BRAIN THERAPY USING ULTRASOUND MEDIATED DRUG DELIVERY

使用超声波介导的药物输送进行脑部治疗

• 批准号: 2731881
• 负责人: LAWRENCE K NG
• 金额: $ 21.69万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2731881
• 关键词: biomedical equipment development; blood brain barrier; brain disorder chemotherapy; cis platinum compound; combination cancer therapy; drug delivery systems; laboratory rat; membrane permeability; membrane transport proteins; neoplasm /cancer chemotherapy; neuropharmacology; nonhuman therapy evaluation; phantom model; tissue /cell culture; ultrasound therapy

Disorders of the brain, including cancer and various forms of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease are currently among the leading causes of illness and death in the United States. The financial burden of these diseases is enormous. The research proposed in this study will, therefore, address a critical need to develop safe, non-invasive and non-chemical methods to enhance the delivery of nonlipophilic neuropharmaceuticals to the brain through the use of ultrasound, which has been shown to enhance membrane transport phenomena in a non-invasive manner. However, the clinical use of ultrasound-enhanced transport of therapeutic agents across the blood- brain barrier (BBB) has yet to be demonstrated, nor have optimal therapeutic ultrasound parameters been defined. Therefore, in this proposal, the major goals are to A) delineate the parameter space for safe administration of ultrasound to mediate the transport of nonlipophilic compounds across the BBB, and (B) verify the safety and effectiveness of ultrasound in mediating the transport of nonlipophilic drugs across the BBB in animals. To accomplish these goals, the project will: (1) develop custom ultrasound units to perform both an enhanced range of in vitro measurements on a cell-culture model of the BBB and in vivo measurements on live rats, (2) determine the effects of various ultrasonic parameters (intensity, frequency, waveform) on the BBB permeability of a polar molecule; (3) determine the effects of various ultrasonic parameters on biochemical and morphological characteristics of the BBB cells by (a) following the functional expression of various BBB-specific enzymes and membrane-bound protein, (b) studying the morphological and cytological characteristics of BBB cells using standard histological techniques, and (c) determining the BBB cell viability, as a function of various ultrasound parameters; (4) determine the conditions for effective trans-cranial delivery of ultrasound using phantoms constructed to model in vivo brain; (5) verify the safety and effectiveness of ultrasound in mediating BBB drug transport in rats by examining the ultrasound-treated rat brain for the presence of lesions using standard histological techniques, and by determining whether trans-cranial application of ultrasound can promote BBB transport of a nonlipophilic drug (cisplatin) to alter the mean survival times of rats with one-week established brain tumors. In order to reduce costs and the unnecessary use of animals, specific aims 2 through 4 of the proposed study will be addressed using a well- established in vitro BBB cell culture model based on growing bovine brain microvessel endothelial cells (BBMEC) on a cell culture insert. It is anticipated that this study will also provide fundamental insights into the underlying mechanisms of ultrasound drug transport across the BBB as well as the knowledge needed for the design of a safe and effective trans-cranial ultrasound delivery system.

脑部疾病，包括癌症和各种形式的 阿尔茨海默病和帕金森氏症等神经退行性疾病 疾病目前是#年疾病和死亡的主要原因之一。 美国。这些疾病造成的经济负担是巨大的。 因此，这项研究中提出的研究将解决一个关键的 需要开发安全、非侵入性和非化学的方法来加强 通过将非亲脂性神经药物输送到大脑 超声波的使用，已被证明可以增强细胞膜 以非侵入性的方式传输现象。然而，临床应用 超声波增强了治疗剂在血液中的传输- 脑屏障(BBB)尚未得到证实，也没有最佳的 确定了治疗性超声参数。 因此，在这项建议中，主要目标是A)划定 超声安全给药的参数空间 非亲脂性化合物通过血脑屏障的传输，以及(B)核实 超声介导药物转运的安全性和有效性 动物体内血脑屏障中的非亲脂性药物。要实现这些目标 目标，该项目将：(1)开发定制超声设备以执行 在细胞培养模型上增加了体外测量的范围 血脑屏障和活体大鼠的测量，(2)确定 不同的超声参数(强度、频率、 波形)关于极性分子的BBB渗透率；(3)确定 不同超声参数对生化和血液生化指标的影响 血脑屏障细胞的形态特征：(A)遵循 多种BBB特异酶和膜结合蛋白的功能表达 蛋白质，(B)研究形态和细胞学特征 使用标准组织学技术对血脑屏障细胞进行检测，以及(C)确定 血脑屏障细胞活力，作为各种超声参数的函数； (四)确定有效经颅分娩的条件 使用构建的模型来模拟活体大脑的超声波；(5)验证 超声介导血脑屏障药物的安全性和有效性 通过检测经超声波处理的大鼠脑组织中的 使用标准组织学技术和通过 确定经颅应用超声波是否能促进 血脑屏障转运非亲脂性药物(顺铂)以改变平均 建立脑瘤一周的大鼠的存活时间。按顺序 为减少成本和不必要地使用动物，具体目标2 拟议研究的第4部分将使用一口井- 生长牛血脑屏障细胞体外培养模型的建立 脑微血管内皮细胞(BBMEC)在细胞培养插入物上。 预计这项研究还将提供基本的见解。 探讨超声药物跨血管转运的潜在机制 BBB以及设计一个安全和 有效的经颅超声传输系统。