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Ultrasound contrast agents are known to enhance high intensity focused ultrasound (HIFU) ablation, but these perfluorocarbon microbubbles are limited to the vasculature, have a short half-life in vivo, and may result in unintended heating away from the target site. Herein, a nano-sized (100-300 nm), dual perfluorocarbon (decafluorobutane/dodecafluoropentane) droplet that is stable, is sufficiently small to extravasate, and is convertible to micron-sized bubbles upon acoustic activation was investigated. Microbubbles and nanodroplets were incorporated into tissue-mimicking acrylamide-albumin phantoms. Microbubbles or nanodroplets at 0.1 × 10(6) per cm(3) resulted in mean lesion volumes of 80.4 ± 33.1 mm(3) and 52.8 ± 14.2 mm(3) (mean ± s.e.), respectively, after 20 s of continuous 1 MHz HIFU at a peak negative pressure of 4 MPa, compared to a lesion volume of 1.0 ± 0.8 mm(3) in agent-free control phantoms. Magnetic resonance thermometry mapping during HIFU confirmed undesired surface heating in phantoms containing microbubbles, whereas heating occurred at the acoustic focus of phantoms containing the nanodroplets. Maximal change in temperature at the target site was enhanced by 16.9% and 37.0% by microbubbles and nanodroplets, respectively. This perfluorocarbon nanodroplet has the potential to reduce the time to ablate tumors by one-third during focused ultrasound surgery while also safely enhancing thermal deposition at the target site.

Perfluorocarbon microbubbles are known to enhance high intensity focused ultrasound (HIFU) ablation by cavitation. However, they can result in superficial skin heating, minimizing their clinical translation. Perfluorocarbon nanodroplets activate only at the higher pressures present at the acoustic focus. We hypothesized that a mixed perfluorocarbon nanodroplet formulation would minimize surface heating while still enhancing ablation. Tissue-mimicking phantoms containing microbubbles or nanodroplets were sonicated (1 MHz, 15 W, 60 s) to assess heating and lesion formation in vitro. Microbubbles or nanodroplets were injected into rats (n = 3) and HIFU (1 MHz, 15 W, 15 s) was focused into each liver while under MRI guidance. Temperature throughout the liver was tracked by MR thermometry. In vitro, microbubbles caused excess surface heating during HIFU, whereas nanodroplets did not. In vivo, microbubbles typically circulate for less than 15 min. In comparison, the nanodroplets remained viable in circulation for at least 96 min. HIFU lesions of consistent volume were produced during this time and reached the same maximal temperature rise (Δ550 °C). In the absence of nanodroplets or microbubbles, significantly greater power (25 W) and twice as much time (30 s) was required to generate an ablation lesion in the liver. These results demonstrate the ability of nanodroplets to more safely shorten ablation procedures.