Transport characteristics of a novel peptide platform for CNS therapeutics

被引：51

作者：

Bertrand, Yanick ^{[1
]}

Currie, Jean-Christophe ^{[1
]}

Demeule, Michel ^{[2
]}

Regina, Anthony ^{[2
]}

Che, Christian ^{[2
]}

Abulrob, Abedelnasser ^{[3
]}

Fatehi, Dorothy ^{[3
]}

Sartelet, Herve ^{[4
]}

Gabathuler, Reinhard ^{[2
]}

Castaigne, Jean-Paul ^{[2
]}

Stanimirovic, Danica ^{[3
]}

Beliveau, Richard ^{[1
]}

机构：

[1] Univ Quebec, Mol Med Lab, Montreal, PQ H3C 3P8, Canada

[2] Angiochem Inc, Montreal, PQ, Canada

[3] Natl Res Council Canada, Inst Biol Sci, Cerebrovasc Res Grp, Ottawa, ON K1A 0R6, Canada

[4] Univ Montreal, Dept Pathol, Montreal, PQ H3C 3J7, Canada

来源：

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE | 2010年 / 14卷 / 12期

基金：

加拿大自然科学与工程研究理事会;

关键词：

blood-brain barrier; therapeutics; drug delivery; Angiopeps; low-density lipoprotein receptor-related protein-1; receptor-mediated transcytosis; brain disease; RECEPTOR-RELATED PROTEIN; BLOOD-BRAIN-BARRIER; GLYCOPROTEIN-DEFICIENT MICE; DELIVERY VECTOR ANGIOPEP-2; AMYLOID-BETA; ALPHA-2-MACROGLOBULIN RECEPTOR; APOLIPOPROTEIN-E; CELLULAR UPTAKE; DRUG DISCOVERY; BINDING;

D O I：

10.1111/j.1582-4934.2009.00930.x

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：2827 / 2839

页数：13

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