Research Project
7481034
[unreadable] 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. [unreadable] [unreadable] [unreadable]
