Enhanced in vivo and in vitro high intensity focused ultrasound ablation via phase-shift nanodroplets compared to microbubbles

Abstract

Both pefluorocarbon microbubbles and nanodroplets have been investigated as enhancers of high intensity focused ultrasound (HIFU) thermal ablation, however microbubbles often lead to surface or skin lesions. We have designed and investigated a dual-perfluorocarbon (PFC) nanodroplet which has the benefits of sufficiently small size to extravasate from tumors, enhanced stability at body temperature, and sufficiently low acoustic threshold for vaporization. In vitro, microbubbles enhanced thermal depostion at the target site by 21%, but were found to cause surface heating up to 60.2±2.2°C. Nanodroplets caused no more surface heating (10.1±1.1°C) than the temperature rise observed in agent-free controls (9.8±0.8°C), and enhanced heating at the target by 51%. Circulation time of the nanodroplets was investigated in vivo. HIFU (1 MHz, 4.06 MPa, CW, 15 seconds) was applied to rat livers (n=3) up to 95 minutes after nanodroplet injection, and any thermal enhancement was detected simultaneously by MR thermometry. Temperature rises of up to 55 degrees above body temperature were observed out to 95 minutes. HIFU applied to control livers without nanodroplets induced only a 22°C maximal temperature rise. These results suggest that the nanodroplets are sufficiently stable to enhance HIFU ablation in vivo for at least 1.5 hours and could reduce focused ultrasound surgical procedure times by as much as 5 fold by more quickly ablating a larger region of tissue, without compromising safety.