Stability of the disulfide bond in an avidin-biotin linked chimeric peptide during in vivo transcytosis through brain endothelial cells

Journal of Drug Targeting
Y S KangU Bickel

Abstract

Drug delivery of potential neuropharmaceuticals with poor intrinsic permeability through the blood-brain barrier (BBB), such as peptides, is facilitated by coupling to a vector that undergoes receptor-mediated transcytosis through the endothelial cells of brain microvessels. When cleavable disulfide linkers are used in the synthesis of such "chimeric peptides", it is crucial that the S-S-bridge is stable during transcytosis. Cleavage within endothelial cells could result in sequestration of the drug moiety instead of passage through the BBB. In the present study the metabolically stable opioid peptide [3 H]DALDA ([3 H]Tyr-DArg-Phe-Lys-NH2 ) was used as a model drug. It was monobiotinylated with the cleavable biotin reagent sulfosuccinimidyl 2-(biotinamido)ethyl-1,3'-dithiopropionate (NHS-SS-biotin) to obtain bio-[3 H]DALDA. The biotinylated peptide was then bound to a vector for brain delivery after intravenous injection in rats, a covalent conjugate of streptavidin and the transferrin receptor monoclonal antibody, OX26. Compared to peptide without vector, brain uptake of bio-[3 H]DALDA after was increased 18-fold to reach 0.12% of the injected dose per g tissue. Transcranial microdialysis was performed for 60 min after an intr...Continue Reading

References

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Citations

Jul 10, 2003·Lancet Neurology·Eain M Cornford, Marcia E Cornford
Oct 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Hui DingJulia Y Ljubimova
Aug 20, 2014·BioMed Research International·Ravi Kant Upadhyay
Dec 18, 2003·British Journal of Clinical Pharmacology·G A FordS H D Jackson
Mar 23, 2017·Bioconjugate Chemistry·Devora Cohen-KarniSaadyah Averick
Aug 4, 2019·Progress in Neurobiology·Kasper Bendix JohnsenTorben Moos

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