Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 14, Issue 12, Pages 2827-2839Publisher
WILEY
DOI: 10.1111/j.1582-4934.2009.00930.x
Keywords
blood-brain barrier; therapeutics; drug delivery; Angiopeps; low-density lipoprotein receptor-related protein-1; receptor-mediated transcytosis; brain disease
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Funding
- National Research Council of Canada's Industrial Research Assistance Program (NRC-IRAP)
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- Angiochem
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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.
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