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，其相对较小的尺寸和较长的循环时间，通过“增强渗透性和潴留”（EPR）效应，提供了被动积聚在实体肿瘤间质的潜力。这些液滴可以通过暴露于外部超声波而蒸发，转化为微米大小的气泡，可以在血管腔室外提供对比，以检测早期肿瘤，并增强治疗性生物效应，如热消融和药物输送。为了实现这种新一代超声造影剂，液滴需要足够小和稳定，以便通过EPR被动积累。此外，液滴应能够在诊断功率和频率的安全范围内被超声蒸发。最后，产生的间隙气泡应该足够稳定，可以通过超声波检测，最好使用依赖于所产生气泡的非线性共振振荡的脉冲序列。尽管最近取得了进展，亚微米液滴汽化的基本物理仍然知之甚少。最近对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，但这仍然无法解释由低沸点全氟碳化合物合成的较小亚微米微液滴的实验结果。由于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），因此尚无理论框架来优化其设计和应用。本研究是在前人研究的基础上合成候选亚微米液滴配方，以系统地开发相移液滴作为新型超声造影剂。具体: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。设计和优化候选液滴配方，满足其作为超声造影剂应用所需的物理标准；I)亚微米大小，ii)足够的寿命，iii)在诊断限制内汽化，iv)产生可以用超声波检测到的稳定微泡。合成这些候选液滴配方，并在体外和体内环境中实验验证其物理设计标准。在完成这项工作后，我们期望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见解也将为相移液滴的其他设计标准的未来发展提供信息，例如那些优化的超声治疗致敏和药物输送。

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.