Nanoparticle-mediated Histotripsy (NMH) for Noninvasive and Targeted Ablation of Metastatic Breast Cancer

项目总结 乳腺癌是女性中最常见的恶性肿瘤，近170万名患者被诊断为乳腺癌。 每年一次。尽管目前有很有希望的治疗选择，但转移性疾病仍然是一个重要的 挑战。事实上，绝大多数乳腺癌死亡是转移和无法治愈的直接后果。 一旦发展成转移性疾病就可以使用。因此，需要新的治疗策略来消除 与转移性乳腺癌相关的死亡率。这项建议的重点是发展 纳米粒子介导的组织摩擦(NMH)作为一种非侵入性的靶向消融方法 多灶性乳腺肿瘤的治疗。组织探查是一种非侵入性、非电离和非热超声。 一种通过精确控制高能激光产生的声空化来破坏组织的消融方法 压力(&gt；25-30兆帕)脉冲。组织摩擦检查没有热消融的限制，可以产生 持续消融，即使在血管附近也是如此。组织检验法的其他优点包括高精度和实时 成像制导。然而，尽管组织摩擦检查显示出作为一种改进的消融方法的前景 治疗原发肿瘤，这种治疗方法需要很高的超声压力，并且仍然局限于 可以在治疗前识别和成像的肿瘤，这在转移性乳腺癌中通常是不可行的 多发肿瘤结节的患者。为了满足这种需求，我们团队最近发明了NMH作为一种有针对性的 全氟己烷纳米粒子联合消融治疗多灶性肿瘤 进行组织检查。NMH利用了这些粒子的空化阈值显著降低的优势， 从而允许仅在包含颗粒的区域中选择性地产生组织摩擦。在这项提案中，我们 开发NMH用于转移性乳腺肿瘤的选择性消融。在目标1中，我们设计并表征了全氟化氢 具有更小的尺寸(~50 nm)、更高的稳定性和功能化的靶向能力 我们之前测试过的粒子。Aim 2将测试这些全氟化氢“纳米锥”的体外可行性，用于靶向和 在组织工程3D乳腺癌模型中选择性地消融乳腺癌细胞。目标3将调查 NMH在小鼠原位模型中靶向消融转移性乳腺癌的体内可行性。 总之，这些研究有望证明NMH用于多焦点肿瘤消融的可行性， 对开发这项新技术的潜力至关重要。如果成功，这项工作将为 NMH作为一种靶向多焦点癌症治疗方法，能够显著提高癌症的护理水平 通过增加靶向特异性和治疗太小而无法通过成像发现的肿瘤来治疗患者。

PROJECT SUMMARY Breast cancer is the most common malignancy among women, with almost 1.7 million patients diagnosed annually. Although promising treatment options are currently available, metastatic disease remains a significant challenge. Indeed, the vast majority of breast cancer deaths are a direct consequence of metastasis and no cure is available once metastatic disease has developed. Thus, new treatment strategies are needed to eliminate mortality associated with metastatic breast cancer. This proposal is focused on the development of nanoparticle-mediated histotripsy (NMH) as a non-invasive and targeted ablation method for the treatment of multi-focal breast tumors. Histotripsy is a non-invasive, non-ionizing, and non-thermal ultrasound ablation method that destroys tissue through the precise control of acoustic cavitation generated by high- pressure (>25-30 MPa) pulses. Histotripsy does not have the limitations of thermal ablation and can produce consistent ablation, even in near vessels. Additional benefits of histotripsy include high precision and real-time imaging guidance. However, although histotripsy shows promise as an improved ablation method for the treatment of primary tumors, this treatment method requires high ultrasound pressures and remains limited to tumors that can be identified and imaged prior to treatment, which is often not feasible in metastatic breast cancer patients with multiple tumor nodules. To address this need, our team recently invented NMH as a targeted ablation approach for treating multi-focal tumors by combining perfluorohexane (PFH) nanoparticles with histotripsy. NMH takes advantage of the significantly reduced cavitation threshold of these particles, allowing for histotripsy to be selectively generated only in regions containing the particles. In this proposal, we develop NMH for the selective ablation of metastatic breast tumors. In Aim 1 we engineer and characterize PFH “nanocones” with a smaller size (~50nm), higher stability, and functionalized targeting capabilities compared to our previously tested particles. Aim 2 will test the in vitro feasibility of these PFH “nanocones” for targeting and selectively ablating breast cancer cells in a tissue engineered 3D breast cancer model. Aim 3 will investigate the in vivo feasibility of NMH for the targeted ablation of metastatic breast tumors in an orthotopic mouse model. Together, these studies are expected to demonstrate the feasibility of NMH for multi-focal tumor ablation, which is essential to establishing the potential of this new technology. If successful, this work will lay the foundation for NMH as a targeted multi-focal cancer therapy capable of significantly improving the standard of care for cancer patients by increasing targeting specificity and treating tumors too small to detect by imaging.