Technology for controlling ultrasound targeted drug delivery in brain

我们已经开发出一种技术，将超声波和微气泡剂结合起来，暂时 破坏血脑屏障(BBB)。血脑屏障通常通过排除大多数物质的进入来保护大脑。 是中枢神经系统使用治疗剂的主要障碍。 系统。使用聚焦超声诱导的血脑屏障破坏(FUS-BBBD)靶向药物的能力 大脑中所需的体积，以及能够安全和精确地聚焦超声波能量的设备 通过人类的头骨，展示了一项潜在的巨大的神经科学进步。该方法还可以增加 血-肿瘤屏障的通透性，它保留了正常血脑屏障的许多特征，并显著 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转化为临床的主要剩余限制：缺乏有效的方法来控制 程序。我们还假设，我们可以利用成像方法来预测每个药物的浓度 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，以提供有效的 FUS-BBBD的治疗计划、监测和评估。对于规划(目标1)，我们将使用磁力 共振声辐射力成像和脑血流成像提供测量 以反映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，并可提供超声暴露水平的初步估计。在AIM 2、我们将优化、建造和测试被动空化探测器，以监测由 超声场中的微泡。此发射包含的信息将用作实时 安全监测和作为一种在线手段，以完善超声波暴露水平，使其足以生产 健壮的BBBD。最后，对于治疗评估(目标3)，我们将比较药物和其他 利用质谱学成像将FUS-BBBD后的物质与MRI造影剂的物质进行比较。这部作品 将提供一个“校准”FUS后成像的框架，以便我们可以对 基于造影剂替代测量的局部药物传递。不仅能够瞄准 非侵入性地输送药物，但也量化输送的药物的量将带来新的水平 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测试，以及它们确保一致的治疗方法的能力 结果将在两个脑瘤模型中得到验证。总体而言，如果我们成功，这项工作将提供 使FUS-BBBD更安全和更可控所需的工具。

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.