Ultrasound-Responsive Nanoparticles for Drug Delivery

The potential of acoustic inertial cavitation, i.e., the radial collapse of a bubble due to ultrasound exposure, has been widely recognised for enhancing both transport and uptake of drugs in cancer treatment.  For example, it has been proposed to provide a triggering mechanism for drug release from liposomes that extravasate into tumours due to the enhanced permeability and retention (EPR) effect and to increase the permeation of drugs throughout the tumour volume. In the past decade, much research has been devoted to initiating and controlling inertial cavitation using microbubbles.  However for tumour therapy, microbubbles have a number of limitations: They are too large take advantage of the EPR effect and are also rapidly destroyed following ultrasound exposure. Recently, there has been a surge in development of nanoscopic cavitation agents such as phase change nanodroplets and nanobubbles. Here, we present novel nanoscopic particles that trap bubbles within nano-crevices, and function as nucleation agents for inertial cavitation.  We demonstrate that these particles reproducibly generate inertial cavitation for extended periods of time, and facilitate enhanced drug penetration in in vitro and in vivo cancer mimicking models. Additionally, we show that the inertial cavitation threshold for these nanoparticles can be reliably predicted over a range of frequencies using a modified Raleigh-Plesset equation for crevice-stabilised bubbles.