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

描述（由申请人提供）：用相移纳米乳液增强超声介导的肿瘤消融有充分的证据表明，微泡可以增强超声在组织中的吸收。因此，有可能提高免疫调节剂的效率和临床效用。 超声消融通过在肿瘤内引入或产生微泡用于癌症治疗。不幸的是，在组织中产生气泡所需的压力超过100个大气压，并且所产生的气泡在破碎成较小的、响应性较低的气体体之前剧烈地塌陷并机械地损伤组织。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化碳相移纳米乳液（PSNE），它可以以可控和可预测的方式蒸发，在需要时形成微泡。我们已经表明，在以前的研究中，PSNE可以用短的声脉冲蒸发，蒸发的阈值取决于大小，组成的液体全氟化碳核心，和环境温度。此外，我们已经表明，PSNE可以通过渗漏的肿瘤血管系统中的窗孔外渗，并以空化核填充肿瘤细胞。在PSNE的声汽化后，形成的气泡用于增强组织对所发射的超声的吸收，从而导致使用较短和较低功率的超声暴露来消融较大的肿瘤体积。这项工作将测试使用PSNE，以加强非侵入性聚焦超声热消融引导下的磁共振成像和测温在肾癌。将进行体外和体内研究的组合，以评估PSNE的生物分布和肿瘤蓄积作为理化性质的函数，确定汽化和空化阈值作为全氟化碳成分的函数，评价持续空化活性和热沉积之间的空间相关性，并评估肿瘤和动物存活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.