Ultrasound-assisted convection-enhanced drug delivery to the brain

描述(申请人提供)：该项目的目标是利用超声的时间反转声学(TRA)聚焦来提高对流增强药物向大脑输送(CED)的有效性。CED是一种很有前途的脑内给药方法，用于治疗几种疾病，包括多形性胶质母细胞瘤，这是一种高度恶性的胶质瘤，患者的预后特别差。CED通过针头将化合物直接注入脑实质或脑瘤，从而绕过血脑屏障。CED已经在动物和人类中进行了广泛的测试，以输送各种药物，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，一旦输注材料被注入大脑，治疗的结果很大程度上取决于对其空间分布的控制。因此，任何增加穿透距离和控制输液材料空间分布的技术都可以在临床上显著提高CED的疗效。我们之前已经证明，超声波可以增强CED中输注的分子的运输。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，特别是在回声腔内，如颅骨。我们已经开发出一种“智能针”，这是一种CED输液导管，其尖端包含一个微型换能器，充当聚焦超声的信标。我们在这项应用中的目标是证明TRA系统可以用于聚焦与大脑中的病变或其他目标组织匹配的三维体积的超声波。然后，我们将演示由CED注入的液体优先填充聚焦超声的区域。将利用人体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在啮齿动物大脑中的活体实验来证实。这将是第一次展示一种方法来控制CED中输液的空间分布，这有可能显著提高这种关键治疗的患者结果。

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.