Technology for controlling ultrasound targeted drug delivery in brain

我们已经开发出一种技术，将超声波爆破与微泡剂相结合， 破坏血脑屏障（BBB）。血脑屏障通常通过阻止大多数物质进入大脑来保护大脑 并且是在中枢神经系统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）靶向药物的能力， 沿着能够安全、精确地聚焦超声能量的装置 通过人类的头骨，展示了一个潜在的巨大的神经科学进步。该方法还可以增加 “血肿瘤屏障”的渗透性，其保留了正常BBB的许多特征， 阻碍了化疗药物向脑肿瘤的充分输送。我们的目标是克服 将FUS-BBBD转化为临床的主要局限性：缺乏有效的方法来控制 procedure.我们还假设，我们可以利用成像方法来预测药物浓度在每个 目标为了满足这些需求，我们将开发和验证一套全面的工具来提供有效的 FUS-BBBD的治疗计划、监测和评价。对于规划（目标1），我们将使用Magnetic 共振声辐射力成像和脑血流成像提供测量 反映局部超声强度和血管密度。我们希望这些因素能够预测 并且可以提供对超声暴露水平的初始估计。在Aim中 2、我们将优化、建造和测试被动空化探测器，以监测 超声场中的微泡。这种发射包含的信息将被用作实时 安全监测器，并作为一种在线手段，以改善超声暴露水平，使其足以产生 强大的BBBD。最后，对于治疗评估（目标3），我们将比较药物和其他药物的输送。 FUS-BBBD后的物质与使用质谱成像的MRI造影剂的物质进行比较。这项工作 将提供一个框架，以“校准”后FUS成像，使我们可以作出定量估计 基于造影剂的替代测量的局部药物递送。不仅能够瞄准 非侵入性地递送药物，而且还量化递送的药物量将带来一个新的水平， 控制药物治疗，允许最佳剂量，并确保治疗的一致性。方法将是 在啮齿动物和非人类灵长类动物的大脑中进行了测试，以及它们确保一致治疗的能力， 将在两个脑肿瘤模型中验证结果。总的来说，如果我们成功了，这项工作将提供 使FUS-BBBD更安全、更可控所需的工具。

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.