Contrast-Enhanced Ultrasound Imaging and in Vivo Circulatory Kinetics with Low-Boiling-Point Nanoscale Phase-Change Perfluorocarbon Agents

Abstract

Many studies have explored phase-change contrast agents (PCCAs) that can be vaporized by an ultrasonic pulse to form microbubbles for ultrasound imaging and therapy. However, few investigations have been published demonstrating the utility and characteristics of PCCAs as contrast agents in vivo. In this study, we examine the properties of low boiling point nanoscale PCCAs evaluated in vivo, and compare data to conventional microbubbles with respect to contrast generation and circulation properties. In order to do this, we develop a custom pulse sequence to vaporize and image PCCAs using the Verasonics research platform and a clinical array transducer. Results show that droplets can produce similar contrast enhancement to microbubbles (7.29 to 18.24 dB over baseline, depending on formulation), and can be designed to circulate for as much as 3.3 times longer than microbubbles. This study also demonstrates for the first time the ability to capture contrast wash-out kinetics of the target organ as a measure of vascular perfusion.

In vitro methods to study bubble-cell interactions: Fundamentals and therapeutic applications

“…2.A.a), which vaporize to form microbubbles upon injection into the body or subsequently to exposure to ultrasound. The fluids commonly chosen are octafluoropropane, decafluorobutane, or dodecafluoropentane 127 that have boiling points of À37 C, À4 C, and 29 C, respectively. These boiling points are lower than normal body temperature, so that these fluids become superheated in vivo.…”

“…This facilitates imaging and/or treatment, e.g., within a tumor mass. 127,128 The interest of using such precursors lies in the injection in the bloodstream of a nanosized agent that is able to extravasate through large pores as typically found in tumor blood vessels (EPR (enhanced permeability and retention) effect 129 ). Upon vaporization, the resulting micronsized bubbles can interact with the deeper-lying tissue.…”

Wideband acoustic activation and detection of droplet vaporization events using a capacitive micromachined ultrasonic transducer

“…16 This leads to a rapid increase in core volume resulting in the production of microbubble contrast agents having contrast properties similar to those currently used for diagnostic applications. 17,18 Moreover, the mechanical perturbations produced during the ADV process could induce bioeffects on nearby cells and enhance localized drug delivery. 19 To date, only few studies have investigated the bioeffects related to ADV.…”

Ultrasound contrast agents: bubbles drops and particles

“…The fluids commonly chosen are octafluoropropane, decafluorobutane or dodecafluoropentane 114 that have boiling points of -37 • C, -4 • C and 29 • C. These boiling points are lower than normal body temperature, thus these fluids become superheated in vivo. These perfluorinated liquids present a number of advantages: first they have a tunable boiling point depending on the carbon chain length that falls precisely in the range that is relevant for medical application.…”

“…This implies that the surfactant initially stabilizing the droplet can also stabilize the bubble and support non-linear oscillations 117 . Perfluorocarbon droplets also offer the potential to be used as multi-modality agents since they can be activated using ultrasound 114,116,117 but also using light when internally loaded with plasmonic nanoparticles 118 , which leads to an increase in photoacoustic contrast and the creation of a ultrasound microbubble contrast agent simultaneously. 13 …”