Hollow Fiber Catheter for Drug Delivery into the Brain

描述(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。利用对流增强递送(CED)将药物直接注入脑实质，能够治疗大面积组织并在原位浓缩输液，从而绕过血脑屏障和输液在血液中的稀释所造成的递送障碍。尽管CED的疗效已得到证实，但目前的导管和输液方案有很大的局限性。已经进行了多项临床试验，将CED作为一种将化疗和免疫毒素输送到胶质瘤患者体内的手段，但导管轨迹上的输液回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。为了克服传统导尿管的局限性，我们研制了一种具有数百万个微孔的中空纤维导尿管。中空纤维导管是完全多孔的，与输液接触的组织表面积增加了100倍以上。假设：我们认为，中空纤维导管可以将输液输送到至少50%的肿瘤体积，而不会导致自发性脑瘤犬的返流或剪切。申请人提出的新方法对所有直接传递到组织的药物都很重要，这些药物明显受到扩散的限制。初步数据：在啮齿动物模型和凝胶模型中，我们分别证明了中空纤维介导的输液显著增加了输液的分布，并消除了反流和剪切。具体目标：该项目需要对中空纤维导管进行临床前测试，最终应用于患有中枢神经系统疾病的人类患者。在具体目标1中，我们将构建和验证适用于患有脑瘤的狗的人体规模的中空纤维导管。临床上广泛使用的CED导管将被直接比作中空纤维，将染料输送到真实的人脑凝胶模型中。输液的回流和输液分布将与每个导管的其他特性一起量化。将进行MRI兼容性和机械测试。在特定的目标2中，我们将使用经过验证的导管来治疗被诊断为恶性胶质瘤的客户拥有的宠物狗。卡铂化疗/MRI造影剂溶液将在肿瘤内输注，输注分布将由MRI确定。总之，这些研究将证明中空纤维导管在CED中的应用，并加速中空纤维临床应用的商业化进程。公共卫生相关性：药物进入大脑是实现临床疗效的一个重大障碍。我们已经开发了一种新型的“中空纤维”导管，并证明它在药物输送到小鼠大脑中是有效的。在这个项目中，我们将在患有脑肿瘤的狗身上进行中空纤维导管的临床前测试，为这项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.