Ultrasound-assisted convection-enhanced drug delivery to the brain

描述（由申请人提供）：拟议项目的目标是使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递送（CED）的有效性。CED是一种很有前途的药物递送到大脑的方法，用于治疗多种疾病，包括多形性胶质母细胞瘤，一种对患者预后特别差的高级别胶质瘤。CED通过将化合物通过针直接输注到脑实质或脑肿瘤中来绕过血脑屏障。CED已在动物和人类中进行了广泛的测试，以递送各种药剂，包括小分子、蛋白质、化疗剂和病毒载体。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输注到大脑中就控制输注材料的空间分布。因此，任何增加穿透距离并提供对输注材料的空间分布的控制的技术都可以显著提高CED在临床实践中的功效。我们先前已经表明，超声可以增强CED中输注分子的转运。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。我们已经开发了一种“智能针”，它是一种CED输注导管，在其尖端包含一个微型换能器，该换能器用作聚焦超声的信标。我们在本申请中的目标是证明TRA系统可用于将超声聚焦在与脑部病变或其他靶组织匹配的三维体积中。然后，我们将证明CED注入的流体优先填充聚焦超声的区域。将进行一系列使用人类颅骨模型的实验，以确定在具有复杂形状的体积中精确聚焦的最佳超声参数。然后，模型研究的结果将通过啮齿动物脑的体内实验来证实。这将首次证明一种控制CED中输注液体空间分布的方法，该方法有可能显著提高这种关键治疗的患者结局。 公共卫生相关性：该项目的目标是开发一种治疗性超声设备，以控制使用对流增强输送的脑灌注化疗剂的分布，用于治疗脑癌。从使用治疗性超声场控制药物分布中获得的技术、方法和知识可能具有深远的医学和研究应用。

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. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop a therapeutic ultrasound device to control the distribution of chemotherapeutic agents in the brain infused using convection enhanced delivery for the treatment of brain cancers. The technology, approach and knowledge gained from using therapeutic ultrasound fields to control drug distribution may have far reaching medical and research applications.