Role of cerebrospinal fluid dynamics in brain drug delivery

描述（由申请人提供）：由于人口老龄化、对创伤性脑损伤的长期影响的认识增加以及脑癌的发病率，神经系统障碍和脑部疾病是日益普遍的健康问题。由于组织的微妙性质和血脑屏障所带来的特殊环境，治疗大脑面临着独特的挑战。药物递送系统已被用于将药物运送到大脑和中枢神经系统（CNS），然而脑脊液（CSF）周转可快速从CNS清除药物并降低治疗功效。该提案将探索通过调节CSF产生将药物局部递送到大脑并减少药物外排的策略。本提案将检验CSF动力学影响CNS中药物暴露的假设。在指导阶段，我将学习设备制造技术，并开发药物输送微型设备能够局部提供多种化合物到脑实质。这些装置的开发是必要的，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CSF调节药物如乙酰唑胺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该资助的独立阶段在脑癌啮齿动物模型中评估CSF调节药物递送系统。在独立阶段，我将联合收割机结合我在化学和疾病动物模型方面的背景和新学到的制造专业知识，探索减少药物CSF外排和啮齿动物脑部疾病模型治疗效果之间的关系。我将使用啮齿动物脑癌模型测试这些药物输送系统的有效性，并设计新的分子输送载体。这一系列研究将导致更有效的方法来治疗脑癌，神经退行性疾病和其他脑部疾病。

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.