"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: 10618814
• 负责人: Konstantinos-Costas Arvanitis
• 金额: $ 42.17万
• 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/10618814
• 关键词: 3-Dimensional; 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; Cephalic; 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; Genes; Glioblastoma; Glioma; Human; Intervention; Interventional Ultrasonography; Investigation; KRAS2 gene; Location; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Measurement; Measures; Mediating; Medical; Meditation; Methods; Microbubbles; Modeling; Molecular; Molecular Weight; Monitor; Mus; Mutation; Noise; Patients; Penetration; Pharmaceutical Preparations; Phase; Phenotype; Pre-Clinical Model; Proteins; Safety; Signal Transduction; Surface; System; Techniques; Technology; Testing; Therapeutic; Tissues; Translations; Ultrasonic Transducer; Work; acoustic imaging; 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; scale up; sex; spatiotemporal; translational potential; 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。经颅磁共振引导 聚焦超声（MRgFUS）是一种独特的脑内非侵入性聚焦治疗技术。增强后 FUS通过微泡促进血脑屏障（BBB）的瞬时开放，提高药物的耐受性， 在脑肿瘤中的递送。这种技术可以导致药物的递送和渗透增加超过4倍。 一系列抗癌剂，包括小分子量化学治疗剂。近期临床试验已经 证实了在临床前模型中观察到的BBB渗透性增加，证明了其安全性，并提供了 证明了它的功效。尽管这些有希望的发现，治疗不足（即中度至低度BBB）的人数 开放）和过度治疗（即MR明显的组织损伤）的FUS患者超过40%，突出了 翻译的挑战以及对新方法和技术的需求，以指导这种微创 干预如何在三维空间中映射和控制微泡是该领域的一个突出问题 这是一种介导BBB透化但不能通过MRI检测到的动力学。该提案旨在建立 基于频谱分辨被动声成像的测绘和控制新闭环方法 脑血管微泡动力学的研究此外，通过设计创新的 高灵敏度、宽带宽和自适应有源表面的接收器阵列技术，该方案将 提供所需的信噪比（SNR）和方向性，以检测产生的微弱声发射 通过FUS激发的微泡穿过人类头骨和整个大脑。这个数组， 建议的闭环方法，将被集成到一个MRgFUS相控阵，并用于表征 微泡振动通过人体颅骨的类型和强度，将治疗窗口扩大到理论上 限值（即单个微泡检测），并提供局部定义和优化暴露设置的能力 在FUS干预期间。除了用于安全和稳健的BBB打开的最佳曝光设置之外， 评估和定量FUS介导的BBB通透性变化对于鉴别肿瘤至关重要， 和药物特异性治疗窗口。通过认识到跨越BBB的运输是双向的， 假设癌症可溶性分子可以提供一种简单、安全和有效的方法， 评估FUS介导的BBB通透性变化，并能够监测对治疗的反应。 因此，通过整合生物分析和计算方法，该建议旨在建立一个最低限度的 侵入性测定以指导脑中的FUS干预。如果成功，所提出的方法、技术和 这些发现将在胶质母细胞瘤模型中用小分子量化疗剂进行测试 并且在临床相关条件下，不仅能够将肿瘤杀伤分子递送到高级别的细胞， 神经胶质瘤，但也促进成功翻译这种潜在的变革FUS干预临床。