Targeting choroid plexus epithelia and ventricular ependyma for drug delivery to the central nervous system

Ana Maria Gonzalez,Conrad E Johanson,Edward G Stopa,Karen Sims,Tetsuya Terasaki,Michael Burg,Andrew Baird,Wendy E Leadbeater,Brian P Eliceiri

doi:10.1186/1471-2202-12-4

Abstract

BackgroundBecause the choroid plexus (CP) is uniquely suited to control the composition of cerebrospinal fluid (CSF), there may be therapeutic benefits to increasing the levels of biologically active proteins in CSF to modulate central nervous system (CNS) functions. To this end, we sought to identify peptides capable of ligand-mediated targeting to CP epithelial cells reasoning that they could be exploited to deliver drugs, biotherapeutics and genes to the CNS.MethodsA peptide library displayed on M13 bacteriophage was screened for ligands capable of internalizing into CP epithelial cells by incubating phage with CP explants for 2 hours at 37C and recovering particles with targeting capacity.ResultsThree peptides, identified after four rounds of screening, were analyzed for specific and dose dependant binding and internalization. Binding was deemed specific because internalization was prevented by co-incubation with cognate synthetic peptides. Furthermore, after i.c.v. injection into rat brains, each peptide was found to target phage to epithelial cells in CP and to ependyma lining the ventricles.ConclusionThese data demonstrate that ligand-mediated targeting can be used as a strategy for drug delivery to the central nervous system and opens the possibility of using the choroid plexus as a portal of entry into the brain.

Highlights

Because the choroid plexus (CP) is uniquely suited to control the composition of cerebrospinal fluid (CSF), there may be therapeutic benefits to increasing the levels of biologically active proteins in CSF to modulate central nervous system (CNS) functions
We show that a combinatorial peptide library containing over 109 different peptides can be selectively mined for ligands that allow binding and internalization into mouse CP explants
Biopanning PhD-C7C libraries of phage for peptides internalizing into CP Explants As shown in Table 1, three recovered peptides named “Peptide B” (R3P3.9), “Peptide C” (R4P4.5) and “Peptide D” (R4P4.7) were selected from the 25 unique sequences obtained for further analysis from 3-4 rounds of biopanning on explants of 4th ventricle mouse choroid plexus

Summary

Introduction

Because the choroid plexus (CP) is uniquely suited to control the composition of cerebrospinal fluid (CSF), there may be therapeutic benefits to increasing the levels of biologically active proteins in CSF to modulate central nervous system (CNS) functions. To this end, we sought to identify peptides capable of ligand-mediated targeting to CP epithelial cells reasoning that they could be exploited to deliver drugs, biotherapeutics and genes to the CNS. The ligand, EGF, has intrinsic epidermal cell growth promoting biological activity [23,24] that significantly limits its utility as a drug- and particle-targeting agent

Methods

Results

Discussion

Conclusion