Image-guided focused ultrasound-mediated intranasal brain drug delivery technique (FUSIN)
图像引导聚焦超声介导鼻内脑内给药技术(FUSIN)
基本信息
- 批准号:10091431
- 负责人:
- 金额:$ 37.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAlgorithmsAmericanBiophysical ProcessBlood - brain barrier anatomyBrainBrain DiseasesBrain StemBrain regionBrain-Derived Neurotrophic FactorBypassCardiovascular systemClinicalClinical ManagementConvectionDextransDiffuse intrinsic pontine gliomaDiseaseDisease modelDoseDrug Delivery SystemsEconomic BurdenEnsureExtracellular SpaceFailureFeedbackFocused UltrasoundFutureHigh PrevalenceHippocampus (Brain)ImageKnowledgeLabelLocationMalignant Childhood NeoplasmMediatingMethodsMicrobubblesModelingMusNormal tissue morphologyNoseOperative Surgical ProceduresOrganOutcomePatientsPenetrationPharmaceutical PreparationsProteinsPublic HealthPumpResearchRouteSiteTechniquesTechnologyTestingTherapeutic AgentsTimeTissuesToxic effectUltrasonographyUnited StatesVariantbaseblood-brain barrier disruptionbrain tissueclinical translationconventional therapycostimage guidedimage-guided drug deliveryimprovedin vivoinnovationmouse modelnanoGoldnervous system disordernovelnovel strategiesputamensafety and feasibilityside effectsystemic toxicitytargeted deliverytherapy outcometumortwo photon microscopy
项目摘要
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.
项目总结/摘要
每年有超过5000万美国人受到神经系统疾病的影响,费用超过650美元
亿尽管患病率很高,经济负担很重,但目前患者的前景
由于传统疗法的失败,许多类型的脑部疾病的治疗效果仍然很差。治疗脑
疾病是具有挑战性的,因为侵入性手术会破坏健康的脑组织,血脑屏障
(BBB)阻止大多数全身给药的药物进入大脑,
许多治疗剂,
在大脑中的有益作用在其他器官和组织中具有不利的副作用。当前可用的
用于脑药物递送的技术是侵入性的(例如,对流增强输送),缺乏针对性,
患病部位(例如,鼻内脑药物递送),或与全身毒性相关[例如,集中
超声(FUS)诱导的血脑屏障破坏(FUS-BBBD),用于输送注射到全身的药物
循环系统]。本提案的目的是开发聚焦超声结合
微泡介导的鼻内给药(FUSIN),这将实现非侵入性和空间靶向
将治疗剂递送到患病的脑部位而不危害脑的健康区域
和其他器官。FUSIN利用鼻内途径进行直接鼻-脑给药,从而
绕过血脑屏障并使全身暴露最小化。它使用聚焦超声诱导微泡
FUS光束聚焦区内的空化(微泡的膨胀和收缩),导致
增强了FUS靶向大脑位置的药物递送。我们的目标将通过完成
以下三个具体的目标,使用金纳米颗粒(AuNPs)作为模型药物和小鼠模型的弥漫性
内在脑桥胶质瘤,儿童中最致命的癌症,作为模型疾病。目标1将确定生物物理
使用体内双光子显微镜观察融合蛋白介导的药物转运机制。目标2将系统地
评价FUSIN递送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
FUSIN通过空化剂量涂抹控制AuNP输送位置和浓度。拟议
本研究主要有三个创新点:(1)提出了微气泡泵效应
FUSIN是一种新型的脑空间靶向给药系统
(3)空化剂量涂敷是一种新的药物控制释放方法。这个项目是
重要的是,因为FUSIN有可能影响广泛的临床管理,
通过显著增强治疗剂向患病脑部位的递送,
显著降低对健康大脑区域和其他器官的毒性,
侵入性手术
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Hong Chen的其他文献
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{{ truncateString('Hong Chen', 18)}}的其他基金
Role of PXR in drug-elicited cardiovascular disease
PXR 在药物引起的心血管疾病中的作用
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10576675 - 财政年份:2022
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Sonobiopsy for Noninvasive Genetic Evaluation of Glioblastoma Patients
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The Role of Adaptor Protein Disabled-2 in Maintaining Endothelial Cell Function in Atherosclerosis
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10600825 - 财政年份:2021
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