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

“采用闭环超声图像引导和循环肿瘤 DNA 的经颅 FUS 治疗

• 批准号: 9973375
• 负责人: Konstantinos-Costas Arvanitis
• 金额: $ 56.64万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9973375
• 关键词: 3-Dimensional; Accounting; Acoustics; Address; Animals; Antineoplastic Agents; Biological Assay; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Tests; Blood Vessels; Body Fluids; Brain; Brain Neoplasms; C57BL/6 Mouse; Cell Death; Cell Proliferation; Ceramics; Clinic; Clinical; Clinical Data; Clinical Trials; Computing Methodologies; Detection; Dimensions; Dose; Drug Delivery Systems; Drug Monitoring; Drug Targeting; Effectiveness; Electronics; Elements; Engineering; Experimental Models; Filtration; Focused Ultrasound; Focused Ultrasound Therapy; Gene Proteins; Glioblastoma; Glioma; Human; Intervention; Interventional Ultrasonography; Investigation; KRAS2 gene; Lead; Location; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Measurement; Measures; Mediating; Medical; Methods; Microbubbles; Modeling; Molecular; Molecular Weight; Monitor; Mus; Mutation; Noise; Patients; Penetration; Pharmaceutical Preparations; Phase; Phenotype; Pre-Clinical Model; Safety; Signal Transduction; Surface; System; Techniques; Technology; Testing; Therapeutic; Tissues; Translations; Ultrasonic Transducer; Work; acoustic imaging; base; blood-brain barrier permeabilization; cancer cell; cerebrovascular; chemotherapeutic agent; chemotherapy; clinically relevant; contrast enhanced; cranium; design; effective therapy; image guided; imaging modality; improved; in vivo; innovation; insight; mathematical model; minimally invasive; mouse model; novel; operation; pre-clinical; prospective; response; scale up; sex; spatiotemporal; treatment response; tumor; tumor DNA; vibration

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.

项目概要 高级别神经胶质瘤患者的治疗仍然是一个主要的医学问题。经颅磁共振引导 聚焦超声（MRgFUS）是一种独特的脑部非侵入性聚焦治疗技术。增强时 通过微泡，FUS可以促进血脑屏障（BBB）短暂开放，从而提高药效 脑肿瘤中的递送。这项技术可以使药物的输送和渗透增加 4 倍以上 一系列抗癌药物，包括小分子量化疗药物。最近的临床试验有 证实了临床前模型中观察到的 BBB 通透性增加，证明了其安全性，并提供了 其功效的证据。尽管有这些令人鼓舞的发现，但治疗不足的人数（即中度至低 BBB 开放）和过度治疗（即 MR 明显的组织损伤）患者中 FUS 的比例超过 40%，这凸显了 翻译面临的挑战以及指导这种微创治疗的新方法和技术的需求 干涉。该领域的一个突出问题是如何在 3D 空间中映射和控制微泡 介导 BBB 通透但无法通过 MRI 检测到的动力学。该提案旨在建立 基于光谱分辨被动声成像的新型闭环方法，用于测绘和控制 通过人类头骨的脑血管微泡动力学。此外，通过设计创新 具有高灵敏度、宽带宽和自适应有源表面的接收阵列技术，该提案将 提供所需的信噪比 (SNR) 和方向性来检测所产生的微弱声发射 FUS 激发微泡穿过人类头骨和整个大脑。这个数组，这是可以接受的 对于所提出的闭环方法，将集成到 MRgFUS 相控阵中并用于表征 通过人类头骨的微泡振动的类型和强度，将治疗窗口扩大到理论值 限制（即单个微泡检测）并提供本地定义和细化曝光设置的能力 FUS 干预期间。除了实现安全、稳健的 BBB 打开的最佳曝光设置外，纵向 FUS 介导的 BBB 通透性变化的评估和量化对于识别肿瘤至关重要 和药物特异性治疗窗口。通过认识到 BBB 上的传输是双向的， 假设癌症可溶性分子可以提供一种简单但安全有效的方法来纵向 评估 FUS 介导的 BBB 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，该提案旨在建立一个最小的 指导 FUS 大脑干预的侵入性测定。如果成功，所提出的方法、技术和 研究结果将在使用小分子量化疗剂的胶质母细胞瘤模型中进行测试 在临床相关条件下，不仅能够将肿瘤杀伤分子输送到高级别 神经胶质瘤，还有助于将这种潜在的变革性 FUS 干预成功转化为临床。