Transport characteristics of a novel peptide platform for CNS therapeutics

J Cell Mol Med. 2010 Dec;14(12):2827-39. doi: 10.1111/j.1582-4934.2009.00930.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Nuclear / analysis
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism*
  • Brain / blood supply
  • Brain / drug effects
  • Brain / metabolism*
  • Carbocyanines
  • Drug Delivery Systems*
  • Endothelial Cells / metabolism
  • Glial Fibrillary Acidic Protein / analysis
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism
  • Mice
  • Microscopy, Fluorescence
  • Nerve Tissue Proteins / analysis
  • Peptides / metabolism*
  • Protein Transport
  • Radioligand Assay
  • Rats
  • Transcytosis


  • Angiopep-2
  • Antigens, Nuclear
  • CY5.5 cyanine dye
  • Carbocyanines
  • Glial Fibrillary Acidic Protein
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Nerve Tissue Proteins
  • Peptides
  • neuronal nuclear antigen NeuN, human