Acoustic activation of submicron liquid droplets for ultrasound contrast imaging

亚微米相移液滴是一种新兴的超声造影剂。与商用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“增强渗透性和滞留”(EPR)效应在固体肿瘤间质中被动积聚的潜力。这些液滴可以通过暴露在外部超声波中蒸发，转化为微米大小的气泡，这些气泡可以在血管腔外提供对比，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。*要实现这种下一代超声造影剂，液滴需要足够小和稳定，以使EPR能够被动积累。此外，在诊断功率和频率的安全范围内，液滴应能够被超声波蒸发。最后，产生的间质气泡应该足够稳定，可以被超声波检测到，最好使用依赖于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机制仍然知之甚少。最近对大的、非挥发性微滴的建模工作表明了非线性声聚焦效应的重要性，但这仍然不能解释由低沸点全氟碳化合物(PFC)合成的较小亚微米液滴的实验结果。由于液滴转化的确切过程尚不清楚，可能涉及内在因素(如PFC、封装材料)和外在因素(如声音及其传播介质)，因此还没有优化设计和应用的理论框架。*本建议建立在我们之前的研究基础上，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。具体来说：*1.开发和实验验证物理框架以了解液滴的稳定性和汽化阈值*2.设计和优化满足其作为超声造影剂应用所需的物理标准的候选液滴配方；I)亚微米尺寸，ii)足够长的寿命，iii)在诊断范围内蒸发，iv)产生可用超声波检测到的稳定微泡*3.合成这些候选液滴配方并在体外和体内环境中实验验证它们的物理设计准则*在本工作完成后，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配方。从这项工作中获得的物理洞察力也将为相移液滴的未来开发提供信息，并采用其他一套设计标准，例如那些为超声波治疗敏化和药物输送而优化的标准。**

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.**