Abstract
Molecular medicine has discovered many new therapeutic modalities using state-of-the art techniques in molecular biology. High through-put, in vitro assays that screen for pharmacological actions on the cell type of interest are frequently used in the design of new drugs. Although the potential for such agents is great and certainly justified by their success in vitro, they frequently perform much less effectively in vivo where the agent must reach its target cells in a tissue in sufficient quantities to be potent, while sparing bystander organs. Depending on the route of administration, the endothelium and/or epithelium form significant barriers that greatly limit the in vivo accessibility of many drugs, antibodies, and gene vectors to their intended target sites of pharmacological action, namely specific cells inside the tissue (1, 2). For example, poor tissue penetration has hindered the ability of many monoclonal antibodies to reach their cell-specific antigens and thus to achieve effective tissue- or cell-directed pharmaco-delivery in vivo (1–3). Understanding general and selective transport across key cell barriers to pharmaco-delivery in vivo is fundamental to achieving effective directed therapy. Moving the target from the tissue cell surface to the surface of the cell barrier, such as the vascular endothelium, has many theoretical advantages in tissue-specific delivery (4–7). The newly discovered molecular heterogeneity of endothelia among different tissues invites a new strategy of vascular targeting. Yet, this vascular targeting strategy still requires both validation in vivo and, to be useful for many therapies, a means by which to cross the vascular wall for access to underlying tissue cells (4). This chapter will not focus on all the elements and requirements for the “ideal” drug delivery system (for review, see (1)) but will be limited to an essential and critical component of access and getting intravenously injected agents specifically to a single tissue as well as inside the tissue across the endothelial cell border to the intended target cells.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Tomlinson, E. Theory and practice of site-specific drug delivery. Advanced Drug Delivery Reviews 1987; 1: 87–198.
Jain, R. K. The next frontier of molecular medicine: delivery of therapeutics. Nat Med 1998; 4: 655–7.
Dvorak, H. F., Nagy, J. A. and Dvorak, A. M. Structure of solid tumors and their vasculature: implications for therapy with monoclonal antibodies. Cancer Cells 1991; 3: 77–85.
Schnitzer, J. E. Vascular targeting as a strategy for cancer therapy. N Engl J Med 1998; 339: 472–4.
Schnitzer, J. E. Update on the cellular and molecular basis of capillary permeability. Trends in Cardiovasc. Med. 1993; 3: 124–30.
Denekamp, J. Vasculature as a target for tumour therapy. Progr. Appli. Microcirc. 1984; 4: 28–38.
Burrows, F. J. and Thorpe, P. E. Vascular targeting-a new approach to the therapy of solid tumors. Pharmacol Ther 1994; 64: 155–74.
Schnitzer, J. E. “The endothelial cell surface and caveolae in health and disease.” in Vascular Endothelium: Physiology, Pathology and Therapeutic Opportunities, G.V.R. Born and C.J. Schwartz, ed. Stuttgart, Schattauer, 1997.
McIntosh, D. P., Tan, X.-Y., Oh, P. and Schnitzer, J. E. Targeting endothelium and its dynamic caveolae for tissue-specific transcytosis in vivo: A pathway to overcome cell barriers to drug and gene delivery. Proc Natl Acad Sci U S A 2002; 99: 1996–2001.
Renkin, E. M. Capillary transport of macromolecules: pores and other pathways. J. Appl. Physiol. 1985; 134: 375–82.
Schnitzer, J. E. “Transport functions of the glycocalyx, specific proteins and caveolae in endothelium.” in Capillary Permeation, Cellular Transport and Reaction Kinetics, J.B. Bassingthwaighte, C.A. Goresky and J.H. Lineham, ed. London, Oxford Press, 1997.
Montesano, R., Roth, J., Robert, A. and Orci, L. Non-coated membrane invaginations are involved in binding and internalization of cholera and tetanus toxins. Nature 1982; 296: 651–53.
Schnitzer, J. E., Oh, P., Pinney, E. and Allard, J. Filipin-sensitive caveolae-mediated transport in endothelium: reduced transcytosis, scavenger endocytosis, and capillary permeability of select macromolecules. J. Cell. Biol. 1994; 127: 1217–32.
Schnitzer, J. E., Oh, P., Pinney, E. and Allard, J. NEM inhibits transcytosis, endocytosis and capillary permeability: implication of caveolae fusion in endothelia. Am. J. Physiol. 1995; 37: H48–55.
Schnitzer, J. E., Oh, P. and McIntosh, D. P. Role of GTP hydrolysis in fission of caveolae directly from plasma membrane [publisher’s erratum appears in Science 1996 Nov 15;274(5290):1069]. Science 1996; 274: 239–42.
Bundgaard, M. Vesicular transport in capillary endothelium: does it occur? Federation Proc. 1983; 42: 2425–30.
Schnitzer, J. E. Caveolae: from basic trafficking mechanisms to targeting transcytosis for tissue-specific drug and gene delivery in vivo. Adv Drug Deliv Rev 2001; 49: 265–80.
Schnitzer, J. E., McIntosh, D. P., Dvorak, A. M., Liu, J. and Oh, P. Separation of caveolae from associated microdomains of GPI-anchored proteins. Science 1995; 269: 1435–39.
Oh, P., McIntosh, D. P. and Schnitzer, J. E. Dynamin at the neck of caveolae mediates their budding to form transport vesicles by GTP-driven fission from the plasma membrane of endothelium. J Cell Biol 1998; 141: 101–14.
Oh, P. and Schnitzer, J. E. Dynamin-mediated fission of caveolae from plasma membranes. Mol. Biol. Cell 1996; 7: 83a.
Stewart, P. A. and Wiley, M. J. Developing nervous tissue induces formation of blood-brain barrier characteristics in invading endothelial cells: a study using quail-chick transplantation chimeras. Develop Biol 1981; 84: 183–92.
Pasqualini, R. and Ruoslahti, E. Organ targeting in vivo using phage display peptide libraries. Nature 1996; 380: 364–66.
Arap, W., Pasqualini, R. and Ruoslahti, E. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 1998; 279: 377–80.
Johnson, R. C., Zhu, D., Augustin-Voss, H. G. and Pauli, B. U. Lung endothelial dipeptidyl peptidase IV is an adhesion molecule for lung-metastatic rat breast and prostate carcinoma cells. J Cell Biology 1993; 121: 1423–32.
Auerbach, R., Lu, W. C., Pardon, E., Gumkowski, F., Kaminska, G. and Kaminski, M. Specificity of adhesion between murine tumor cells and capillary endothelium: an in vitro correlate of preferential metastasis in vivo. Cancer Res 1987; 47: 1492–96.
Nicolson, G. L. Cancer metastasis: tumor cell and host organ properties important in metastasis to specific secondary sites. Biochim Biophys Acta 1988; 948: 175–224.
Springer, T. A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep program. Cell 1994; 76: 301–14.
Schnitzer, J. E., Liu, J. and Oh, P. Endothelial caveolae have the molecular transport machinery for vesicle budding, docking and fusion including VAMP, NSF, SNAP, annexins and GTPases. J. Biol. Chem. 1995; 270: 14399–404.
Washburn, M. P., Wolters, D. and Yates, J. R., 3rd Large-scale analysis of the yeast proteome by multidimensional protein identification technology. Nature Biotechnology 2001; 19: 242–47.
Hughes, B. J., Kennel, S. K., Lee, R. and Huang, L. Monoclonal antibody targeting of liposomes to mouse lung in vivo. Cancer Res 1989; 49: 6214–20.
Muzykantov, V. R., Atochina, E. N., Ischiropoulos, H., Danilov, S. M. and Fisher, A. B. Immunotargeting of antioxidant enzyme to the pulmonary endothelium. Proc Natl Acad Sci U S A 1996; 93: 5213–8.
Scherpereel, A., Wiewrodt, R., Christofidou-Solomidou, M., Gervais, R., Murciano, J. C., Albelda, S. M. and Muzykantov, V. R. Cell-selective intracellular delivery of a foreign enzyme to endothelium in vivo using vascular immunotargeting. Faseb J 2001; 15: 416–26.
Shin, S. U., Friden, P., Moran, M., Olson, T., Kang, Y. S., Pardridge, W. M. and Morrison, S. L. Transferrin-antibody fusion proteins are effective in brain targeting. Proc Natl Acad Sci U S A 1995; 92: 2820–4.
Lee, H. J., Engelhardt, B., Lesley, J., Bickel, U. and Pardridge, W. M. Targeting rat anti-mouse transferrin receptor monoclonal antibodies through blood-brain barrier in mouse. J Pharmacol Exp Ther 2000; 292: 1048–52.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2002 Springer Science+Business Media New York
About this chapter
Cite this chapter
Carver, L.A., Schnitzer, J.E. (2002). Tissue-Specific Pharmacodelivery and Overcoming Key Cell Barriers in Vivo: Vascular Targeting of Caveolae. In: Muzykantov, V., Torchilin, V. (eds) Biomedical Aspects of Drug Targeting. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-4627-3_6
Download citation
DOI: https://doi.org/10.1007/978-1-4757-4627-3_6
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4419-5312-4
Online ISBN: 978-1-4757-4627-3
eBook Packages: Springer Book Archive