"Transcranial FUS therapy with closed-loop US image guidance and circulating tumor DNA

项目摘要 高级别胶质瘤患者的治疗仍然是一个主要的医学问题。经颅脑MR导引 聚焦超声(MRgFUS)是一种独特的非侵入性脑内局部治疗技术。在增强时 通过微泡作用，FUS可促进血脑屏障(BBB)的一过性开放，从而改善药物 在脑瘤中分娩。这项技术可以将交付和渗透率提高4倍以上 一系列抗癌药物，包括小分子化疗药物。最近的临床试验已经 证实了临床前模型中观察到的血脑屏障通透性增加，证明了其安全性，并提供了 证明其有效性的证据。尽管有这些令人振奋的发现，但未得到充分治疗(即中度至低血脑屏障)的人数 开放)和过度治疗(即磁共振明显的组织损伤)的FUS患者超过40%，突出了 翻译面临的挑战，以及对指导这种微创手术的新方法和技术的需求 干预。如何在三维空间中对微气泡进行映射和控制是该领域的一个突出问题 调节血脑屏障通透性的动力学，但MRI无法检测到。这项提案旨在建立 基于谱分辨被动声成像的新型闭环测绘与控制方法 脑血管微泡通过人体颅骨的动力学研究。此外，通过设计一种创新的 具有高灵敏度、宽带宽、自适应有源表面的接收机阵列技术，该方案将 提供所需的信噪比(SNR)和方向性，以检测产生的弱声发射 通过FUS激发的微泡穿过人的头骨和整个大脑。这个阵列，它是可服从的 将所提出的闭环系统方法，集成到MRgFUS相控阵中，并用来表征 人体颅骨微泡振动的类型和强度，将治疗窗口扩大到理论 限制(即单个微泡检测)，并提供本地定义和改进曝光设置的能力 在FUS干预期间。除了安全和坚固的BBB开口的最佳曝光设置外，纵向 评估和量化血脑屏障通透性的人为变化是识别肿瘤的关键 和药物特异性治疗窗口。通过认识到跨BBB的传输是双向的，它是 假设癌症可溶性分子可以提供一种简单、安全和有效的纵向治疗方法 评估FUS介导的血脑屏障通透性变化，并监测治疗反应。 因此，通过整合生物分析和计算方法，这项提议寻求建立一个最低限度的 指导脑内FUS干预的侵入性分析。如果成功，建议的方法、技术和 这一发现将在使用小分子化疗药物的胶质母细胞瘤模型中进行测试 而在临床相关条件下，不仅能将肿瘤杀伤分子输送到高级别 胶质瘤还有助于成功地将这种潜在的变革性FUS干预转移到临床。

Project Summary The treatment of patients with high-grade gliomas remains a major medical problem. Transcranial MR guided focused ultrasound (MRgFUS) is a unique technology for noninvasive focal therapy in the brain. When enhanced by microbubbles, FUS can promote the transient opening of the blood brain barrier (BBB) to improve drug delivery in brain tumors. This technique can lead to more than 4-fold increase in the delivery and penetration of a range of anticancer agents, including small molecular weight chemotherapeutics. Recent clinical trials have confirmed the increased BBB permeability observed in preclinical models, demonstrated its safety, and provided evidence of its efficacy. Despite these promising findings, the number of under-treated (i.e. moderate to low BBB opening) and over-treated (i.e. MR-evident tissue damage) patients with FUS is above 40%, highlighting the challenges for translation and the need for new methods and technologies for guiding this minimally invasive intervention. An outstanding question in the field is how to map and control in the 3D space the microbubble dynamics that mediate the BBB permeabilization but cannot be detected by MRI. This proposal aims to establish novel closed-loop methods based on spectrally resolved passive acoustic imaging for mapping and controlling the cerebrovascular microbubble dynamics through human skull. Moreover, by engineering an innovative receiver array technology with high sensitivity, wide bandwidth, and adaptive active surface, this proposal will provide the required signal-to-noise ratio (SNR) and directivity to detect the weak acoustic emissions generated by the FUS excited microbubbles through human skull and throughout the brain. This array, which is amenable to the proposed closed-loop methods, will be integrated to an MRgFUS phased array and used to characterize the type and strength of microbubble vibration through human skull, expand the treatment window to theoretical limits (i.e. single microbubble detection) and provide the ability to locally define and refine the exposure settings during FUS interventions. In addition to optimum exposure settings for safe and robust BBB opening, longitudinal assessment and quantification of the FUS-meditated changes in BBB permeability is crucial for identifying tumor and drug-specific treatment windows. By recognizing that the transport across the BBB is bidirectional, it is hypothesized that cancer soluble molecules can provide a simple, yet safe and effective method to longitudinally assess the FUS-mediated changes to the BBB permeability and enable monitoring the response to therapy. Thus, by integrating bioanalytical and computational methods, this proposal seeks to establish a minimally invasive assay to guide FUS-interventions in the brain. If successful, the proposed methods, technology, and findings, which will be tested in models of glioblastoma with a small molecular weight chemotherapeutic agent and under clinically relevant conditions, will not only enable the delivery of tumor killing molecules to high-grade gliomas but also facilitate the successful translation this potentially transformative FUS intervention to the clinics.