Enhancing ultra-sound-mediated tumor ablation with phase-shift nanoemulation

描述(申请人提供)：利用相移纳米乳剂增强超声介导性肿瘤消融已有文献证明微泡可增强组织对超声波的吸收。因此，有可能提高治疗的效率和临床实用性。 超声消融通过在肿瘤内引入或产生微泡来治疗癌症。不幸的是，在组织中产生气泡所需的压力超过100个大气压，产生的气泡在碎裂成更小、反应较慢的气体之前会猛烈坍塌并机械地损坏组织。为了降低体内气泡形成所需的压力，我们开发了一种液体全氟碳相移纳米乳液(PSNE)，它可以以可控和可预测的方式蒸发，在需要的时候随时随地形成微泡。我们在以前的研究中已经证明，PSNE可以在短声脉冲下汽化，汽化的阈值取决于液体全氟碳核心的大小、组成和环境温度。此外，我们还发现，PSNE可以通过漏水的肿瘤血管中的窗孔渗出，并用空洞核填充肿瘤间质。在声学汽化PSNE后，形成的气泡用于增强组织对传输的超声波的吸收，从而使用较短和较小功率的超声波照射来消融更大的肿瘤体积。这项工作将测试PSNE在肾癌磁共振成像和测温引导下加强无创聚焦超声热消融的应用。将进行体外和体内研究相结合的研究，以评估PSNE的生物分布和肿瘤积累作为物理化学性质的函数，确定汽化和空化阈值作为全氟碳组成的函数，评估持续空化活动和热沉积之间的空间相关性，并评估肿瘤和动物对气泡增强消融治疗的反应。

DESCRIPTION (provided by applicant): Enhancing ultrasound-mediated tumor ablation with phase-shift nanoemulsion It is well documented that microbubbles can enhance the absorption of ultrasound in tissue. Thus, it may be possible to improve the efficiency and clinical utility of ultrasound ablation for cancer therapy by introducing or creating microbubbles within the tumor. Unfortunately, the pressure required for creating bubbles in tissue exceeds 100 atmospheres, and the bubbles created collapse violently and damage tissue mechanically before fragmenting into smaller, less responsive gas bodies. In order to reduce the pressure required for bubble formation in vivo, we have developed a liquid perfluorocarbon phase-shift nanoemulsion (PSNE) that can be vaporized in a controlled and predictable manner, forming microbubbles when and where needed. We have shown in previous studies that PSNE can be vaporized with short acoustic pulses, and the threshold for vaporization depends upon the size, composition of the liquid perfluorocarbon core, and ambient temperature. Furthermore, we have shown that PSNE can extravasate through fenestrae in leaky tumor vasculature and populate the tumor interstitium with cavitation nuclei. Upon acoustic vaporization of the PSNE, the bubbles formed are used to enhance tissue absorption of transmitted ultrasound, resulting in the ablation of larger tumor volumes using shorter and less powerful ultrasound exposures. This work will test the use of PSNE to enhance noninvasive focused ultrasound thermal ablation guided by magnetic resonance imaging and thermometry in renal cancer. A combination of in vitro and in vivo studies will be conducted to assess the biodistribution and tumor accumulation of PSNE as function of physicochemical properties, identify vaporization and cavitation thresholds as a function of perfluorocarbon composition, evaluate the spatial correlation between sustained cavitation activity and heat deposition, and assess the response of tumors and animal survival to bubble-enhanced ablation therapy.