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: 6350334
• 负责人: LAWRENCE K NG
• 金额: $ 19.9万
• 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 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6350334
• 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 神经退行性疾病如阿尔茨海默病和帕金森病 疾病目前是疾病和死亡的主要原因， 美国的 这些疾病的经济负担是巨大的。 因此，本研究中提出的研究将解决一个关键问题， 需要开发安全、非侵入性和非化学方法， 将非亲脂性神经药物递送到大脑， 超声波的使用，已被证明可以增强膜 以非侵入性的方式传输现象。 然而，临床应用 超声波增强治疗剂在血液中的运输 脑屏障（BBB）尚未得到证实，也没有最佳的 定义了治疗超声参数。 因此，在本提案中，主要目标是：A） 参数空间的安全管理超声调解 非亲脂性化合物穿过BB B的转运，和（B）验证 超声波介导转运的安全性和有效性 非亲脂性药物在动物体内穿过血脑屏障。 完成这些 目标，该项目将：（1）开发定制的超声单元，以执行 在细胞培养模型上的体外测量范围都有所增加， 的BBB和活大鼠的体内测量，（2）确定 各种超声参数（强度，频率， 波形）对极性分子的BBB通透性的影响;（3）确定 研究了不同超声参数对生化和 BBB细胞的形态学特征，通过（a）遵循 各种BBB特异性酶的功能性表达和膜结合 蛋白质，（B）研究形态学和细胞学特征 使用标准组织学技术测定BBB细胞，和（c）测定 BBB细胞活力，作为各种超声参数的函数; (4)确定有效的经颅递送的条件 超声使用构建的模型在体内脑;（5）验证 超声介导血脑屏障药物安全性和有效性 通过检查超声波处理的大鼠大脑中的 使用标准组织学技术检查是否存在病变， 确定超声波的经颅应用是否可以促进 非亲脂性药物（顺铂）的BBB转运改变平均 存活时间的大鼠与一个星期建立脑肿瘤。 为了 为了减少成本和不必要的使用动物，具体目标2 第四，研究的重点将放在一个好的 建立了生长牛血脑屏障细胞体外培养模型 脑微血管内皮细胞（BBMEC）在细胞培养插入物上。 预计这项研究也将提供基本的见解 超声药物运输的基本机制， BBB以及设计安全和 有效的经颅超声传输系统。