cells treated by sonication. This is the first result representing O-1(2) generation of TiO2 nanoparticles in HeLa cells by sonication. Further, the micelles can selectively exhibit a cell-killing effect at only the ultrasound-irradiated area.