Image-guided focused ultrasound-mediated intranasal brain drug delivery technique (FUSIN)

项目摘要/摘要 每年有超过5000万美国人受到神经系统疾病的影响，花费超过650美元 十亿美元。尽管患病率高，经济负担沉重，但目前患者面临的前景是 由于传统疗法的失败，许多类型的脑部疾病的发病率仍然很低。脑的治疗 疾病具有挑战性，因为侵入性手术会损害健康的脑组织，即血脑屏障 (Bbb)阻止大多数全身用药进入大脑，以及 许多治疗药物具有 对大脑的有益影响对其他器官和组织也有不利的副作用。当前可用的 脑部给药技术是有创的(例如，对流增强给药)，缺乏特异性靶向 病变部位(例如，鼻腔内脑内给药)，或与全身毒性有关[例如，集中 超声(FUS)诱导的血脑屏障破坏(FUS-BBBD)用于向全身注射药物 循环系统]。这项计划的目标是发展聚焦超声和 微泡介导的鼻腔给药(Fusin)，将实现无创和空间靶向 在不损害大脑健康区域的情况下将治疗剂输送到患病的脑部位 和其他器官。Fusin利用鼻腔途径直接给药给药，从而 绕过血脑屏障，将系统性风险降至最低。它使用聚焦的超声波来诱导微泡 FUS光束焦区内的空化(微泡的膨胀和收缩)，导致 增强了FUS靶向大脑部位的药物输送。我们的目标将通过完成 利用金纳米颗粒(AuNPs)作为模型试剂和小鼠弥漫模型，研究了以下三个特定目标 先天性桥脑胶质瘤是儿童中最致命的癌症，是一种典型的疾病。目标1将确定生物物理 利用体内双光子显微镜研究纤溶酶介导的药物转运机制。目标2将系统地 评估融合蛋白的传递效率和对正常组织的影响，以评估其作为平台技术的潜力 用于脑部药物输送。目标3将评估实时被动空化成像引导的可行性和安全性 福辛通过空化剂量涂布控制AuNP的释放位置和浓度。建议数 研究内容主要有三个方面的创新：(1)提出了一种新颖的微泡泵浦效应 微泡介导的药物释放机制；(2)岩藻毒素是一种新型的空间靶向脑内药物释放 (3)空化剂量涂布是一种控制给药的新方法。这个项目是 意义重大，因为Fusin有可能影响广泛的 通过显著增加治疗药物对患病大脑部位的输送， 大幅减少对健康大脑区域和其他器官的毒性，并消除对 侵入性手术。

PROJECT SUMMARY/ABSTRACT More than 50 million Americans are affected by neurological diseases each year, with a cost of more than $650 billion. Despite the high prevalence and substantial economic burden, the present outlook for patients suffering from many types of brain diseases remains poor due to the failure of conventional therapies. Treatment of brain diseases is challenging because invasive surgeries can damage healthy brain tissue, the blood-brain barrier (BBB) blocks most systemically administered drugs from entering the brain, and many therapeutic agents with beneficial effects in the brain have adverse side effects in other organs and tissues. The currently available techniques for brain drug delivery are invasive (e.g., convection-enhanced delivery), lack specific targeting to the diseased site (e.g., intranasal brain drug delivery), or are associated with systemic toxicity [e.g., focused ultrasound (FUS)-induced BBB disruption (FUS-BBBD) for the delivery of drugs injected into the systemic circulatory system]. The objective of this proposal is to develop f ocused ultrasound combined with microbubble-mediated intranasal delivery (FUSIN), which will achieve noninvasive and spatially targeted delivery of therapeutic agents to diseased brain sites without jeopardizing healthy regions of the brain and other organs. FUSIN utilizes the intranasal route for direct nose-to-brain drug administration, thereby bypassing the BBB and minimizing systemic exposure. It uses focused ultrasound to induce microbubble cavitation (expansion and contraction of microbubbles) within the focal zone of the FUS beam, leading to enhanced drug delivery at the FUS-targeted brain location. Our objective will be achieved by completing the following three specific aims using gold nanoparticles (AuNPs) as model agents and a mouse model of diffuse intrinsic pontine glioma, the deadliest cancer in children, as a model disease. Aim 1 will identify the biophysical mechanisms of FUSIN-mediated agent transport using in vivo two-photon microscopy. Aim 2 will systematically evaluate FUSIN delivery efficiency and effect on normal tissue to assess its potential as a platform technology for brain drug delivery. Aim 3 will assess the feasibility and safety of real-time passive cavitation imaging-guided FUSIN to control AuNP delivery location and concentration through cavitation dose painting. The proposed research contains three main innovations: (1) the microbubble pump effect is proposed as a novel mechanism for microbubble-mediated drug delivery; (2) FUSIN is a novel spatially targeted brain drug delivery technique; and (3) cavitation dose painting is a novel approach for controlled drug delivery. This project is significant because FUSIN has the potential to impact the clinical management of a broad spectrum of brain disorders by significantly enhancing therapeutic agent delivery to diseased brain sites, substantially reducing toxicity to healthy brain regions and other organs, and eliminating the need for invasive surgery.