Enhancing High-Intensity Focused Ultrasound for Tumor Ablation with Phase-Changing Nanoagents

 描述（由申请人提供）：随着全球癌症诊断的增加，对安全有效的治疗技术的需求不断增加。高强度聚焦超声（HIFU）是一种很有前途的选择，可以集中声能进行肿瘤的非手术消融，同时避免手术并发症和较长的恢复时间。利用HIFU，声能被递送到目标位置，并且在该过程中，通过使组织过热和/或引起机械损伤而引起必要的损伤。对于HIFU，由于声能输送要求，仍然存在关于长手术时间、高能量要求和脱靶效应（诸如皮肤灼伤）的问题。一种可以增加输送到病理部位的热量，同时减少脱靶热损伤的新技术将具有高度的临床意义。微泡已经显示出通过空化提供声能到热能和机械能的增强转换来降低能量需求的潜力。微泡直径的限制防止外渗到循环系统外，并且它们的薄壳使它们在体内的半衰期非常短。相变纳米试剂是超声领域的一种新型纳米粒子，它可以通过将微泡的气核压缩成液体来制备。这些药剂具有几百纳米的直径范围，由于增强的渗透性和保留（EPR）效应，可能能够通过肿瘤的渗漏脉管系统外渗并在肿瘤中积聚。在以下建议中，我们的目标是优化纳米制剂，并通过进一步开发PCNAs提高HIFU性能。关于评估和优化体内PCNA行为，特别是优化其外渗和积累潜力以及评估其体内循环时间，几乎没有做过什么。我们建议致力于生成PCNA，其设计为在肿瘤中积累并提供持续的肿瘤循环，其可有效地用于HIFU消融。通过改变所用的全氟化碳气体的类型、PCNA制剂的直径分布和壳的组成，可以改变PCNA的性质。用于HIFU的理想纳米剂将具有长循环时间、肿瘤内长积累时间和肿瘤内几乎没有沉积的性质。 健康的组织，并在目标处增强消融，同时具有最小的脱靶损伤。将在小鼠黑素瘤肿瘤的治疗中测试PCNA制剂以检验该假设。希望所有三个目标的成功完成将证明纳米药物的多功能性，并推动PCNA技术在超声治疗和诊断成像中的临床应用。

 DESCRIPTION (provided by applicant): The demand for safe and effective therapeutic technology continues to increase as worldwide cancer diagnoses increase. High intensity focused ultrasound (HIFU) is a promising option to focus acoustic energy for non-surgical ablation of tumors, while avoiding surgical complications and long recovery times. With HIFU, acoustic energy is delivered to a target location, and in the process, causes warranted damage by over-heating the tissue and/or causing mechanical injury. There remain concerns with HIFU regarding long surgical time, high energy requirements, and off-target effects, such as skin burns, due to acoustic energy delivery requirements. A new technology which could increase the amount of heating delivered to the site of pathology, while reducing off-target thermal damage would be highly clinically significant. Microbubbles have shown potential to decrease energy requirements by providing enhanced conversion of acoustic energy to thermal and mechanical energy through cavitation. Limitations in microbubble diameter prevent extravasation outside the circulatory system, and their thin shells give them a very short half-lif in vivo. Phase-changing nanoagents (PCNAs), a novel nanoparticle in the field of ultrasound, can be developed by compressing the gas-core of microbubbles into a liquid. These agents possess a diameter range of several hundred nanometers, likely capable of extravasating through the leaky vasculature of tumors and accumulating in tumors due to the enhanced permeability and retention (EPR) effect. In the following proposal we aim to optimize nanoagent formulation and improve HIFU performance through further development of PCNAs. Little has been done in regards to evaluating and optimizing in vivo PCNA behavior, specifically optimizing their extravasation and accumulation potential as well as evaluating their circulation time in vivo. We propose to work towards generation of a PCNA designed to accumulate in tumors and provide sustained tumor circulation, which can be used for HIFU ablation effectively. PCNA properties will be modified by varying the type of perfluorocarbon gas used, the diameter distribution of PCNA formulation, and the shell composition. Ideal nanoagents for HIFU will have properties of long circulation time, long accumulation time inside tumors with little deposition in healthy tissue, and enhanced ablation at the target with minimal off-target damage. PCNA formulations will be tested in the treatment of mouse melanoma tumors to test this hypothesis. It is the hope that the successful completion of all three proposed aims will demonstrate the versatility of the nanoagents and advance the PCNA technology for clinical applications in ultrasound for therapy and diagnostic imaging.