Technology for controlling ultrasound targeted drug delivery in brain

控制脑内超声靶向药物输送的技术

• 批准号: 8506193
• 负责人: Nathan J. McDannold
• 金额: $ 36.51万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-05 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8506193
• 关键词: Ablation; Acoustics; Address; Animal Disease Models; Animal Model; Animals; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Blood flow; Brain; Brain Neoplasms; Cerebrovascular Circulation; Characteristics; Clinic; Clinical; Clinical Treatment; Clinical Trials; Contrast Media; Data; Development; Devices; Disease; Dose; Drug Delivery Systems; Drug Targeting; Ensure; Evaluation; Focused Ultrasound Therapy; Frequencies; Grant; Human; Image; Instruction; Left; Macaca; Magnetic Resonance; Magnetic Resonance Imaging; Maps; Mass Spectrum Analysis; Measurement; Measures; Methods; Microbubbles; Modeling; Monitor; Neuraxis; Neurosciences; Outcome; Patients; Permeability; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Procedures; Property; Radiation; Rattus; Rodent; Safety; Schedule; Sonication; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stream; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Tracer; Translating; Ultrasonic Therapy; Ultrasonography; Work; acoustic imaging; base; cranium; density; design; detector; effective therapy; imaging modality; improved; local drug delivery; nonhuman primate; prevent; research study; sensor; targeted delivery; tool; treatment planning; tumor; validation studies; Ablation; Acoustics; Address; Animal Disease Models; Animal Model; Animals; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Blood flow; Brain; Brain Neoplasms; Cerebrovascular Circulation; Characteristics; Clinic; Clinical; Clinical Treatment; Clinical Trials; Contrast Media; Data; Development; Devices; Disease; Dose; Drug Delivery Systems; Drug Targeting; Ensure; Evaluation; Focused Ultrasound Therapy; Frequencies; Grant; Human; Image; Instruction; Left; Macaca; Magnetic Resonance; Magnetic Resonance Imaging; Maps; Mass Spectrum Analysis; Measurement; Measures; Methods; Microbubbles; Modeling; Monitor; Neuraxis; Neurosciences; Outcome; Patients; Permeability; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Procedures; Property; Radiation; Rattus; Rodent; Safety; Schedule; Sonication; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stream; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Tracer; Translating; Ultrasonic Therapy; Ultrasonography; Work; acoustic imaging; base; cranium; density; design; detector; effective therapy; imaging modality; improved; local drug delivery; nonhuman primate; prevent; research study; sensor; targeted delivery; tool; treatment planning; tumor; validation studies

We have developed a technique that combines ultrasound bursts with a microbubble agent to temporarily disrupt the blood-brain barrier (BBB). The BBB normally protects the brain by excluding entry to most substances from the blood stream and is the primary hurdle to the use of therapeutic agents in the central nervous system. The ability to use focused ultrasound-induced BBB disruption (FUS-BBBD) to target drugs to desired volumes in the brain, along with devices that can safely and precisely focus ultrasound energy through the human skull, presents a potentially huge advance neuroscience. The method can also increase the permeability of the "blood-tumor barrier", which retains many characteristics of the normal BBB and significantly impedes the adequate delivery of chemotherapeutics into brain tumors. We aim to overcome the major remaining limitations in translating FUS-BBBD to the clinic: the lack of effective methods to control the procedure. We also hypothesize that we can utilize imaging methods to predict drug concentrations at each target. To address these needs, we will develop and validate a comprehensive set of tools to provide effective treatment planning, monitoring, and evaluation for FUS-BBBD. For planning (Aim 1), we will use Magnetic Resonance Acoustic Radiation Force Imaging and cerebral blood flow imaging to provide measurements that reflect the local ultrasound intensity and the vascular density. We expect these factors to be predictive of the BBBD magnitude and can provide an initial estimate for the ultrasound exposure level. In Aim 2, we will optimize, build, and test passive cavitation detectors to monitor the acoustic emission produced by the microbubbles in the ultrasound field. This emission contains information that will be used as a real-time safety monitor and as an online means to refine the ultrasound exposure level so that it is sufficient to produce robust BBBD. Finally, for treatment evaluation (Aim 3), we will compare the delivery of drugs and other substances after FUS-BBBD to that of an MRI contrast agent using mass spectroscopy imaging. This work will provide a framework to "calibrate" the post-FUS imaging so that we can make quantitative estimates of local drug delivery based on the surrogate measurements of the contrast agent. Being able to not only target the delivery of drugs noninvasively, but to also quantify the amount of drug delivered will bring a new level of control over drug therapy, allow for optimal dosing, and ensure treatment consistency. The methods will be tested in the brains of rodents and non-human primates, and their ability to ensure a consistent therapeutic outcome will be validated in two brain tumor models. Overall, if we are successful, this work will provide the tools needed to make FUS-BBBD safer and more controlled.

我们已经开发了一种将超声爆发与微泡剂相结合的技术 破坏血脑屏障（BBB）。 BBB通常通过排除大多数物质来保护大脑 从血流中，是中枢神经中使用治疗剂的主要障碍 系统。使用聚焦超声诱导的BBB破坏（FUS-BBBD）的能力将药物靶向 大脑中所需的体积，以及可以安全，精确聚焦超声能量的设备 通过人类头骨，提出了潜在的巨大进步神经科学。该方法也可以增加 “血肿瘤屏障”的渗透性保留了正常BBB的许多特征，并且显着 阻碍了将化学治疗剂的足够递送到脑肿瘤中。我们旨在克服 将FUS-BBBD转换为诊所的主要剩余局限性：缺乏控制的有效方法 程序。我们还假设我们可以利用成像方法来预测每种药物的浓度 目标。为了满足这些需求，我们将开发并验证一套全面的工具以提供有效 FUS-BBD的治疗计划，监测和评估。对于计划（AIM 1），我们将使用磁性 共振声辐射力成像和脑血流成像以提供测量 这反映了局部超声强度和血管密度。我们希望这些因素具有预测性 BBBD的大小，可以为超声曝光水平提供初始估计。目标 2，我们将优化，构建和测试被动空化检测器，以监视由 超声场中的微泡。该排放包含将用作实时的信息 安全监控器和作为在线的在线意味着完善超声曝光水平，以便足以生产 强大的BBBD。最后，为了进行治疗评估（AIM 3），我们将比较药物和其他药物的输送 FUS-BBD后使用质谱成像的MRI对比剂的物质。这项工作 将提供一个框架来“校准”后将成像，以便我们可以进行定量估计 基于对比剂的替代测量的局部药物输送。不仅能够定位 非侵入性的药物递送，但也要量化输送的药物量将带来新的水平 控制药物疗法，允许最佳给药，并确保治疗一致性。这些方法将是 在啮齿动物和非人类灵长类动物的大脑中进行测试，并确保一致的治疗能力 结果将在两个脑肿瘤模型中得到验证。总的来说，如果我们成功，这项工作将提供 使FUS-BBBD更安全，更受控的工具。