High-intensity focused ultrasound ablation enhancement in vivo via phase-shift nanodroplets compared to microbubbles

Abstract

BackgroundDuring high-intensity focused ultrasound (HIFU) surgical procedures, there is a need to rapidly ablate pathological tissue while minimizing damage to healthy tissue. Current techniques are limited by relatively long procedure times and risks of off-target heating of healthy tissue. One possible solution is the use of microbubbles, which can improve the efficiency of thermal energy delivery during HIFU procedures. However, microbubbles also suffer from limitations such as low spatial selectivity and short circulation time in vivo. In this study, the use of a dual-perfluorocarbon nanodroplet that can enhance thermal ablation, yet retains high spatial selectivity and circulation half-life, was evaluated in vivo and compared to traditional microbubble agents during HIFU ablations of rat liver.MethodsHigh-intensity focused ultrasound (1.1 MHz, 4.1 MPa, 15-s continuous wave) was applied to rat liver in vivo, and heating was monitored during sonication by magnetic resonance thermometry. Thermometry data were analyzed to quantify temperature rise and ablated area, both at the target and prefocally, for HIFU applied 5, 15, or 95 min after intravenous injection of either nanodroplet or microbubble agents. Sham control experiments (no injected agents) were also performed.ResultsAt all three time points, nanodroplets significantly enhanced thermal delivery to the target, achieving temperatures 130 % higher and ablated areas 30 times larger than no-agent control sonications. Nanodroplets did not significantly enhance off-target surface heating. Microbubbles also resulted in significantly greater thermal delivery, but heating was concentrated at the proximal surface of the animal, causing skin burns. Furthermore, microbubbles resulted in lower thermal delivery to the desired target than even the control case, with the notable exception of the 95-min time point.ConclusionsResults indicate that the nanodroplet formulation studied here can substantially increase thermal delivery at the acoustic focus while avoiding prefocal heating. In contrast, microbubbles resulted in greater prefocal heating and less heating at the target. Furthermore, nanodroplets are sufficiently stable to enhance HIFU ablation in vivo for at least 1.5 h after injection. The use of a dual-perfluorocarbon nanodroplet formulation as described herein could substantially reduce HIFU procedure times without increasing the risk of skin burns.

Nonthermal ablation of deep brain targets: A simulation study on a large animal model

“…This finding may be a result of shielding caused by microbubbles in the prefocal and focal regions 55 . We also did not observe enhancement in white matter in the prefocal region.…”

“…This finding may be a result of shielding caused by microbubbles in the prefocal and focal regions. 55 We also did not observe enhancement in white matter in the prefocal region. This result was probably due to white matter's lower vascular density, which results in less extravasated MRI contrast agent after BBB disruption.…”

Introducing clinical protocol for ultrasound-guided high-intensity focused ultrasound ablation of uterine fibroids in patients in Europe, provided from experienced Chinese center-prospective comparative

“…A reduction of up to 98% in myoma volume and symptoms has been reported with MRI-guided HIFU for symptomatic myomas [7]. To increase the therapeutic efficiency of HIFU in achieving large ablation volume rapidly, various ultrasound contrast agents have been used with heating and cavitation effects, by modifying the acoustic environment in various tissues [8][9][10][11][12][13][14][15]. Among these, a phospholipid-shelled ultrasound contrast agent containing sulfur hexafluoride (SonoVue) is widely applied for diagnosis or evaluation after local ablation therapy in clinical settings, and assessed for enhancing the ablative effects of HIFU treatment [11,16,17].…”

High-intensity focused ultrasound-triggered nanoscale bubble-generating liposomes for efficient and safe tumor ablation under photoacoustic imaging monitoring

“…Since they are unable to access tumor interstitial spaces, they could shift the target area of HIFU ablation or increase the temperature and damage normal tissue. 4 One group recently attempted to use perfluorocarbon nanoparticles to improve HIFU treatment and obtained good synergistic effects. 5 The nanoparticles are very stable and can extravasate through leaky tumor vessels and accumulate in the tumor interstitial space, leading to an enhanced permeability and retention (EPR) effect that helps overcome the deficiencies of microbubbles.…”

“…To overcome these problems, some researchers prepared liquid perfluorocarbon nanoparticles with a liquid core to make them stable in the blood circulation and accumulate in tumor interstitial space by the EPR effect. 4,5 When HIFU ablated the tumor, these nanoparticles would turn into microbubbles through acoustic droplet vaporization, further enhancing the HIFU effect. However, not all the nanoparticles will collect in the tumor interstitial space; some nanoparticles will still circulate in the tumor vasculature.…”