Thumbnail Image
Publication

Modulation of Intercellular Junctions by Cyclic-ADT Peptides as a Method to Reversibly Increase Blood-Brain Barrier Permeability

Laksitorini, Marlyn D.
; 
Kiptoo, Paul
; 
On, Ngoc
; 
Thliveris, James A.
; 
Miller, Donald W.
; 
Siahaan, Teruna J.
Citations
Altmetric:
Abstract
It is challenging to deliver molecules to the brain for diagnosis and treatment of brain diseases. This is primarily due to the presence of the blood-brain barrier (BBB), which restricts the entry of many molecules into the brain. In this study, cyclic ADT peptides (ADTC1, ADTC5, and ADTC6) have been shown to modify the BBB to enhance the delivery of marker molecules (e.g., 14C-mannitol, Gd-DTPA) to the brain via the paracellular pathways of the BBB. The hypothesis is that these peptides modulate cadherin interactions in the adherens junctions of the vascular endothelial cells forming the BBB to increase paracellular drug permeation. In vitro studies indicated that ADTC5 had the best profile to inhibit adherens junction resealing in MDCK cell monolayers in a concentration-dependent manner (IC50 = 0.3 mM) with a maximal response at 0.4 mM. Under the current experimental conditions, ADTC5 improved the delivery of 14C-mannitol to the brain about twofold compared to the negative control in the in situ rat brain perfusion model. Furthermore, ADTC5 peptide increased in vivo delivery of Gd-DTPA to the brain of Balb/c mice when administered intravenously (i.v.). In conclusion, ADTC5 has the potential to improve delivery of diagnostic and therapeutic agents to the brain.
Description
Date
2015-03
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier
Collections
Pharmaceutical Chemistry Scholarly Works
Show all metadata
Files
Thumbnail Image
Laksitorini_2015.pdf
Adobe PDF, 1.31 MB
Research Projects
Organizational Units
Journal Issue
Keywords
Citation
Laksitorini, M. D., Kiptoo, P. K., On, N. H., Thliveris, J. A., Miller, D. W., & Siahaan, T. J. (2015). Modulation of Intercellular Junctions by Cyclic-ADT Peptides as a Method to Reversibly Increase Blood-Brain Barrier Permeability. Journal of Pharmaceutical Sciences, 104(3), 1065–1075. http://doi.org/10.1002/jps.24309
URI
https://hdl.handle.net/1808/23773
DOI
10.1002/jps.24309
Embedded videos