Pulsed High Intensity Focused Ultrasound Mediated Nanoparticle Delivery: Mechanisms and Efficacy in Murine Muscle

Abstract

High intensity focused ultrasound (HIFU) is generally thought to interact with biological tissues in two ways: hyperthermia (heat) and acoustic cavitation. Pulsed mode HIFU has recently been demonstrated to increase the efficacy of a variety of drug therapies. Generally, it is presumed that the treatment acts to temporarily increase the permeability of the tissue to the therapeutic agent, however, the precise mechanism remains in dispute. In this paper, we present evidence precluding hyperthermia as a principal mechanism for enhancing delivery, using a quantitative analysis of systemically administered fluorescent nanoparticles delivered to muscle in the flanks of mice. Comparisons were carried out on the degree of enhancement between an equivalent heat treatment, delivered without ultrasound, and that of the pulsed-HIFU itself. In the murine calf muscle, pulsed-HIFU treatment resulted in a significant increase in distribution of 200 nm particles (p<0.016, N=6), while the equivalent thermal dose showed no significant increase. Additional studies using this tissue/ agent model also demonstrated that the pulsed HIFU enhancing effects persist for more than 24 hours, which is longer than that of hyperthermia and acoustic cavitation, and offers the possibility of a novel third mechanism for mediating delivery.

Pulsed focused ultrasound exposures enhance locally administered gene therapy in a murine solid tumor model

“…More detailed investigations on their contributions for similar purposes (i.e., enhancing permeability) were recently carried out, where the evidence collected appears to point to a more minor or even insignificant role for either mechanism (O'Neill et al, 2009;Hancock et al, 2009). …”

Localized micro‐scale disruption of cells using laser‐generated focused ultrasound

“…The LGFU technique might also be promising for delivery of other agents, such as nano-particles, which can be useful for controlled drug release. Conventionally, pulsed HIFU systems have been used already with some success to enhance localized nano-particle delivery into tissues [23,24]. For the biomolecule delivery, the pulsed approach is preferred to avoid irreversible thermal deformation of cells and tissues.…”

An MRI‐compatible system for focused ultrasound experiments in small animal models

“…The interleaved sonication strategy can also be extended to other applications requiring intermittent pulses of ultrasound in locations other than the brain. 30,31 Beyond BBB disruption, this system has applications in a range of therapeutic ultrasound experiments. In particular, the system can be used to deliver continuous exposures of ultrasound precisely to soft tissue targets for heating and other bioeffects in raster, scanned, or other spatial patterns.…”