EXTH-61. NANOPARTICLE DELIVERY TO THE SPINAL CORD VIA DIRECT ADMINISTRATION TO CEREBROSPINAL FLUID

Abstract

Direct delivery of active agents to cerebrospinal fluid (CSF) is one approach used in neuro-oncology for improving drug delivery and activity in the central nervous system; for example, cytarabine-loaded liposomes (DepoCyt©) is a clinically approved formulation for treating lymphomatous meningitis and has also been tested for treatment of leptomeningeal metastasis in medulloblastoma. Although the brain has received substantial attention as a site for tissue-targeted delivery of drug loaded nanocarriers, relatively little is known about the spinal cord. Here, we were interested to engage in deeper characterization of the movement of polymeric nanoparticles through CSF to deliver encapsulated molecules to the brain and spinal cord. First, we utilized polystyrene nanoparticles to study size-dependent distribution and clearance of nanoparticles in the spinal cord after fourth ventricle injection in healthy mice. Next, we encapsulated DiR, a lipophilic drug surrogate, within 130nm poly(lactide)-b-poly(ethylene glycol) polymeric nanoparticles to evaluate the differential fate of nanoparticle versus payload. Our preliminary data show that nanoparticles administered to the fourth ventricle rapidly distribute down the central canal of the spinal cord at 30 min and at 2 hours post-injection, although the distribution of DiR appears to be more concentrated near the injection site, even 6 hours after injection. We observed penetration of nanoparticles hundreds of microns into the spinal cord parenchyma, which may be facilitated by nanoparticle movement through perivascular spaces. Finally, we have encapsulated a small library of chemotherapeutic agents within nanoparticles and are currently evaluating nanoparticle-drug tolerability and activity when administered directly to the CSF. These studies deepen our understanding of CSF as a drug delivery medium and bring us closer to our long-term goal of developing targeted nanoparticle therapeutics for treating metastatic disease in the spinal cord.