Modulation of Blood–Brain Barrier Permeability in Mice Using Synthetic E-Cadherin Peptide

Abstract

The present work characterizes the effects of synthetic E-cadherin peptide (HAV) on blood–brain barrier (BBB) integrity using various techniques including magnetic resonance imaging (MRI) and near-infrared fluorescent imaging (NIRF). The permeability of small molecular weight permeability marker gadolinium diethylenetriaminepentaacetate (Gd-DTPA) contrast agent, the large molecular weight permeability marker, IRDye 800CW PEG, and the P-glycoprotein (P-gp) efflux transporter contrast agent, rhodamine 800 (R800), were examined in the presence and absence of HAV peptide. The results consistently demonstrated that systemic iv administration of HAV peptide resulted in a reversible disruption of BBB integrity and enhanced the accumulation of all the dyes examined. The magnitude of increase ranged from 2-fold to 5-fold depending on the size and the properties of the permeability markers. The time frame for BBB disruption with HAV peptide was rapid, occurring within 3–6 min following injection of the peptide. Furthermore, modulation of BBB permeability was reversible with the barrier integrity being restored within 60 min of the injection. The increased BBB permeability observed following HAV peptide administration was not attributable to changes in cerebral blood flow. These studies support the potential use of cadherin peptides to rapidly and reversibly modulate BBB permeability of a variety of therapeutic agents.

Comparison of Linear and Cyclic His-Ala-Val Peptides in Modulating the Blood-Brain Barrier Permeability: Impact on Delivery of Molecules to the Brain

“…37 Despite these regional differences in basal BBB permeability, the cadherin peptides were able to modulate BBB permeability in all regions examined. These results were consistent with previous studies with other cadherin peptides such as HAV6 25 and cyclic ADTC5. 26 …”

“…Before administration of Gd-DTPA, T1- and T2-weighted brain images were obtained as background. 25 Then Gd-DTPA (0.4 mmol/kg) along with cHAVc3 (0.001–0.10 mmol/kg), HAV4 (0.001–0.10 mmol/kg), or PBS was administered via tail vein. Every 3 min, a T1-weighted image was obtained up to 21-min imaging session followed by a second dose of Gd-DTPA at 21 min; then, T1-weighted images were collected every 3 min for another 21-min.…”

“…25,28,29 IRDye 800CW PEG (0.01 μmol/kg), a pegylated dye of approximately 25 kDa molecular weight, and R800 (0.032 μmol/kg) as P-gp substrate were delivered and detected in the brain using NIRF. 6,30 These marker molecules were delivered via i.v, route into mice in three different treatment regimens.…”

Assessing Blood Brain Barrier Permeability in Traumatic Brain Injury Research

“…Infra-red imaging contrast agents of various sizes have also been used by preclinical investigators in direct and indirect BBB permeability assays. An example of a small agent is the P-glycoprotein efflux transporter contrast molecule, rhodamine 800 (0.5 kDa) [23,24]. Larger molecular weight permeability markers include IRDye 800CW which can vary in size from 15 kDa and upwards, depending on conjugation [25].…”

Brain Delivery of Drug and MRI Contrast Agent: Detection and Quantitative Determination of Brain Deposition of CPT-Glu Using LC–MS/MS and Gd-DTPA Using Magnetic Resonance Imaging

“…10-12 HAV and ADT peptides derived from the EC1 domain of E-cadherin caused increases in paracellular permeation of 14 C-mannitol through Madin-Darby canine kidney (MDCK) cell monolayers, and these peptides caused a drop in transepithelial electrical resistance (TEER) values of the cell monolayers. 13, 14 Furthermore, HAV6 peptide (Ac-SHAVSS-NH 2 ) enhanced the paracellular permeation of the anticancer drug 3 H(G)-daunomycin and 14 C-mannitol across the BBB in an in situ brain perfusion rat model.…”