Investigation of the ultrasound-mediated toxicity mechanisms of various sonosensitive drugs

There is a current pressing need to develop novel platform cancer therapeutics that are efficient, reduce side effects, and are minimally invasive. One of these platforms is photodynamic therapy where light is used as an external stimulus to activate drugs at a target location; however, clinical applications are limited due to poor light penetration. Previously, it has been shown that ultrasound with and without cavitation nuclei can be used to activate photodynamic drugs (sonodynamic therapy – SDT); however, the mechanism of this activation remains unclear. Recently, sonoluminescence has been detected in real time using a photomultiplier tube setup, up to millisecond temporal resolution; however, the spectra of light produced as well as the associated intensity has yet to be characterized. A proposed mechanism for SDT is that this light produced can activate photodynamic drugs at the target location resulting in reactive oxygen species (ROS) production (which leads to cell death). However, through temporal uncoupling of ultrasound application and compound administration in vitro and in vivo, this work shows that intracellular uptake of compound via cell permeabilization (sonoporation) plays an important role in SDT-induced cell death and potentially explains the high levels of cell death observed for comparatively low concentrations of ROS.