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

Abstract

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 (¹O₂) by sonication. Furthermore, the micelles are taken up into HeLa cells and the TiO₂ nanoparticles generate ¹O₂, 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 ¹O₂ 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.