Nanoparticle distribution in the central nervous system following intrathecal administration: A multi-modal analysis of lumbar versus cisterna magna routes.

Intrathecal drug delivery refers to the direct administration of compounds to cerebrospinal fluid (CSF), which can enhance delivery to the central nervous system (CNS) while minimizing peripheral exposure. Our prior work demonstrated that 100 nm, solid polystyrene nanoparticles surface modified with poly(ethylene glycol) (PEG) distribute within the CNS after intrathecal administration via the cisterna magna route (IT-CM). Here, we focus on comparing nanoparticle fate following administration to IT CM versus lumbar (IT-L) access points. We utilized dynamic a variety of imaging techniques to track the movement of model, 64Cu-radiolabeled, fluorescent nanoparticles, hypothesizing that the IT-CM route would enable greater brain-localized delivery of nanoparticles when compared with the IT-L route. Spatiotemporal patterns of nanoparticle distribution and clearance were studied through a combination of quantitative positron emission tomography/computer tomography (PET/CT), fluorescent imaging (confocal microscopy), and biodistribution experiments (liquid scintillation counting). These studies revealed that: (1) the IT-CM route yielded greater brain-wide nanoparticle delivery while the IT-L route yielded greater spinal delivery, (2) the IT-CM route resulted in sustained retention of nanoparticles within the CNS and proximal lymphatics while the IT-L route resulted in higher nanoparticle clearance to peripheral organs, and (3) both the IT-CM and IT-L routes resulted in detectable though incomplete parenchymal delivery of nanoparticles, with the majority of signal remaining confined to the subarachnoid space. These findings underscore the pivotal role of intrathecal location in influencing nanoparticle biodistribution and clearance pathways within the CNS, identifying access point as an important design parameter when optimizing nanomedicine for intrathecal drug delivery.