title: High-intensity focused ultrasound ablation enhancement in vivo via phase-shift nanodroplets compared to microbubbles.
abstract: BACKGROUND
  During 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.
  
  
  METHODS
  High-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.
  
  
  RESULTS
  At 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.
  
  
  CONCLUSIONS
  Results 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.
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina-Chapel Hill and NC State University Campus, Box 7575, Chapel Hill, NC 27599 USA.
authors.forename: Linsey C
authors.initials: LC
authors.lastname: Moyer
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Box 800759, Charlottesville, Virginia 22908 USA.
authors.forename: Kelsie F
authors.initials: KF
authors.lastname: Timbie
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina-Chapel Hill and NC State University Campus, Box 7575, Chapel Hill, NC 27599 USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Sheeran
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Box 800759, Charlottesville, Virginia 22908 USA ; Department of Radiology and Medical Imaging, University of Virginia, Box 801339, Charlottesville, Virginia 22908 USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Price
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Box 800759, Charlottesville, Virginia 22908 USA ; Department of Radiology and Medical Imaging, University of Virginia, Box 801339, Charlottesville, Virginia 22908 USA.
authors.forename: G Wilson
authors.initials: GW
authors.lastname: Miller
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina-Chapel Hill and NC State University Campus, Box 7575, Chapel Hill, NC 27599 USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dayton
keywords: Ablation; Acoustic droplet vaporization; Decafluorobutane; Dodecafluoropentane; Focused ultrasound surgery; Nanodroplet; Nanoemulsion; Perfluorocarbon; Phase-change contrast agent