Acoustic activation of submicron liquid droplets for ultrasound contrast imaging

亚微米相移液滴是一类新兴的超声造影剂。与商业预成型微泡超声造影剂不同，它们相对较小的尺寸和较长的循环时间提供了通过“增强的渗透性和保留”（EPR）效应在实体瘤的结缔组织中被动积累的可能性。这些液滴可以通过暴露于外部超声而蒸发，转化为微米级气泡，可以在血管腔室外部提供对比度，以检测早期肿瘤并增强治疗生物效应，如热消融和药物输送。为了实现这种下一代超声造影剂，液滴需要足够小和稳定，以通过EPR实现被动积累。此外，液滴应该能够在诊断功率和频率的安全限度内被超声汽化。最后，所产生的间隙气泡应该足够稳定以通过超声检测，优选地使用依赖于所产生的气泡的非线性共振振荡的脉冲序列。* 尽管最近取得了进展，但亚微米液滴蒸发的基本物理学仍然知之甚少。最近的大型非挥发性微液滴的建模工作表明非线性声聚焦效应的重要性，但这仍然不能解释实验结果的较小的亚微米液滴合成低沸点的全氟化碳（PFC）。 由于负责液滴转化的精确过程仍然未知，可能涉及内在因素（例如PFC，封装材料）和外在因素（例如声音及其传播介质），因此还没有理论框架用于其最佳设计和应用。这个建议建立在我们以前的研究合成候选亚微米液滴配方，有条不紊地开发液体相移液滴作为一种新的超声造影剂。 具体如下：**1。开发和实验验证物理框架，以了解液滴的稳定性和蒸发阈值 *2。设计和优化候选液滴制剂，满足其作为超声造影剂应用所需的物理标准; i）亚微米尺寸，ii）足够的寿命，iii）在诊断限制范围内汽化，iv）产生可以用超声检测的稳定微泡 *3。合成这些候选液滴制剂，并在体外和体内环境中通过实验验证其物理设计标准 * 在完成这项工作时，我们预计将设计出适合作为下一代超声成像造影剂的亚微米液滴制剂。 从这项工作中获得的物理见解也将为未来开发具有其他设计标准的相移液滴提供信息，例如那些针对超声治疗敏化和药物输送进行优化的设计标准。

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.**