Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector Angiopep-2
Article first published online: 19 MAY 2008
© 2008 The Authors. Journal Compilation © 2008 International Society for Neurochemistry
Journal of Neurochemistry
Volume 106, Issue 4, pages 1534–1544, August 2008
How to Cite
Demeule, M., Currie, J.-C., Bertrand, Y., Ché, C., Nguyen, T., Régina, A., Gabathuler, R., Castaigne, J.-P. and Béliveau, R. (2008), Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector Angiopep-2. Journal of Neurochemistry, 106: 1534–1544. doi: 10.1111/j.1471-4159.2008.05492.x
- Issue published online: 1 AUG 2008
- Article first published online: 19 MAY 2008
- Received April 3, 2008; revised manuscript received May 8, 2008; accepted May 9, 2008.
- blood–brain barrier;
- low-density lipoprotein receptor-related protein;
The blood–brain barrier (BBB) restricts the entry of proteins as well as potential drugs to cerebral tissues. We previously reported that a family of Kunitz domain-derived peptides called Angiopeps can be used as a drug delivery system for the brain. Here, we further characterize the transcytosis ability of these peptides using an in vitro model of the BBB and in situ brain perfusion. These peptides, and in particular Angiopep-2, exhibited higher transcytosis capacity and parenchymal accumulation than do transferrin, lactoferrin, and avidin. Angiopep-2 transport and accumulation in brain endothelial cells were unaffected by the P-glycoprotein inhibitor, cyclosporin A, indicating that this peptide is not a substrate for the efflux pump P-glycoprotein. However, competition studies show that activated α2-macroglobulin, a specific ligand for the low-density lipoprotein receptor-related protein-1 (LRP1) and Angiopep-2 can share the same receptor. In addition, LRP1 was detected in glioblastomas and brain metastases from lung and skin cancers. Fluorescent microscopy also revealed that Alexa488-Angiopep-2 co-localized with LRP1 in brain endothelial cell monolayers. Overall, these results suggest that Angiopep-2 transport across the BBB is, in part, mediated by LRP1.