Interaction of Oligopeptides with Heparin

  • Ruifeng Zhao
  • Mamoru Haratake
  • Raphael M. Ottenbrite

Abstract

Macromolecular drugs, such as heparin and insulin, are easily degraded by acids and enzymes in the GI tract and do not readily penetrate the lipophilic biomembranes, resulting in low bioavailability by the oral route.1–3 Currently, these drugs have to be administered by injections. Proteinoids,4–8 which can form microspheres with certain macromolecular drugs, such as heparin and insulin, have been studied as an oral drug delivery system.9–16 These spheres can protect drugs from acid and enzyme degradation in the GI tract.10–13,15 Recently, it was found that these proteinoids can facilitate drug transport through the biomembranes, possibly, in the form of a proteinoid-drug complex.9–12,17 This non-covalent complex would alter the conformation of hydrophilic drug molecules into a more hydrophobic form for lipophilic biomembrane absorption.9,17–18 However, these proteinoid materials are mixtures of oligopeptide dimers, trimers and tetramers with different structures and amino acid sequences.10–11 Based on the proteinoid results, several series of structurally defined oligopeptides with specific amino acid sequences were synthesized as potential oral drug delivery carriers in order to study the mechanism of this novel oral drug delivery system.18

Keywords

Organic Modifier Aromatic Group Cyanogen Bromide Phthalic Anhydride Oral Drug Delivery 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Byrickweiss, K. H.; Discover 1992, July, 64.Google Scholar
  2. 2.
    Erickson, D. M.; Sci. Am. 1992, Feb., 108.Google Scholar
  3. 3.
    Lee, V. H. L.; Peptide and Protein Drug Delivery, Chaps. 10 and 16, Marcel Dekker: New York, 1991.Google Scholar
  4. 4.
    Fox, S. W.; Harada, K.; J. Am. Chem. Soc. 1960, 82, 3745.CrossRefGoogle Scholar
  5. 5.
    Fox, S. W.; Nature 1965, 205, 328.CrossRefGoogle Scholar
  6. 6.
    Rohlfing, D. L.; Fox, S. W.; Arch. Biochem. Biophys. 1967, 118, 122.CrossRefGoogle Scholar
  7. 7.
    Rohlfing, D. L.; Arch. Biochem. Biophys. 1967, 118, 468.CrossRefGoogle Scholar
  8. 8.
    Fox, S. W.; Wang, C. T.; Science 1968, 160, 547.CrossRefGoogle Scholar
  9. 9.
    Milstein, S.; Unified Mechanism for Oral Drug Delivery 1997 (in press).Google Scholar
  10. 10.
    Ottenbrite, R. M.; Zhao, R.; Milstein, S.; Advanced Biomaterials in Biomedical Engineering and Drug Delivery System p 51, Springer-Verlag Tokyo, 1996.CrossRefGoogle Scholar
  11. 11.
    Ottenbrite, R. M.; Zhao, R.; Milstein, S. J.; Macrom. Symp. 1996, 101, 379.CrossRefGoogle Scholar
  12. 12.
    Ottenbrite, R. M; Zhao, R.; Chine. J. of Polym. Sci. 1995, 13(4), 187.Google Scholar
  13. 13.
    Santiago, N.; Milstein, S. J.; Rivera, T.; Gracia, E.; Chang, T. C; Baughman, R. A.; Bucher, D.; Proceed. Int’l. Symp. Contr. Release Bioact. Mater. 1992, 19, 116.Google Scholar
  14. 14.
    Santiago, N.; Rivera, T.; Mayer, E.; Milstein, S. J.; Proceed. Infl. Symp. Contrl. Release Bioact. Mater. 1992, 19, 116.Google Scholar
  15. 15.
    Ma, X.; Santiago, N.; Chen, Y-S.; Chaudhary, K.; Milstein, S. J.; Baughman, R. A.; J. Drug Targeting 1994, 2, 9.CrossRefGoogle Scholar
  16. 16.
    Steiner, S.; Rosen, R.; U. S. Patent 4925 673 1990.Google Scholar
  17. 17.
    Milstein, S.; Robinson, J. R.; Oral Bioavailability of Partially Folded Proteins 1997 (submitted for Science).Google Scholar
  18. 18.
    Zhao, R.; Haratake, M.; Ottenbrite, R. M.; Polymer Preprint 1996, 37(1), 614 and 37 (2) 153.Google Scholar
  19. 19.
    Ottenbrite, R. M.; Yang, J.; Buriana, E.; George, S. A.; Wan, M.; Reports I-IX to Emisphere Technologies Inc., 1991-1995.Google Scholar
  20. 20.
    Mascotti, D. P.; Lohman, T. M.; Biochemistry 1995, 34, 2908.CrossRefGoogle Scholar
  21. 21.
    Tyler-Cross, R.; Sobel, M.; Marques, D.; Harris, R. B.; Protein Science 1994, 3, 620.CrossRefGoogle Scholar
  22. 22.
    Mailhot, H.; Peters, R. H.; Environ. Sci. Technol. 1988, 22, 1479.CrossRefGoogle Scholar
  23. 23.
    Miyake, K.; Kitaura, F.; Mizuno, N.; Terada, H.; Chem. Phar Bull. 1987, 35(1), 377.CrossRefGoogle Scholar
  24. 24.
    Affinity Chromatography: Principles and Methods 18-1022-29, Pharmacia LKB Biotechnology, 1995.Google Scholar
  25. 25.
    Kline, T.; Handbook of Affinity Chromatography p 293, Marcel Dekker Inc.: New York, 1993.Google Scholar
  26. 26.
    Mizuno, K.; Hayashi, T.; J. Biochem. 1994, 116, 1257.Google Scholar
  27. 27.
    Jones, C; Mulloy, B.; Thomas, A. H.; Methods in Molecular Biology, v. 22: Microscopy, Optical Spectroscopy, and Macroscopic Techniques p 109–149, Human Press: Totowa, 1994.Google Scholar
  28. 28.
    Leone-Bay, A.; Milstein, S.; Paton, D.; J. Med. Chem. 1995, 38, 4257.CrossRefGoogle Scholar
  29. 29.
    Haratake, M.; Zhao, R.; Ottenbrite, R. M.; Polymer Preprints 1996, 37(2), 131.Google Scholar
  30. 30.
    Haratake, M.; Zhao, R.; Ottenbrite, R. M.; Polymer Preprints 1996, 37(2), 753.Google Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Ruifeng Zhao
    • 1
  • Mamoru Haratake
    • 1
  • Raphael M. Ottenbrite
    • 1
  1. 1.Department of ChemistryVirginia Commonwealth UniversityRichmondUSA

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