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

聚焦超声介导的鼻内脑内给药技术（FUSIN）

• 批准号: 10753173
• 负责人: Hong Chen
• 金额: $ 54.37万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753173
• 关键词: Address; Animal Disease Models; Animal Model; Animals; Biodistribution; Biophysical Process; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Diseases; Brain Neoplasms; Brain region; Bypass; Cancer Biology; Central Nervous System Diseases; Cephalic; Clinic; Clinical; Clinical Trials; Convection; Data; Dependence; Detection; Devices; Disease; Disease model; Dose; Drug Delivery Systems; Drug Transport; Engineering; Exposure to; Family suidae; Focused Ultrasound; Funding; Future; Glioblastoma; Goals; Immune checkpoint inhibitor; Implant; Intranasal Administration; Intravenous; Knowledge; Location; Mediating; Microbubbles; Modeling; Monitor; Mus; National Institute of Biomedical Imaging and Bioengineering; Neuronavigation; Nose; Operative Surgical Procedures; Organ; Outcome; Patient-Focused Outcomes; Patients; Penetration; Pharmaceutical Preparations; Phase; Positioning Attribute; Positron-Emission Tomography; Public Health; Radiochemistry; Radiolabeled; Radiology Specialty; Research; Route; Safety; Site; Sonication; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Translating; Transportation; Treatment outcome; United States; United States National Institutes of Health; animal data; anti-PD-L1; anti-PD-L1 antibodies; blood-brain barrier disruption; brain tissue; clinical translation; extracellular; glymphatic system; improved; in vivo; innovation; insight; intravenous injection; microscopic imaging; mouse model; multidisciplinary; neoplastic cell; neuro-oncology; neuroinflammation; novel; optimal treatments; pre-clinical; pressure; safety assessment; scale up; side effect; success; systemic toxicity; targeted delivery; technology platform; translational potential; two photon microscopy; ultrasound

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.

项目概要/摘要 为了解决临床挑战，对创新脑部药物输送策略的需求长期未得到满足 治疗脑肿瘤和其他中枢神经系统疾病，这些疾病是重大公共卫生问题 聚焦超声与微泡介导的鼻内注射相结合的问题。 递送（FUSIN）可以通过实现无创、空间靶向和高效的药物来解决这一未满足的需求 FUSIN 可以在不损害健康大脑区域和其他器官的情况下输送到患病的大脑部位。 鼻内途径直接从鼻到脑给药，绕过血脑屏障最小化和全身给药 它还使用经颅聚焦超声 (FUS) 诱导微泡空化（即体积测量）。 微泡的膨胀和收缩）以增强 IN 施用的药物向 FUS 的递送 我们得到了 NIH/NIBIB (R01EB027223, 4/1/2019–1/31/2023) 的支持来开发。 FUSIN 在小鼠中的更新应用的目的是建立 FUSIN 的生物物理机制。 并获得令人信服的大动物数据来支持 FUSIN 的临床转化。 通过完成以下三个具体目标来实现： 目标 1 将建立 使用小鼠模型的 FUSIN；Aim 2 将优化 FUSIN，以在大型动物中实现高效、安全的脑部药物输送 模型（猪）；目标 3 将展示 FUSIN 在大型动物疾病模型中的临床转化潜力 （猪胶质母细胞瘤模型）。这个项目意义重大，因为 FUSIN 有潜力从根本上推进这一研究。 通过增强治疗剂向患病大脑部位的输送来治疗多种脑部疾病， 显着降低全身毒性，并消除侵入性手术的需要。 拥有超声工程、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 FUSIN通过研究推进阶段并进入未来的临床试验，该研究具有三个主要创新点： (1)提出了FUSIN的新机制，即通过微泡空化增强类淋巴 鼻内给药制剂的运输；（2）它是第一个将 FUSIN 从小动物扩展到大动物的规模； 猪胶质母细胞瘤模型提供了一个独特的模型，对于获得明确的支持证据至关重要 这项研究预计将对 FUSIN 的临床转化产生重大影响。 该项目的成果预计将提高我们对脑药物输送的认识。 大脑中微泡介导的药物转运的生物物理机制产生了一个独特的平台 大型动物大脑中的药物输送技术，并收集翻译所需的大型动物数据 FUSIN走进诊所。