Role of cerebrospinal fluid dynamics in brain drug delivery

描述(申请人提供)：由于人口老龄化，人们对创伤性脑损伤的长期影响的认识日益增强，以及脑癌的发病率，神经疾病和脑部疾病日益普遍。由于组织的微妙性质和血脑屏障的特殊环境，脑的治疗面临着独特的挑战。药物递送系统被用来将药物输送到大脑和中枢神经系统(CNS)，然而脑脊液(CSF)的周转会迅速将药物从CNS中清除出去，从而降低治疗效果。这项提议将探索通过调节脑脊液的产生来局部将药物输送到大脑并减少药物外流的策略。这项提议将检验脑脊液动力学影响中枢神经系统药物暴露的假设。在指导阶段，我将学习装置制造技术，并开发能够将多种化合物局部输送到脑实质的药物输送微型装置。开发这些设备是必要的，因为许多药物在全身给药时不能有效地进入大脑。我将使用这些设备和体内成像技术来量化乙酰唑胺等调节脑脊液的药物如何影响药物分布和暴露。在指导阶段获得的数据和技能将导致在这项赠款的独立阶段对脑癌啮齿动物模型的脑脊液调节药物输送系统进行评估。在独立阶段，我将把我在化学和疾病动物模型方面的背景与新学到的制造专业知识结合起来，探索减少药物的脑脊液外流与脑疾病啮齿动物模型治疗效果之间的关系。我将使用脑癌的啮齿动物模型来测试这些药物输送系统的有效性，并设计新的分子输送工具。这一系列研究将导致治疗脑癌、神经退行性疾病和其他脑部疾病的更有效的方法。

DESCRIPTION (provided by applicant): Neurological disorders and diseases of the brain are increasingly prevalent health concerns due to an aging population, increased awareness of long term effects of traumatic brain injury, and incidence of brain cancer. Treating the brain presents a unique challenge for due to the delicate nature of the tissue and privileged environment due to the blood-brain barrier. Drug delivery systems have been used to ferry drugs to the brain and central nervous system (CNS), however cerebrospinal fluid (CSF) turnover can rapidly clear drugs from the CNS and reduce treatment efficacy. This proposal will explore strategies to locally deliver drugs to the brain and reduce drug efflux by modulating CSF production. This proposal will test the hypothesis that CSF dynamics affect drug exposure in the CNS. During the mentored phase, I will learn device fabrication techniques and develop drug delivery micro devices capable of locally delivering multiple compounds into the brain parenchyma. Development of these devices is necessary, as many drugs do not efficiently cross into the brain when administered systemically. I will use these devices and in vivo imaging techniques to quantify how CSF-modulating drugs such as acetazolamide affect drug distribution and exposure. The data and skills acquired during the mentored phase will lead to the evaluation of CSF-modulating drug delivery systems in rodent models of brain cancer during the independent phase of this grant. During the independent phase, I will combine my background in chemistry and animal models of disease with newly learned fabrication expertise and explore the relationship between reducing CSF efflux of drugs and treatment efficacy in rodent models of brain disease. I will test the effectiveness of these drug delivery systems using rodent models of brain cancer and design new, molecular delivery vehicles. This line of research will lead to more effective ways to treat brain cancers, neurodegenerative diseases, and other diseases of the brain.