Advertisement

Annals of Biomedical Engineering

, Volume 33, Issue 8, pp 1113–1124 | Cite as

Targeting Drugs to Combinations of Receptors: A Modeling Analysis of Potential Specificity

  • Michael R. CaplanEmail author
  • Elena V. Rosca
Article

Abstract

Targeting drugs to specific cells by conjugating the drug to an antibody or ligand for a cell surface receptor currently requires that the receptor be uniquely over-expressed by the target cell (the target cell over-expresses a particular receptor in comparison with untargeted cells, which do display this receptor type but a lesser number of them). Here we develop a mathematical model to predict the behavior of multivalent ligand–drug constructs containing two different ligands for two different receptors, which would allow targeting cells that do not uniquely over-express any receptor. In this model, target cells express both receptors at a high level; whereas, untargeted cells express one receptor type at the high level but the other at a lower level. The model predicts that these heterovalent conjugates (containing two different types of ligands) can achieve specificity even when the target cell does not uniquely over-express any one receptor type. Using the current approach, constructs in which only one ligand type is used will bind as much to untargeted cells as to the target cells. Therefore, this combination strategy can enormously expand the number of applications for which cell surface receptor targeting of drugs is an appropriate option.

Keywords

Mathematical model Multivalent Biomaterial Drug delivery 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Al-Kuraya, K., P. Schraml, J. Torhorst, C. Tapia, B. Zaharieva, H. Novotny, H. Spichtin, R. Maurer, M. Mirlacher, O. Kochli, M. Zuber, H. Dieterich, F. Mross, K. Wilber, R. Simon, and G. Sauter. Prognostic relevance of gene amplifications and coamplifications in breast cancer. Cancer Res. 64(23):8534–8540, 2004.CrossRefPubMedGoogle Scholar
  2. 2.
    David, A., P. Kopeckova, T. Minko, A. Rubinstein, and J. Kopecek. Design of a multivalent galactoside ligand for selective targeting of HPMA copolymer–-doxorubicin conjugates to human colon cancer cells. Eur. J. Cancer 40:148–157, 2004.CrossRefPubMedGoogle Scholar
  3. 3.
    Gillies, R. J., and V. J. Hruby. Expression-driven reverse engineering of targeted imaging and therapeutic agents. Expert Opin. Therap. Targets 7(2):137–139, 2003.CrossRefGoogle Scholar
  4. 4.
    Goldstein, B. Desensitization, histamine release and the aggregation of IgE on human basophils. In: Theoretical Immunology, Part One: SFI Studies in the Sciences of Complexity, edited by A. S. Perelson. Redwood City, CA: Addison-Wesley, 1988, pp. 3–40.Google Scholar
  5. 5.
    Handl, H. L., J. Vagner, H. Han, E. Mash, V. J. Hruby, and R. J. Gillies. Hitting multiple targets with multimeric ligands. Expert Opin. Therap. Targets 8(6), 565–586 (22), 200.Google Scholar
  6. 6.
    Hlavacek, W. S., R. G. Posner, and A. S. Perelson. Steric effects on multivalent ligand–receptor binding: Exclusion of ligand sites by bound cell surface receptors. Biophys. J. 76:3031–3043, 1999.PubMedGoogle Scholar
  7. 7.
    Kiessling, L. L., L. E. Strong, and J. E. Gestwicki. Principles for multivalent ligand design. Annu. Rep. Med. Chem. 35:321–330, 2000.CrossRefGoogle Scholar
  8. 8.
    Kramer, R. H., and J. W. Karpen. Spanning binding sites on allosteric proteins with polymer-linked ligand dimers. Nature 395:710–713, 1998.CrossRefPubMedGoogle Scholar
  9. 9.
    Lauffenburger, D. A., and J. J. Linderman. Receptors: Models for Binding, Trafficking, and Signaling. New York: Oxford University Press, 1993, 365 pp.Google Scholar
  10. 10.
    Macken, C. A., and A. S. Perelson. Branching Processes Applied to Cell Surface Aggregation Phenomena. Heidelberg: Springer-Verlag, 1985.Google Scholar
  11. 11.
    Mammen, M., S.-K. Choi, and G. M. Whitesides. Polyvalent interactions in biological systems: Implications for design and use of multivalent ligands and inhibitors. Angew. Chem. Int. Edn. 37:2754–2794, 1998.CrossRefGoogle Scholar
  12. 12.
    Mariani, L., C. Beaudry, W. S. McDonough, D. B. Hoelzinger, T. Demuth, K. R. Ross, T. Berens, S. W. Coons, G. Watts, J. M. Trent, J. S. Wei, A. Giese, and M. E. Berens. Glioma cell motility is associated with reduced transcription of proapoptotic and proliferation genes: A cDNA microarray analysis. J. Neurooncol. 53:161–176, 2001.CrossRefPubMedGoogle Scholar
  13. 13.
    H. D. Maynard, S. Y. Okada, R. H. Grubbs. Synthesis of norbornenyl polymers with bioactive oligopeptides by ring-opening metathesis polymerization. Macromolecules 33:6239–6248, 2000.CrossRefGoogle Scholar
  14. 14.
    Maynard, H. D., S. Y. Okada, and R. H. Grubbs. Inhibition of cell adhesion to fibronectin by oligopeptide-substituted polynorbornenes. J. Am. Chem. Soc. 123:1275–1279, 2001.CrossRefPubMedGoogle Scholar
  15. 15.
    Molema, G. Drug targeting: Basic concepts and novel advances. In: Drug Targeting: Organ Specific Strategies, edited by G. Molema and D. K. Meijer. Weinheim: Wiley, 2001, pp. 1–22.Google Scholar
  16. 16.
    Olivier, V., I. Meisen, B. Meckelein, T. R. Hirst, J. Peter-Katalinic, M. A. Schmidt, and A. Frey. Influence of targeting ligand flexibility on receptor binding of particulate drug delivery systems. Bioconjug. Chem. 14:1203–1208, 2003.CrossRefPubMedGoogle Scholar
  17. 17.
    Perelson, A. S. Some mathematical models of receptor clustering by multivalent ligands. In: Cell Surface Dynamics: Concepts and Models, edited by A. S. Perelson, C. DeLisi, and F. W. Wiegel. New York: Marcel Dekker, 1984, pp. 223–276.Google Scholar
  18. 18.
    Ramanathan, M., B. Weinstock-Guttman, L. T. Nguyen, D. Badgett, C. Miller, K. Patrick, C. Brownscheidle, and L. Jacobs. In vivo gene expression revealed by cDNA arrays: The pattern in relapsing-remitting multiple sclerosis patients compared with normal subjects. J. Neuroimmunol. 116(2):213–219, 2001.CrossRefPubMedGoogle Scholar
  19. 19.
    Sakhalkar, H. S., M. K. Dalal, A. K. Salem, R. Ansari, J. Fu, M. F. Kiani, D. T. Kurjiaka, J. Hanes, K. M. Shakesheff, and D. J. Goetz. Leukocyte-inspired biodegradable particles that selectively and avidly adhere to inflamed endothelium in vitro and in vivo. Proc. Natl. Acad. Sci. U.S.A. 100(26):15895–15900, 2003.CrossRefPubMedGoogle Scholar
  20. 20.
    Sawyer, T. K., P. J. Sanfilippo, V. J. Hruby, M. H. Engel, C. B. Heward, J. B. Burnett, and M. E. Hadley. 4-Norleucine, 7-D-phenylalanine-α-melanocyte-stimulating hormone: A highly potent α-melanotropin with ultralong biological activity. Proc. Natl. Acad. Sci. U.S.A. 77(10):5754–5758, 1980.PubMedGoogle Scholar
  21. 21.
    Shadidi, M., and M. Sioud. Selective targeting of cancer cells using synthetic peptides. Drug Resist. Updates 6:363–371, 2003.CrossRefGoogle Scholar
  22. 22.
    Vagner, J., H. L. Handl, R. J. Gillies, and V. J. Hruby. Novel targeting strategy based on multimeric ligands for drug delivery and molecular imaging: Homooligomers of alpha-MSH. Bioorg. Med. Chem. Lett. 14:211–215, 2004.CrossRefPubMedGoogle Scholar
  23. 23.
    Wang, X. Z., X. C. Chen, Y. X. Chen, L. J. Zhang, D. Li, F. L. Chen, Z. X. Chen, H. Y. Chen, and Q. M. Tao. Overexpression of HBxAg in hepatocellular carcinoma and its relationship with Fas/FasL system. World J. Gastroenterol. 9(12):2671–2675, 2003.PubMedGoogle Scholar

Copyright information

© Biomedical Engineering Society 2005

Authors and Affiliations

  1. 1.Harrington Department of BioengineeringArizona State UniversityTempe

Personalised recommendations