Intranasal delivery through the blood-brain barrier using focused ultrasound

 描述(申请人提供)：聚焦超声(FUS)，结合微泡，仍然是唯一可以非侵入性和区域性地诱导局部BBB开放的技术。鼻腔给药(IN)已成为一种很有前途的脑内给药方法。传统上，它被成功地用作一种方便的药物输送到体循环的方法，因为IN给药的药物可以通过鼻腔中丰富的血管网络被吸收到体循环中。尽管由于血脑屏障的原因，大多数药物被吸收到血液循环中不能进入脑实质，但动物和临床研究证明，药物可以绕过血脑屏障直接从鼻子输送到大脑。在过去的几年里，我们的团队已经证明，使用FUS和静脉(IV)注射与神经退行性疾病相关的特定皮质下区域的微泡可以重复地打开BBB。包括葡聚糖、神经营养因子和病毒载体在内的约0.5 kDa-4丙二醛分子已被成功地递送并定位于触发神经细胞内信号通路的神经元的细胞内空间。在这项研究中，我们假设血脑屏障开放可以完全非侵入性地应用(即，无需注射)，同时降低全身毒性的风险。因此，FUS和鼻内给药首次被结合起来，以提高鼻内给药到靶区的效率，而纳米微滴(ND)由于其尺寸较小，应有助于鼻内给药(FUS+IN+ND)，因此取代了微泡。我们建议开发一种完全非侵入性的跨血脑屏障传递方法，该方法具有以下优点：1)由于鼻腔(吸入)给药而无需注射，2)由于所使用的纳米液滴载体而具有更高的选择性，3)由于鼻腔和纳米液滴途径都具有较低的毒性。因此，其具体目的是：1)证明通过鼻腔给药的纳米微滴开放血脑屏障的可行性；2)证明在帕金森病小鼠模型中促进蛋白质和基因治疗的有效性。载体(纳米微滴)和药物(蛋白质或病毒)的鼻腔给药与FUS相结合，可以提供一种完全非侵入性的、更有针对性的、毒性更低的替代方法，从而促进临床翻译和接受。

 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.