Acoustic activation of submicron liquid droplets for ultrasound contrast imaging

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Submicron phase-shift liquid droplets are an emerging class of ultrasound contrast agent. Unlike commercial pre-formed microbubble ultrasound contrast agents, their relatively small size and long circulation times offer the potential to passively accumulate in the interstitium of solid tumours through the “enhanced permeability and retention” (EPR) effect. These droplets can be vaporized by exposure to external ultrasound, converting into micron-sized gas bubbles that can provide contrast outside of the vascular compartment to detect early stage tumours and potentiate therapeutic bio-effects such as thermal ablation and drug delivery.***To realize this next generation ultrasound contrast agent, droplets need to be sufficiently small and stable to enable passive accumulation by EPR. In addition, droplets should be capable of being vaporized by ultrasound within the safety limits of diagnostic power and frequency. Finally, the resulting interstitial bubbles should be stable enough to be detected by ultrasound, preferably using pulse sequences that rely of nonlinear resonant oscillation of the resulting bubbles. ***Despite recent progress, the underlying physics of submicron droplet vaporization remains poorly understood. Recent modeling work on large, non-volatile microdroplets suggest the importance of nonlinear acoustic focusing effects, however this still cannot explain experimental results on smaller submicron droplets synthesized from lower boiling-point perfluorocarbons (PFCs). As the precise process responsible for droplet conversion remains unknown, likely involving both intrinsic (e.g. PFC, encapsulation material) and extrinsic (e.g. sound and its propagation medium) factors, there is yet no theoretical framework for their optimal design and application.***This proposal builds on our previous studies synthesizing candidate submicron droplet formulations to methodically develop liquid phase-shift droplets as a new ultrasound contrast imaging agent. Specifically:***1. Develop and experimentally validate physical frameworks to understand the stability and vaporization thresholds of liquid droplets***2. Design and optimize candidate liquid droplet formulations that satisfy the physical criteria required for its application as an ultrasound contrast agent; i) submicron size, ii) sufficient longevity, iii) vaporization within diagnostic limitations, iv) result in stable microbubbles that can be detected with ultrasound***3. Synthesize these candidate droplet formulations and experimentally validate their physical design criteria in both in-vitro and in-vivo environments***At the completion of this work, we anticipate having a design for submicron liquid droplet formulations suitable as a next generation ultrasound imaging contrast agent. The physical insight derived from this work will also inform future development of phase-shift droplets with other sets of design criteria, e.g. those optimized for ultrasound therapy sensitization and drug delivery.**