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持续增加。高强度聚焦超声(HIFU)是一种很有前途的选择，用于非手术消融肿瘤的声能，同时避免了手术并发症和较长的恢复时间。使用HIFU，声波能量被传递到目标位置，在这个过程中，通过过热组织和/或导致机械损伤而造成必要的损害。由于声能传递的要求，HIFU仍然存在手术时间长、能量要求高以及非靶点效应，如皮肤烧伤等问题。一种新的技术可以增加向病变部位输送的热量，同时减少目标外的热损害，这将具有非常重要的临床意义。微气泡通过空化将声能转化为热能和机械能，从而显示出降低能量需求的潜力。微泡直径的限制防止了循环系统外的渗出，它们的薄壳使它们在体内的半衰期非常短。相变纳米粒子(PCNAs)是超声领域的一种新型纳米粒子，可以通过将微泡的气核压缩成液体来制备。这些药物的直径范围为数百纳米，由于增强的通透性和滞留(EPR)效应，很可能能够通过肿瘤渗漏的血管系统渗出并在肿瘤中积累。在下面的提案中，我们的目标是通过进一步开发PCNAs来优化纳米制剂的配方和提高HIFU的性能。在评估和优化体内增殖细胞核抗原的行为，特别是优化它们的外渗和蓄积潜力以及评估它们在体内的循环时间方面，几乎没有做过什么工作。我们建议致力于产生一种增殖细胞核抗原，旨在积聚在肿瘤中，并提供持续的肿瘤循环，可以有效地用于HIFU消融。通过改变所使用的全氟化碳气体的类型、增殖细胞核抗原配方的直径分布和壳层成分来改变增殖细胞核抗原的性能。理想的HIFU纳米制剂具有循环时间长、在肿瘤内蓄积时间长、沉积少等特点。 健康的组织，并加强了对目标的消融，最大限度地减少了目标外的损害。为了验证这一假设，将在治疗小鼠黑色素瘤的过程中测试增殖细胞核抗原的配方。希望所有这三个目标的成功完成将展示纳米试剂的多功能性，并推动增殖细胞核抗原技术在超声治疗和诊断成像方面的临床应用。

 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.