Use of micro- and nano-sized inertial cavitation nuclei to trigger and map drug release from cavitation-sensitive liposomes

Abstract

Encapsulation of cytotoxic drugs into liposomes enhances pharmacokinetics and improves passive accumulation in tumors. However, stable liposomes have limited drug release, and thus action, at the target site. This inefficient and unpredictable drug release is compounded by a lack of low-cost, non-invasive methods to map release in real time. We present a new liposomal vehicle that is exclusively triggered by inertial cavitation. Ultrasound exposure of these liposomes in the absence of SonoVue® provided no increase in drug release, whilst with SonoVue® at inertial cavitation pressure levels a substantial (30%) and significant (p < 0.001) increase was observed in vitro. A 16-fold increase in the level of drug release within tumors was similarly observed in the presence of inertial cavitation following intravenous delivery. Passive acoustic mapping of inertial cavitation sources during delivery was also found to correlate strongly with the presence of release. However, variability in tumor perfusion indicated that uneven distribution of micron-sized SonoVue® may limit this approach. Nano-scale cavitation nuclei, which may more readily co-localize with 140 nm liposomes, were thus developed and showed similar cavitation energies to SonoVue® in vitro. These nano-nuclei may ultimately provide a more reliable and uniform way to trigger drug release in vivo.