Submicron decafluorobutane phase-change contrast agents generated by microbubble condensation

Microbubbles (MBs) on the order of 1 - 5 microns have the ability to circulate in the vascular space with sufficient scattering ability to be used as ultrasound contrast and molecular imaging agents. However, for the purposes of extravascular ultrasound imaging, MBs are too large to pass through the endothelial gap junctions of leaky tumor vasculature. Bubbles on the order of 100s of nanometers may extravasate, but would be too small to elicit sufficient backscatter. Previously, we developed stabilized micron-sized decafluorobutane (DFB, bp = -1.1°C) droplets via extrusion at low temperatures for acoustic droplet activation that required less activation energy than similarly sized droplets of higher boiling-point perfluorocarbons. We have extended this by developing a unique method of producing sub-micron sized DFB droplets (200 - 300 nm) that will be sufficiently stable to diffuse through endothelial gap junctions, yet labile enough to undergo ADV at relatively low acoustic intensities. This method utilizes a simple yet novel technique involving compression of pre-formed DFB MBs at reduced temperatures. The simplicity of the method shows promise for future extension to molecular imaging as well as gene/drug delivery.