An in vitro study of a phase-shift nanoemulsion: a potential nucleation agent for bubble-enhanced HIFU tumor ablation

Phase-shift nanoemulsions have the potential to nucleate bubbles and enhance high-intensity focused ultrasound (HIFU) cancer therapy. This emulsion consists of albumin-coated dodecafluoropentane (DDFP) droplets with a mean diameter of approximately 260 nm at 37°C. It is known that superheated perfluorocarbon droplets can be vaporized with microsecond long ultrasound pulses if the acoustic pressure exceeds a specific threshold. In addition, it is well documented that particles smaller than 400 nm can extravasate through leaky tumor vessels and accumulate in the tumor interstitial space. Thus, nanoemulsions may passively target solid tumors, thus localizing cavitation nuclei for bubble-enhanced HIFU-mediated heating. In this study, we investigate the acoustic droplet vaporization of a DDFP nanoemulsion in tissue-mimicking gels and demonstrate the ability to nucleate inertial cavitation (IC) and enhance HIFU-mediated heating. The nanoemulsion was dispersed throughout albumin-acrylamide gel phantoms and sonicated with microsecond-length HIFU pulses (f = 2 MHz). The pressure threshold needed to vaporize the nanoemulsion was measured as a function of degree of superheat, pulse length and nanoemulsion concentration. It was determined that the vaporization threshold was inversely proportional with degree of superheat and independent of pulse length and concentration within the range of values tested. It was also shown that the bubbles formed from vaporized nanoemulsions reduced the IC threshold in the gel phantoms. Finally, it was demonstrated that cavitation from vaporized nanoemulsions accelerated HIFU-mediated heating. The results from this study demonstrate that phase-shift nanoemulsions can be combined with HIFU to provide a high degree of spatial and temporal control of bubble-enhanced heating.