title: Transport characteristics of a novel peptide platform for CNS therapeutics.
abstract: New and effective therapeutics that cross the blood-brain barrier (BBB) are critically needed for treatment of many brain diseases. We characterize here a novel drug development platform that is broadly applicable for the development of new therapeutics with increased brain penetration. The platform is based on the Angiopep-2 peptide, a sequence derived from ligands that bind to low-density lipoprotein receptor-related protein-1 (LRP-1), a receptor expressed on the BBB. Fluorescent imaging studies of a Cy5.5Angiopep-2 conjugate and immunohistochemical studies of injected Angiopep-2 in mice demonstrated efficient transport across the BBB into brain parenchyma and subsequent co-localization with the neuronal nuclei-selective marker NeuN and the glial marker glial fibrillary acidic protein (GFAP). Uptake of [(¹²⁵I]-Angiopep-2 into brain endothelial cells occurred by a saturable mechanism involving LRP-1. The primary sequence and charge of Angiopep-2 were crucial for its passage across the BBB. Overall, the results demonstrate the significant potential of this platform for the development of novel neurotherapeutics.
authors.affiliation: Laboratoire de Médecine Moléculaire, Université du Québec à Montréal, Montréal, Canada Angiochem, Inc., Montréal, Canada.
authors.forename: Yanick
authors.initials: Y
authors.lastname: Bertrand
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Currie
authors.forename: Michel
authors.initials: M
authors.lastname: Demeule
authors.forename: Anthony
authors.initials: A
authors.lastname: Régina
authors.forename: Christian
authors.initials: C
authors.lastname: Ché
authors.forename: Abedelnasser
authors.initials: A
authors.lastname: Abulrob
authors.forename: Dorothy
authors.initials: D
authors.lastname: Fatehi
authors.forename: Hervé
authors.initials: H
authors.lastname: Sartelet
authors.forename: Reinhard
authors.initials: R
authors.lastname: Gabathuler
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Castaigne
authors.forename: Danica
authors.initials: D
authors.lastname: Stanimirovic
authors.forename: Richard
authors.initials: R
authors.lastname: Béliveau
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000032:analysis; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D002232:Carbocyanines; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D009419:Nerve Tissue Proteins / Q000032:analysis; D010455:Peptides / Q000378:metabolism*; D021381:Protein Transport; D011869:Radioligand Assay; D051381:Rats; D057900:Transcytosis
chemical_list: C531860:Angiopep-2; D034961:Antigens, Nuclear; C098793:CY5.5 cyanine dye; D002232:Carbocyanines; D005904:Glial Fibrillary Acidic Protein; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009419:Nerve Tissue Proteins; D010455:Peptides; C506808:neuronal nuclear antigen NeuN, human