title: Modulation of intercellular junctions by cyclic-ADT peptides as a method to reversibly increase blood-brain barrier permeability.
abstract: It is challenging to deliver molecules to the brain for diagnosis and treatment of brain diseases. This is primarily because of 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., (14) C-mannitol, gadolinium-diethylenetriaminepentacetate (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 Madin-Darby canine kidney 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 (14) C-mannitol to the brain about twofold compared with 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. In conclusion, ADTC5 has the potential to improve delivery of diagnostic and therapeutic agents to the brain.
authors: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas, 66047.
authors: Marlyn D
authors: MD
authors: Laksitorini
authors: Paul K
authors: PK
authors: Kiptoo
authors: Ngoc H
authors: NH
authors: On
authors: James A
authors: JA
authors: Thliveris
authors: Donald W
authors: DW
authors: Miller
authors: Teruna J
authors: TJ
authors: Siahaan
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects*; D003287:Contrast Media / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D019786:Gadolinium DTPA / Q000378:metabolism; D007275:Injections, Intravenous; D007365:Intercellular Junctions / Q000187:drug effects* / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008279:Magnetic Resonance Imaging; D008353:Mannitol / Q000378:metabolism; D008807:Mice, Inbred BALB C; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D003287:Contrast Media; D004337:Drug Carriers; D010456:Peptides, Cyclic; D008353:Mannitol; D011092:Polyethylene Glycols; D019786:Gadolinium DTPA
keywords: CNS; absorption enhancer; blood-brain barrier; imaging methods; paracellular transport; permeability; permeation enhancers
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