Hollow Fiber Catheter for Drug Delivery into the Brain

描述（由申请人提供）： 中枢神经系统（CNS）的神经退行性和恶性疾病影响着数百万美国人。这些疾病往往是毁灭性的，难以治疗，药物输送仍然是一个重大障碍。使用对流增强递送（CED）将药物直接输注到脑实质中能够治疗大面积的组织并原位浓缩输注物，从而规避由血脑屏障和血液中的输注物稀释造成的递送障碍。尽管CED的有效性已得到证实，但目前的导管和输注方案具有显著的局限性。已经进行了多项临床试验，使用CED作为向神经胶质瘤患者输送化疗和免疫毒素的手段，但输注液沿导管通道逆流和组织剪切导致药物泄漏到脑脊液中的情况很常见。这些不良事件导致疗效降低和毒性增加。为了克服传统导管的局限性，我们开发了一种具有数百万微孔的中空纤维导管用于药物输送。中空纤维导管是完全多孔的，并将与输注液接触的组织表面积增加了100倍以上。假设：我们认为，在患有自发性脑肿瘤的犬中，中空纤维导管将输注液输送到至少50%的肿瘤体积，而不会发生回流或剪切。申请人提出的新方法对于直接递送到受扩散显著限制的组织的所有药物都是重要的。初步数据：我们证明，中空纤维介导的输注显着增加输注液分布和消除反流和剪切啮齿动物和凝胶模型，分别。具体目标：该项目需要对中空纤维导管进行临床前测试，以最终应用于患有中枢神经系统疾病的人类患者。在特定目标1中，我们将构建并验证适用于患有脑肿瘤的犬的人体规模中空纤维导管。将广泛使用的临床CED导管直接与中空纤维进行比较，以将染料输送到人脑的真实凝胶模型中。将对输注液回流和输送分布以及每根导管的其他特征进行沿着量化。将进行MRI兼容性和机械测试。在特定目标2中，我们将使用经确认的导管治疗诊断为恶性胶质瘤的客户宠物犬。卡铂化疗/ MRI造影剂溶液将在肿瘤内输注，并通过MRI确定输注液分布。总之，这些研究将证明中空纤维导管在CED中的实用性，并加速中空纤维临床应用的商业化。公共卫生相关性：药物输送到大脑是实现临床疗效的一个重大障碍。我们已经开发出一种新型的“中空纤维”导管，并表明它在药物输送到小鼠大脑中是有效的。在本项目中，我们将在患有脑肿瘤的狗中进行中空纤维导管的临床前测试，为该技术在人类患者中的临床应用做准备。

DESCRIPTION (provided by applicant): Neurodegenerative and malignant diseases of the central nervous system (CNS) affect millions of Americans. These diseases are often devastating and difficult to treat and drug delivery remains a significant impediment. Direct infusion of drugs into the brain parenchyma using convection-enhanced delivery (CED) is able to treat large areas of tissue and concentrate the infusate in situ, thereby circumventing the delivery obstacles posed by the blood brain barrier and dilution of infusate in the blood. Despite the proven efficacy of CED, the current catheters and infusion protocols have significant limitations. Multiple clinical trials have been conducted using CED as a means to deliver chemotherapy and immunotoxins into patients with gliomas, but reflux of infusate up the catheter track and tissue shearing leading to leakage of drug into cerebrospinal fluid has been common. These adverse events result in reduced efficacy and increased toxicity. In order to overcome the limitations of conventional catheters, we developed a hollow fiber catheter with millions of micropores for drug delivery. The hollow fiber catheter is completely porous and increases the surface area of tissue in contact with infusate by over 100 times. Hypothesis: We contend that the hollow fiber catheter will deliver infusate to at least 50% of the tumor volume without reflux or shearing in dogs with spontaneous brain tumors. The novel method proposed by the applicants is important for all drugs delivered directly to tissue that are significantly limited by diffusion. Preliminary Data: We demonstrated that hollow fiber-mediated infusion significantly increased infusate distribution and eliminated reflux and shearing in rodent and gel models, respectively. Specific Aims: This project entails preclinical testing of the hollow fiber catheter for eventual application to human patients suffering from diseases of the CNS. In Specific Aim 1, we will construct and validate human-scale hollow fiber catheters that are suitable for use in dogs with brain tumors. A widely used clinical CED catheter will be directly compared to hollow fiber for delivery of dye into a realistic gel model of human brain. Reflux of infusate and delivery distribution will be quantified along with other characteristics of each catheter. MRI compatibility and mechanical testing will be performed. In Specific Aim 2, we will use the validated catheters to treat client owned pet dogs diagnosed with a malignant glioma. A carboplatin chemotherapy / MRI contrast agent solution will be infused intratumorally and infusate distribution will be determined by MRI. Together, these studies will demonstrate the utility of hollow fiber catheters for CED and accelerate the commercialization of hollow fiber for clinical use. PUBLIC HEALTH RELEVANCE: Drug delivery into the brain represents a significant obstacle to achieving clinical efficacy. We have developed a novel "hollow fiber" catheter and shown it is effective at drug delivery into the mouse brain. In this project, we will conduct preclinical testing of the hollow fiber catheter in dogs with brain tumors in preparation for clinical use of this technology in human patients.