Ultrasound-mediated drug release from nanoscale liposomes using nanoscale cavitation nuclei

We have previously presented a liposomal formulation of mean size 140 nm, manufactured using DSPE, cholesterol, DSPC and DSPE-PEG at ratios of 65:25:3:7, which exclusively releases encapsulated doxorubicin in the presence of inertial cavitation nucleated by microbubbles (SonoVue®, Bracco) at peak rarefactional pressures in excess of 1.2 MPa at 0.5 MHz (Graham et al., J. Controlled Release, 2014). However, the benefits of cavitation-sensitive liposomes small enough to pass through the leaky tumor vasculature can only be fully realized if they can be triggered by cavitation nuclei which are also small enough to extravasate into the tumor mass. In the present work, we demonstrate that liposomal release comparable to that mediated by SonoVue® microbubbles can be achieved using gas-stabilizing polymeric nanocups of mean diameter 400 nm, at peak rarefactional pressure amplitudes in excess of 1.5 MPa at 0.5 MHz or 4 MPa at 1.6 MHz. Mechanistically, we hypothesize that release occurs once a threshold peak shear rate is exceeded in the fluid surrounding the collapsing microbubble, thus exceeding the critical shear stress on the liposomal surface. This is confirmed experimentally by demonstrating a correlation between release and the maximum power of broadband acoustic emissions received by a passive cavitation detector.