Efficacy of perfluorobutane as a phase-change contrast agent for low-energy ultrasonic imaging

Most gas-filled ultrasound contrast agents are produced range of several microns in diameter, which limits them to flow within intravascular space. One mechanism proposed to produce extravascular imaging agents is acoustic droplet vaporization. Liquid perfluorocarbon droplets can be manufactured in the sub-micron range and can then passively diffuse through leaky tumor vasculature. It is hypothesized that once extravasated, these droplets could be converted to microbubbles in the micron range through additional energy input in the form of ultrasound, resulting in enhanced imaging contrast. Recent studies show current formulations of phase-change contrast agents in the sub-micron range may require substantial acoustic energy to vaporize, which increases the chance of bioeffects. Thus, phase-change contrast agents with reduced acoustic activation energies would have significant advantages. In this study, the generation and activation of novel phase-change contrast agents formulated with perfluorobutane is demonstrated. Perfluorobutane — normally a gas at room temperature — can be incorporated into metastable liquid sub-micron droplets with lipid encapsulation methods. The resulting droplets are shown to be acoustically vaporizable with substantially less energy than other compounds proposed for phase-change contrast agents such as perfluoropentane and perfluorohexane.