Intrathecal delivery and its applications in leptomeningeal disease

Intrathecal delivery (IT) of opiates into the cerebrospinal fluid (CSF) for anesthesia and pain relief has been used clinically for decades, but this relatively straightforward approach of bypassing the blood-brain barrier has been underutilized for other indications because of its lack of utility in delivering small lipid-soluble drugs. However, emerging evidence suggests that IT drug delivery be an efficacious strategy for the treatment of cancers in which there is leptomeningeal spread of disease. In this review, we discuss CSF flow dynamics and CSF clearance pathways in the context of intrathecal delivery. We discuss human and animal studies of several new classes of therapeutic agents-cellular, protein, nucleic acid, and nanoparticle-based small molecules-that may benefit from IT delivery. The complexity of the CSF compartment presents several key challenges in predicting biodistribution of IT-delivered drugs. New approaches and strategies are needed that can overcome the high rates of turnover in the CSF to reach specific tissues or cellular targets.