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. 1993 Apr 1;90(7):2618–2622. doi: 10.1073/pnas.90.7.2618

Pharmacologic effects in vivo in brain by vector-mediated peptide drug delivery.

U Bickel 1, T Yoshikawa 1, E M Landaw 1, K F Faull 1, W M Pardridge 1
PMCID: PMC46146  PMID: 8385339

Abstract

Pharmacologic effects in brain caused by systemic administration of neuropeptides are prevented by poor transport of the peptide through the brain vascular endothelium, which comprises the blood-brain barrier in vivo. In the present study, successful application of a chimeric peptide approach to enhance drug delivery through the blood-brain barrier for the purpose of achieving a central nervous system pharmacologic effect is described. The chimeric peptide was formed by linkage of a potent vasoactive intestinal peptide (VIP) analogue, which had been monobiotinylated, to a drug transport vector. The vector consisted of a covalent conjugate of avidin and the OX26 monoclonal antibody to the transferrin receptor. Owing to the high concentration of transferrin receptors on brain capillary endothelia, OX26 targets brain and undergoes receptor-mediated transcytosis through the blood-brain barrier. Systemic infusion of low doses (12 micrograms/kg) of the VIP chimeric peptide in rats resulted in an in vivo central nervous system pharmacologic effect: a 65% increase in cerebral blood flow. Biotinylated VIP analogue without the brain transport vector was ineffective.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alpert A. J. Hydrophilic-interaction chromatography for the separation of peptides, nucleic acids and other polar compounds. J Chromatogr. 1990 Jan 19;499:177–196. doi: 10.1016/s0021-9673(00)96972-3. [DOI] [PubMed] [Google Scholar]
  2. Amenta F., Cavalotti C., De Michele M., De Vincentis G., Rossodivita A., Rossodivita I. Vasoactive intestinal polypeptide receptors in rat cerebral vessels: an autoradiographic study. J Auton Pharmacol. 1991 Oct;11(5):285–293. doi: 10.1111/j.1474-8673.1991.tb00252.x. [DOI] [PubMed] [Google Scholar]
  3. Andersson M., Marie J. C., Carlquist M., Mutt V. The preparation of biotinyl-epsilon-aminocaproylated forms of the vasoactive intestinal polypeptide (VIP) as probes for the VIP receptor. FEBS Lett. 1991 Apr 22;282(1):35–40. doi: 10.1016/0014-5793(91)80439-a. [DOI] [PubMed] [Google Scholar]
  4. Dacey R. G., Jr, Bassett J. E., Takayasu M. Vasomotor responses of rat intracerebral arterioles to vasoactive intestinal peptide, substance P, neuropeptide Y, and bradykinin. J Cereb Blood Flow Metab. 1988 Apr;8(2):254–261. doi: 10.1038/jcbfm.1988.56. [DOI] [PubMed] [Google Scholar]
  5. Edvinsson L., McCulloch J., Kelly P. A., Tuor U. I. Role of vasoactive intestinal peptide and peptide histidine isoleucine in the cerebral circulation. Ann N Y Acad Sci. 1988;527:378–392. doi: 10.1111/j.1749-6632.1988.tb26994.x. [DOI] [PubMed] [Google Scholar]
  6. Feener E. P., Shen W. C., Ryser H. J. Cleavage of disulfide bonds in endocytosed macromolecules. A processing not associated with lysosomes or endosomes. J Biol Chem. 1990 Nov 5;265(31):18780–18785. [PubMed] [Google Scholar]
  7. Fishman J. B., Rubin J. B., Handrahan J. V., Connor J. R., Fine R. E. Receptor-mediated transcytosis of transferrin across the blood-brain barrier. J Neurosci Res. 1987;18(2):299–304. doi: 10.1002/jnr.490180206. [DOI] [PubMed] [Google Scholar]
  8. Friden P. M., Walus L. R., Musso G. F., Taylor M. A., Malfroy B., Starzyk R. M. Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4771–4775. doi: 10.1073/pnas.88.11.4771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Goldstein A., Nestor J. J., Jr, Naidu A., Newman S. R. "DAKLI": a multipurpose ligand with high affinity and selectivity for dynorphin (kappa opioid) binding sites. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7375–7379. doi: 10.1073/pnas.85.19.7375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Green N. M. Avidin and streptavidin. Methods Enzymol. 1990;184:51–67. doi: 10.1016/0076-6879(90)84259-j. [DOI] [PubMed] [Google Scholar]
  11. Huffman L. J., Connors J. M., Hedge G. A. VIP and its homologues increase vascular conductance in certain endocrine and exocrine glands. Am J Physiol. 1988 Apr;254(4 Pt 1):E435–E442. doi: 10.1152/ajpendo.1988.254.4.E435. [DOI] [PubMed] [Google Scholar]
  12. Jefferies W. A., Brandon M. R., Hunt S. V., Williams A. F., Gatter K. C., Mason D. Y. Transferrin receptor on endothelium of brain capillaries. Nature. 1984 Nov 8;312(5990):162–163. doi: 10.1038/312162a0. [DOI] [PubMed] [Google Scholar]
  13. Kumagai A. K., Eisenberg J. B., Pardridge W. M. Absorptive-mediated endocytosis of cationized albumin and a beta-endorphin-cationized albumin chimeric peptide by isolated brain capillaries. Model system of blood-brain barrier transport. J Biol Chem. 1987 Nov 5;262(31):15214–15219. [PubMed] [Google Scholar]
  14. Larsson L. I., Edvinsson L., Fahrenkrug J., Håkanson R., Owman C., Schaffalitzky de Muckadell O., Sundler F. Immunohistochemical localization of a vasodilatory polypeptide (VIP) in cerebrovascular nerves. Brain Res. 1976 Aug 27;113(2):400–404. doi: 10.1016/0006-8993(76)90951-3. [DOI] [PubMed] [Google Scholar]
  15. Lee T. J., Saito A., Berezin I. Vasoactive intestinal polypeptide-like substance: the potential transmitter for cerebral vasodilation. Science. 1984 May 25;224(4651):898–901. doi: 10.1126/science.6719122. [DOI] [PubMed] [Google Scholar]
  16. Leroux P., Vaudry H., Fournier A., St-Pierre S., Pelletier G. Characterization and localization of vasoactive intestinal peptide receptors in the rat lung. Endocrinology. 1984 May;114(5):1506–1512. doi: 10.1210/endo-114-5-1506. [DOI] [PubMed] [Google Scholar]
  17. McCulloch J., Edvinsson L. Cerebral circulatory and metabolic effects of vasoactive intestinal polypeptide. Am J Physiol. 1980 Apr;238(4):H449–H456. doi: 10.1152/ajpheart.1980.238.4.H449. [DOI] [PubMed] [Google Scholar]
  18. McMaster D., Suzuki Y., Rorstad O., Lederis K. Iodinated derivatives of vasoactive intestinal peptide (VIP), PHI and PHM: purification, chemical characterization and biological activity. Peptides. 1987 Jul-Aug;8(4):663–676. doi: 10.1016/0196-9781(87)90042-8. [DOI] [PubMed] [Google Scholar]
  19. Munson P. J., Rodbard D. Ligand: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem. 1980 Sep 1;107(1):220–239. doi: 10.1016/0003-2697(80)90515-1. [DOI] [PubMed] [Google Scholar]
  20. O'Donnell M., Garippa R. J., O'Neill N. C., Bolin D. R., Cottrell J. M. Structure-activity studies of vasoactive intestinal polypeptide. J Biol Chem. 1991 Apr 5;266(10):6389–6392. [PubMed] [Google Scholar]
  21. Pardridge W. M., Boado R. J. Enhanced cellular uptake of biotinylated antisense oligonucleotide or peptide mediated by avidin, a cationic protein. FEBS Lett. 1991 Aug 19;288(1-2):30–32. doi: 10.1016/0014-5793(91)80996-g. [DOI] [PubMed] [Google Scholar]
  22. Pardridge W. M., Buciak J. L., Friden P. M. Selective transport of an anti-transferrin receptor antibody through the blood-brain barrier in vivo. J Pharmacol Exp Ther. 1991 Oct;259(1):66–70. [PubMed] [Google Scholar]
  23. Pardridge W. M., Eisenberg J., Cefalu W. T. Absence of albumin receptor on brain capillaries in vivo or in vitro. Am J Physiol. 1985 Sep;249(3 Pt 1):E264–E267. doi: 10.1152/ajpendo.1985.249.3.E264. [DOI] [PubMed] [Google Scholar]
  24. Pardridge W. M., Eisenberg J., Yang J. Human blood-brain barrier transferrin receptor. Metabolism. 1987 Sep;36(9):892–895. doi: 10.1016/0026-0495(87)90099-0. [DOI] [PubMed] [Google Scholar]
  25. Rorstad O. P., Wanke I., Coy D. H., Fournier A., Huang M. Selectivity for binding of peptide analogs to vascular receptors for vasoactive intestinal peptide. Mol Pharmacol. 1990 Jun;37(6):971–977. [PubMed] [Google Scholar]
  26. Suzuki Y., McMaster D., Huang M., Lederis K., Rorstad O. P. Characterization of functional receptors for vasoactive intestinal peptide in bovine cerebral arteries. J Neurochem. 1985 Sep;45(3):890–899. doi: 10.1111/j.1471-4159.1985.tb04077.x. [DOI] [PubMed] [Google Scholar]
  27. Triguero D., Buciak J., Pardridge W. M. Capillary depletion method for quantification of blood-brain barrier transport of circulating peptides and plasma proteins. J Neurochem. 1990 Jun;54(6):1882–1888. doi: 10.1111/j.1471-4159.1990.tb04886.x. [DOI] [PubMed] [Google Scholar]
  28. Wei E. P., Kontos H. A., Said S. I. Mechanism of action of vasoactive intestinal polypeptide on cerebral arterioles. Am J Physiol. 1980 Dec;239(6):H765–H768. doi: 10.1152/ajpheart.1980.239.6.H765. [DOI] [PubMed] [Google Scholar]
  29. Wilson D. A., O'Neill J. T., Said S. I., Traystman R. J. Vasoactive intestinal polypeptide and the canine cerebral circulation. Circ Res. 1981 Jan;48(1):138–148. doi: 10.1161/01.res.48.1.138. [DOI] [PubMed] [Google Scholar]
  30. Yaksh T. L., Wang J. Y., Go V. L. Cortical vasodilatation produced by vasoactive intestinal polypeptide (VIP) and by physiological stimuli in the cat. J Cereb Blood Flow Metab. 1987 Jun;7(3):315–326. doi: 10.1038/jcbfm.1987.69. [DOI] [PubMed] [Google Scholar]
  31. Yoshikawa T., Pardridge W. M. Biotin delivery to brain with a covalent conjugate of avidin and a monoclonal antibody to the transferrin receptor. J Pharmacol Exp Ther. 1992 Nov;263(2):897–903. [PubMed] [Google Scholar]
  32. Zhang E. T., Mikkelsen J. D., Fahrenkrug J., Møller M., Kronborg D., Lauritzen M. Prepro-vasoactive intestinal polypeptide-derived peptide sequences in cerebral blood vessels of rats: on the functional anatomy of metabolic autoregulation. J Cereb Blood Flow Metab. 1991 Nov;11(6):932–938. doi: 10.1038/jcbfm.1991.158. [DOI] [PubMed] [Google Scholar]

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