Translational Research in Ultrasound Theranostics (TRUST) Program, Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
Biomedical Engineering Graduate Program, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
Langmuir. 2020 Mar 24;36(11):2954-2965. doi: 10.1021/acs.langmuir.9b03647. Epub 2020 Mar 9.
Phase-change perfluorocarbon microdroplets were introduced over 2 decades ago to occlude downstream vessels in vivo. Interest in perfluorocarbon nanodroplets has recently increased to enable extravascular targeting, to rescue the weak ultrasound signal of perfluorocarbon droplets by converting them to microbubbles and to improve ultrasound-based therapy. Despite great scientific interest and advances, applications of phase-change perfluorocarbon agents have not reached clinical testing because of efficacy and safety concerns, some of which remain unexplained. Here, we report that the coexistence of perfluorocarbon droplets and microbubbles in blood, which is inevitable when droplets spontaneously or intentionally vaporize to form microbubbles, is a major contributor to the observed side effects. We develop the theory to explain why the coexistence of droplets and microbubbles results in microbubble inflation induced by perfluorocarbon transfer from droplets to adjacent microbubbles. We also present the experimental data showing up to 6 orders of magnitude microbubble volume expansion, which occludes a 200 μm tubing in the presence of perfluorocarbon nanodroplets. More importantly, we demonstrate that the rate of microbubble inflation and ultimate size can be controlled by manipulating formulation parameters to tailor the agent's design for the potential theranostic application while minimizing the risk to benefit ratio.
相变全氟碳微滴在 20 多年前被引入体内以阻塞下游血管。最近，人们对全氟碳纳米液滴的兴趣增加，以实现血管外靶向，通过将其转化为微泡来增强全氟碳液滴的弱超声信号，并改善基于超声的治疗。尽管人们对此非常感兴趣并取得了进展，但由于功效和安全性方面的担忧，相变全氟碳试剂的应用尚未达到临床测试，其中一些仍未得到解释。在这里，我们报告说，当液滴自发或有意蒸发形成微泡时，血液中全氟碳液滴和微泡的共存是观察到的副作用的主要原因。我们提出了理论来解释为什么液滴和微泡的共存会导致微泡膨胀，这是由于全氟碳从液滴转移到相邻微泡而引起的。我们还展示了实验数据，表明在存在全氟碳纳米液滴的情况下，微泡的体积膨胀高达 6 个数量级，这会阻塞 200μm 的管腔。更重要的是，我们证明可以通过操纵配方参数来控制微泡膨胀的速率和最终大小，从而根据潜在的治疗应用需求来设计试剂，同时将风险收益比降至最低。
