Cerebrospinal Fluid Flow Enhancement (CFE) Increases the Spatial Distribution of Methotrexate after Intracerebroventricular Administration in a Sheep Model

For the treatment of central nervous system (CNS) neoplasias, achieving widespread chemotherapy distribution throughout the brain remains a major challenge. Direct infusion of substances into the cerebrospinal fluid (CSF) is one method to bypass the blood-brain barrier (BBB) and increase the exposure of CNS tissues to therapeutic molecules. As of 2024, only a handful of drugs are FDA-approved for CSF administration, including morphine, baclofen, ziconotide, and methotrexate. However, despite the use of these approaches in clinical practice, relatively little is understood regarding the spatial distribution of CSF-administered agents, and these distributions remain to be optimized. Here, we focus on methotrexate (MTX), which is an antifolate antineoplastic agent that has been administered intrathecally to treat numerous conditions, including inflammatory and oncologic diseases. We examined the time course of the distribution of MTX to gain insight into the flow dynamics and hypothesized that CSF flow enhancement (CFE), i.e., manipulation of the pattern by which CSF moves within the CNS, would alter the spatial distribution of MTX in the CNS following CSF administration. This hypothesis was tested with a recirculating device, which we used to continuously recirculate fluid from the intracerebral lateral ventricles (ICV) to the cisterna magna (CM). Our experimental results provide detailed maps of the spatial distribution of MTX following CSF administration in sheep and support our expectation that CFE is an effective method to manipulate CNS drug distribution.