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.

项目总结/文摘