Ultrasound-assisted convection-enhanced drug delivery to the brain

描述（由申请人提供）：拟议项目的目标是利用超声的时间反转声学（TRA）聚焦来提高药物向大脑的对流增强输送（CED）的有效性。CED是一种很有前途的脑内药物输送方法，可用于治疗多种疾病，包括多形性胶质母细胞瘤，这是一种对患者预后特别差的高级胶质瘤。CED绕过血脑屏障，通过针头将化合物直接注入脑实质或脑肿瘤。CED已经在动物和人类身上进行了广泛的测试，以传递各种药物，包括小分子，蛋白质，化疗药物和病毒载体。临床前和临床研究表明，治疗的结果在很大程度上取决于一旦注入物质注入大脑后对其空间分布的控制。因此，任何增加穿透距离和控制注入材料空间分布的技术在临床实践中都可以显著提高CED的疗效。我们之前已经证明超声可以增强CED中注入分子的运输。现在，我们打算使用TRA聚焦来控制注入材料的空间分布。TRA是一种在非均匀介质中聚焦超声的有效方法，特别是在混响腔（如颅骨）内。我们开发了一种“智能针”，这是一种CED输液管，其尖端包含一个微型换能器，可以作为聚焦超声的信标。我们在这个应用程序中的目标是证明TRA系统可以用于在三维体积中聚焦超声，以匹配大脑中的病变或其他目标组织。然后，我们将证明由CED注入的流体优先填充聚焦超声区域。利用人类头骨模型进行一系列实验，以确定在复杂形状的体积中精确聚焦的最佳超声参数。然后，在模型中的研究结果将通过啮齿动物大脑的活体实验得到证实。这将是首次展示一种方法来控制CED中输注液体的空间分布，这有可能显著提高这种关键治疗的患者预后。

DESCRIPTION (provided by applicant): The goal of the proposed project is to use time-reversal acoustics (TRA) focusing of ultrasound to improve the effectiveness of convection-enhanced delivery (CED) of drugs to the brain. CED is a promising method of drug delivery to the brain for the treatment of several disorders, including glioblastoma multiforme, a high-grade glioma that presents an especially poor prognosis for patients. CED bypasses the blood-brain barrier by infusing compounds through a needle directly into brain parenchyma or brain tumor. CED has been tested extensively in animals and humans to deliver a variety of agents including small molecules, proteins, chemotherapeutics, and viral vectors. Preclinical and clinical studies suggest that the outcome of the therapy depends strongly on controlling the spatial distribution of the infused material once it has been infused into the brain. Therefore, any technique that increases the penetration distance and provides control over the spatial distribution of the infused material could significantly improve the efficacy of CED in clinical practice. We have previously shown that ultrasound can enhance the transport of infused molecules in CED. Now, we intend to use TRA focusing to control the spatial distribution of the infused material. TRA is an efficient method of focusing ultrasound in heterogeneous media, especially inside reverberating cavities, such as the skull. We have developed a "smart needle" that is a CED infusion catheter containing a miniature transducer at its tip, which acts as a beacon for focusing ultrasound. Our goal in this application is to demonstrate that the TRA system can be used to focus ultrasound in three-dimensional volumes that match a lesion or other target tissue in the brain. Then, we will demonstrate that fluid infused by CED preferentially fills the regions of focused ultrasound. A series of experiments using human skull models will be carried out to determine the optimal ultrasound parameters for accurate focusing in volumes with complex shapes. Then, the results of the studies in models will be confirmed by experiments in the rodent brain in vivo. This will be first demonstration of a method to control the spatial distribution of infused fluid in CED, which has the potential to significantly enhance patient outcomes of this critical therapy.