Focused ultrasound-mediated intranasal brain drug delivery technique (FUSIN)

项目摘要/摘要 长期以来，对创新的脑部给药策略以解决临床挑战的需求一直未得到满足 在治疗脑瘤和其他中枢神经系统疾病方面，这些疾病是主要的公共卫生 美国的问题。聚焦超声与微泡鼻腔联合应用 递送(Fusin)可以通过实现非侵入性、空间靶向和高效的药物来满足这一未得到满足的需求 在不损害健康的大脑区域和其他器官的情况下，将其输送到患病的大脑部位。Fusin利用 直接鼻腔给药途径，绕过血脑屏障，最大限度地减少全身给药 曝光。它还使用经颅聚焦超声(FUS)诱导的微泡空化(即体积 微泡的膨胀和收缩)，以增强给药药物向FUS的输送。 有针对性的大脑定位。我们得到了NIH/NIBIB(R01EB027223,2019/1-1/31/2023)的支持开发 小白鼠体内的梭菌素。这一更新应用的目的是建立融合的生物物理机制 并获得令人信服的大型动物数据，以支持Fusin的临床翻译。我们的目标将是 通过完成以下三个具体目标来实现：目标1将建立 使用小鼠模型进行融合；Aim 2将优化融合蛋白在大型动物中的高效和安全的脑部给药 模型(猪)；目标3将在大型动物疾病模型中展示Fusin的临床翻译潜力 (猪脑胶质母细胞瘤模型)。这个项目意义重大，因为Fusin有可能从根本上推动 通过加强治疗药物对病变大脑部位的输送来治疗广泛的脑部疾病， 大大降低了全身毒性，消除了侵入性手术的需要。一个多学科的团队 拥有超声波工程、癌症生物学、放射化学、放射学和神经肿瘤学方面的专业知识 推动Fusin通过研究阶段并进入未来的临床试验。本研究有三个主要创新之处： (1)提出了一种新的熔融机理，即微泡空化强化淋巴作用。 鼻腔给药的转运；(2)首次将融合蛋白从小动物扩大到大动物；(3) 猪脑胶质母细胞瘤模型提供了一种独特的模型，该模型对于获得明确的证据支持至关重要。 复信的临床译本。这项拟议的研究预计将对 脑部给药的研究领域。这一项目的成果有望增进我们对 微泡介导的药物在大脑中传输的生物物理机制，产生了一个独特的平台 用于在大型动物的大脑中传递药物的技术，并收集需要翻译的大型动物数据 福辛走进了诊所。

PROJECT SUMMARY/ABSTRACT There is a long-standing unmet need for innovative brain drug delivery strategies to solve clinical challenges in the treatment of brain tumors and other central nervous system diseases, which are major public health problems in the United States. Focused ultrasound combined with microbubble-mediated intranasal delivery (FUSIN) can address this unmet need by achieving noninvasive, spatially targeted, and efficient drug delivery to diseased brain sites without jeopardizing healthy brain regions and other organs. FUSIN utilizes the intranasal route for direct nose-to-brain drug administration, bypassing the BBB and minimizing systemic exposure. It also uses transcranial focused ultrasound (FUS) induced microbubble cavitation (i.e., volumetric expansion and contraction of the microbubble) to enhance the delivery of IN-administered agents to the FUS- targeted brain location. We have been supported by NIH/NIBIB (R01EB027223, 4/1/2019–1/31/2023) to develop FUSIN in mice. The objective of this renewal application is to establish the biophysical mechanism of FUSIN and obtain compelling large-animal data to support the clinical translation of FUSIN. Our objective will be achieved by completing the following three specific aims: Aim 1 will establish the biophysical mechanisms of FUSIN using mouse models; Aim 2 will optimize FUSIN for efficient and safe brain drug delivery in a large animal model (pigs); Aim 3 will demonstrate the clinical translation potential of FUSIN in a large animal disease model (pig glioblastoma model). This project is significant because FUSIN has the potential to radically advance the treatment of a broad spectrum of brain diseases by enhancing therapeutic agent delivery to diseased brain sites, substantially reducing systemic toxicity, and eliminating the need for invasive surgery. A multidisciplinary team with expertise in ultrasound engineering, cancer biology, radiochemistry, radiology, and neuro-oncology will advance FUSIN through the research phase and into future clinical trials. This study has three main innovations: (1) it proposes a novel mechanism for FUSIN, which is through microbubble cavitation-enhanced glymphatic transport of intranasal-administered agents; (2) it is the first to scale-up FUSIN from small to large animals; (3) the pig glioblastoma model provides a unique model that is crucial for obtaining unequivocal evidence in support of the clinical translation of FUSIN. The proposed research is expected to have a powerful impact on the research field of brain drug delivery. The outcomes of this project are expected to advance our knowledge of the biophysical mechanisms underlying microbubble-mediated drug transport in the brain, produce a unique platform technology for drug delivery in the brain of large animals, and gather large animal data needed to translate FUSIN into the clinic.