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Theranostic agents are materials that act both as tracers during diagnostic imaging and as vehicles carrying and releasing therapeutics during treatment. Ultrasoundtriggered theranostic agents comprise shell-encapsulated microbubbles that pulsate during low-amplitude ultrasonic imaging and release their payload upon higher-amplitude sonication whilst simultaneously assisting in the permeation of target tissue. High-amplitude release may be undesirable due to unwanted side effects related to inertial cavitation. However, low-amplitude release from microbubbles typically requires thin encapsulating shells, which in turn may be permanently disrupted under diagnostic imaging conditions. The purpose of this study was to investigate the suitability for theranostic applications of a novel microbubble agent with thick shells composed of calcium carbonate. Hydrophobised calcium carbonate-encapsulated microbubbles of radii between 1.0 μm and 11 μm were subjected to short ultrasound pulses of 1-MHz ultrasound at acoustic amplitudes of 0.5MPa or less, which corresponds to low mechanical indices. During sonication, high-speed video footage was recorded at a frame rate of ten million frames per second. We observed pulsations but no gas release at a 0.1-MPa amplitude and intra-encapsulation fragmentation during sonication at a 0.3-MPa amplitude. At 0.5-MPa amplitude sonication, release was observed from more than 70% of the microbubbles in the field of view. This finding indicates that the microbubbles were stable scatterers during 0.1-MPa sonication, but instable vehicles during 0.5-MPa sonication. The pressures used in this study to observe release were too low to allow for unwanted inertial cavitation. In conclusion, therefore, the microbubbles studied were a promising theranostic agent whose contents could be released at moderate acoustic amplitudes.

Sonic cracking of calcium carbonate-encapsulated microbubbles observed at moderate acoustic amplitudes