Intranasal delivery through the blood-brain barrier using focused ultrasound

 描述（由申请人提供）：聚焦超声（FUS）结合微泡仍然是唯一可以无创和区域性诱导局部BBB开放的技术。鼻内（IN）给药已成为一种有前途的药物递送到大脑的方法。传统上，它已成功地用作将药物递送至体循环的方便方法，因为IN施用的药物可通过鼻腔中丰富的血管网络吸收到体循环中。尽管大多数吸收到血液循环中的药物由于BBB而无法进入脑实质，但动物和临床研究已证明药物可以绕过BBB直接从鼻子输送到大脑是可行的。在过去的几年里，我们的团队已经证明，在与神经退行性疾病相关的特定皮质下区域，使用FUS和静脉（IV）给药的微泡可以可重复地打开BBB。已显示0.5kDa-4 MDa量级的分子，包括葡聚糖、神经营养因子和病毒载体，被成功递送并定位在神经元的细胞内空间内，触发神经元细胞内的信号传导途径。在这项研究中，我们假设BBB开放可以完全非侵入性地应用（即，免注射），同时降低全身毒性的风险。因此，首次将FUS和鼻内递送相结合，以提高鼻内给药药物向靶向区域的递送效率，而纳米液滴（ND）由于其较小的尺寸而替代微泡，这应有助于鼻内递送（FUS+IN+ND）。我们提出开发一种用于trans-BBB递送的完全非侵入性方法，其提供以下优点：1）由于鼻内（吸入）施用而提供的无注射方法，2）由于所使用的纳米液滴媒介物而具有更高的选择性，以及3）由于鼻内和纳米液滴方法而具有更低的毒性。因此，具体目的是：1）证明使用鼻内施用的纳米液滴打开BBB的可行性; 2）证明在帕金森病小鼠模型中促进蛋白质和基因治疗的功效。与FUS组合的媒介物（纳米液滴）和药物（蛋白质或病毒）两者的鼻内递送可以提供对当前使用的方法的完全非侵入性的、更有针对性的和毒性更小的替代方案，从而促进临床转化和接受。

 DESCRIPTION (provided by applicant): Focused Ultrasound (FUS), in conjunction with microbubbles, remains the sole technique that can induce localized BBB opening noninvasively and regionally. Intranasal (IN) administration has emerged as a promising approach for drug delivery to the brain. Traditionally, it has been successfully used as a convenient method for drug delivery to the systemic circulation, because IN administered drugs can be absorbed through a rich vascular network in the nasal cavity into the systemic circulation. Although most drugs absorbed into the blood circulation cannot enter the brain parenchyma because of the BBB, it has been demonstrated feasible in animal and clinical studies that drugs can be directly delivered from the nose to the brain, bypassing the BBB. Over the past few years, our team has shown that the BBB can be reproducibly opened using FUS and intravenously (IV)-administered microbubbles in a specific subcortical region associated with neurodegenerative disease. Molecules on the order of 0.5 kDa-4 MDa, including Dextran, neurotrophic factors and viral vectors, have been shown to be successfully delivered and localized within the intracellular space of neurons triggering signaling pathways within the neuronal cell. In this study, we hypothesize that the BBB opening can be applied entirely noninvasively (i.e., injection-free) while reducing the risk of systemic toxicity. FUS and intranasal delivery are therefore combined for the first time for enhancing the delivery efficiency of intranasally administered drugs to a targeted region while nanodroplets (ND) substitute microbubbles due to their smaller size that should facilitate intranasal delivery (FUS+IN+ND). We propose to develop an entirely noninvasive approach for trans-BBB deliver that offers the advantages of 1) an injection- free approach due to the intranasal (inhalation) administration , 2) higher selectivity due to the nanodroplet vehicle used and 3) lower toxicity due to both intranasal and nanodroplet approaches. The specific aims are thus to: 1) demonstrate feasibility of BBB opening using nanodroplets administered intranasally; 2) demonstrate efficacy of facilitating protein and gene therapy in a Parkinsonian mouse model. Intranasal delivery of both the vehicle (nanodroplet) and the drug (protein or virus) in combination with FUS could provide an entirely noninvasive, more targeted and less toxic alternative to the currently used methodologies facilitating thus clinical translation and acceptance.