Microbubbles, Nanodroplets and Gas-Stabilizing Solid Particles for Ultrasound-Mediated Extravasation of Unencapsulated Drugs: An Exposure Parameter Optimization Study

Ultrasound-induced cavitation has been proposed as a strategy to tackle the challenge of inadequate extravasation, penetration and distribution of therapeutics into tumours. Here, the ability of microbubbles, droplets and solid gas-trapping particles to facilitate mass transport and extravasation of a model therapeutic agent following ultrasound-induced cavitation is investigated. Significant extravasation and penetration depths on the order of millimetres are achieved with all three agents, including the range of pressures and frequencies achievable with existing clinical ultrasound systems. Deeper but highly directional extravasation was achieved with frequencies of 1.6 and 3.3 MHz compared with 0.5 MHz. Increased extravasation was observed with increasing pulse length and exposure time, while an inverse relationship is observed with pulse repetition frequency. No significant cell death or any haemolytic activity in human blood was observed at clinically relevant concentrations for any of the agents. Overall, solid gas-trapping nanoparticles were found to enable the most extensive extravasation for the lowest input acoustic energy, followed by microbubbles and then droplets. The ability of these agents to produce sustained inertial cavitation activity whilst being small enough to follow the drug out of the circulation and into diseased tissue, combined with a good safety profile and the possibility of real-time monitoring, offers considerable potential for enhanced drug delivery of unmodified drugs in oncological and other biomedical applications.