Title:Potential Pathways for CNS Drug Delivery Across the Blood-Cerebrospinal Fluid Barrier
Volume: 22
Issue: 35
Author(s): Nathalie Strazielle and Jean-François Ghersi-Egea
Affiliation:
Keywords:
Choroid plexus, cerebrospinal fluid, cerebral drug delivery, receptor-mediated transcytosis, folate receptor, LRP proteins,
transferrin receptor, insulin receptor.
Abstract: The blood-brain interfaces restrict the cerebral bioavailability of pharmacological
compounds. Various drug delivery strategies have been developed to improve drug penetration
into the brain. Most strategies target the microvascular endothelium forming the bloodbrain
barrier proper. Targeting the blood-cerebrospinal fluid (CSF) barrier formed by the
epithelium of the choroid plexuses in addition to the blood-brain barrier may offer addedvalue
for the treatment of central nervous system diseases. For instance, targeting the CSF
spaces, adjacent tissue, or the choroid plexuses themselves is of interest for the treatment of
neuroinflammatory and infectious diseases, cerebral amyloid angiopathy, selected brain
tumors, hydrocephalus or neurohumoral dysregulation. Selected CSF-borne materials seem
to reach deep cerebral structures by mechanisms that need to be understood in the context of
chronic CSF delivery. Drug delivery through both barriers can reduce CSF sink action towards
parenchymal drugs. Finally, targeting the choroid plexus-CSF system can be especially
relevant in the context of neonatal and pediatric diseases of the central nervous system. Transcytosis appears
the most promising mechanism to target in order to improve drug delivery through brain barriers. The choroid
plexus epithelium displays strong vesicular trafficking and secretory activities that deserve to be explored in
the context of cerebral drug delivery. Folate transport and exosome release into the CSF, plasma protein transport,
and various receptor-mediated endocytosis pathways may prove useful mechanisms to exploit for efficient drug
delivery into the CSF. This calls for a clear evaluation of transcytosis mechanisms at the blood-CSF barrier, and a
thorough evaluation of CSF drug delivery rates.
