"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.

项目摘要 高级神经胶质瘤患者的治疗仍然是一个主要的医学问题。经颅MR指导 聚焦超声（MRGFUS）是用于大脑非侵入性局灶性治疗的独特技术。增强时 通过微泡，FUS可以促进血脑屏障（BBB）的瞬时开放以改善药物 在脑肿瘤中递送。该技术可以导致交付和穿透的4倍以上 一系列抗癌药，包括小分子量化学治疗药。最近的临床试验有 确认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 其功效的证据。尽管有这些有希望的发现，但未经处理的数量（即中度至低BBB） 开放）和过度治疗（即MR-Eventer Tissue损害）FUS患者超过40％，突出显示了 翻译的挑战以及对指导这种微创的新方法和技术的需求 干涉。该领域的一个出色问题是如何在3D空间中映射和控制微泡 介导BBB通透性但MRI无法检测到的动力学。该建议旨在建立 新型闭环方法基于用于映射和控制的光谱分辨的无源声学成像 通过人头骨的脑血管微气泡动力学。而且，通过工程创新 接收器阵列技术具有高灵敏度，宽带宽度和自适应活动表面，该建议将 提供所需的信噪比（SNR）和方向性，以检测产生的弱声学排放 通过FUS激发的微泡穿过人类头骨和整个大脑。这个阵列，这是可正常的 针对拟议的闭环方法，将集成到MRGFUS分阶段阵列中，并用于表征 通过人头骨的微泡振动的类型和强度，将治疗窗口扩展到理论 限制（即单个微泡检测），并提供了局部定义和完善曝光设置的能力 在FUS干预期间。除了最佳的曝光设置，以确保BBB开放，纵向 对BBB渗透率的FUS含量变化的评估和定量对于鉴定肿瘤至关重要 和特定药物的治疗窗口。通过认识到跨BBB的运输是双向的，它是 假设癌症可溶性分子可以为纵向提供一种简单但安全有效的方法 评估FUS介导的BBB渗透性的变化，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，该提案旨在建立最小的 侵入性测定以指导大脑中的FUS干扰。如果成功，提议的方法，技术和 发现，将在具有小分子量化学治疗剂的胶质母细胞瘤模型中进行测试 在临床上相关的条件下，不仅将使肿瘤杀伤分子递送到高级 神经胶质瘤，但也有助于成功地翻译这种潜在的转化FUS干预到诊所。