Targeting Drugs to Combinations of Receptors: A Modeling Analysis of Potential Specificity
- 202 Downloads
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.
KeywordsMathematical model Multivalent Biomaterial Drug delivery
Unable to display preview. Download preview PDF.
- 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
- 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.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
- 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.Macken, C. A., and A. S. Perelson. Branching Processes Applied to Cell Surface Aggregation Phenomena. Heidelberg: Springer-Verlag, 1985.Google Scholar
- 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
- 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
- 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.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.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.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