Applications of sub-micron low-boiling point phase change contrast agents for ultrasound imaging and therapy

Phase change contrast agents (PCCAs) have been studied in the medical ultrasound field for nearly three decades. Their ability to convert from a liquid core droplet to an acoustically active microbubble has enhanced the possibilities of medical ultrasound, enabling new imaging approaches as well as therapeutic directions. However, traditional PCCAs are formulated with perfluorocarbons which are a liquid at standard temperature and pressure, requiring a high amount of energy to transition the encapsulated droplets to gas form, possibly resulting in undesired bioeffects. A new generation of low-boiling point PCCAs, which are formulated from gaseous perfluorocarbons in a metastable liquid state, seeks to overcome these limits. These super-heated liquid perfluorocarbon nanodroplets display longer circulation kinetics than microbubbles, their activation produces unique acoustic signatures, and their small particle size holds potential for extravascular applications. Low-boiling point nanodroplets can be phase-transitioned when activated with ultrasound at pressures and frequencies approved for diagnostic imaging. From the first publication almost 10 years ago, low-boiling point PCCA research has expanded rapidly, and recent advances in super-resolution imaging, drug delivery and neuromodulation made possible by these nanodroplets are just a few examples of this growing field of research. In this review, we discuss low-boiling point phase change contrast agents and their applications in ultrasound imaging and therapeutics.