Transport characteristics of a novel peptide platform for CNS therapeutics.
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.
Bertrand
Yanick
Y
Laboratoire de Médecine Moléculaire, Université du Québec à Montréal, Montréal, Canada Angiochem, Inc., Montréal, Canada.
Currie
Jean-Christophe
JC
Demeule
Michel
M
Régina
Anthony
A
Ché
Christian
C
Abulrob
Abedelnasser
A
Fatehi
Dorothy
D
Sartelet
Hervé
H
Gabathuler
Reinhard
R
Castaigne
Jean-Paul
JP
Stanimirovic
Danica
D
Béliveau
Richard
R
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
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