Abstract
Phage displaying an Arg-Gly-Asp (RGD)-containing peptide with a high affinity for αv integrins homed to tumors when injected intravenously into tumor-bearing mice. A substantially higher amount of αv-directed RGD phage than control phage was recovered from malignant melanomas and breast carcinoma. Antibodies detected the αv-directed RGD phage in tumor blood vessels, but not in several normal tissues. These results show that the αv integrins present in tumor blood vessels can bind circulating ligands and that RGD peptides selective for these integrins may be suitable tools in tumor targeting for diagnostic and therapeutic purposes.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Pauli, B.U., Augustin-Voss, H.G., El-Sabban, M.E., Johnson, R.C., and Hammer, D.A. 1990. Organ-preference of metastasis. The role of endothelial cell adhesion molecules. Cancer Metastasis Rev. 9: 175–189.
Zetter, B.R. 1990. The cellular basis of site-specific tumor metastasis. N. Engl. J. Med. 322: 605–612.
Springer, T.A. 1994. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76: 301–314.
Butcher, E.C. and Picker, L.J. 1996. Lymphocyte homing and homeostasis. Science 272: 60–66.
Goetz, D.J., El-Sabban, M.E., Hammer, D.A., and Pauli, B.U. 1996. Lu-ECAM-1-mediated adhesion of melanoma cells to endothelium under conditions of flow. Int. J. Cancer 65: 192–199.
Pasqualini, R. and Ruoslahti, E. 1996. Organ targeting in vivo using phage display peptide libraries. Nature 380: 364–366.
Baillie, C.T., Winslet, M.C., and Bradley, N.J. 1995. Tumour vasculature—a potential therapeutic target. Br. J. Cancer 72: 257–267.
Burrows, F.J. and Thorpe, P.E. 1994. Vascular targeting—a new approach to the therapy of solid tumors. Pharmacol. Ther. 64: 155–174.
Buckle, R. 1994. Vascular targeting and the inhibition of angiogenesis. Ann. Oncol. 4(suppl.): 45–50.
Mustonen, T. and Alitalo, K. 1995. Endothelial receptor tyrosine kinases involved in angiogenesis. J. Cell Biol. 129: 895–898.
Lappi, D.A. 1995. Tumor targeting through fibroblast growth factor receptors. Semin. Cancer Biol. 6: 279–288.
Martiny-Baron, G. and Marme, D. 1995. VEGF-mediated tumor angiogenesis: a new target for cancer therapy. Curr. Opin. Biotechnol. 6: 675–680.
Rettig, W.J., Garin-Chesa, P., Healey, J.H., Su, S.L., Jaffe, E.A., and Old, L.J. 1992. Identification of endosialin, a cell surface glycoprotein of vascular endothelial cells in human cancer. Proc. Natl. Acad. Sci. USA 89: 10832–10836.
Brooks, P.C., Clark R.A., and Cheresh, D.A. 1994. Requirement of vascular integrin αvβ3 for angiogenesis. Science 264: 569–571.
Friedlander, M., Brooks, P.C., Sharffer, R.W., Kincaid, C.M., Varner, J.A., and Cheresh, D.A. 1995. Definition of two angiogenic pathways by distinct αv integrins. Science 270: 1500–1502.
Brooks, P.C., Montgomery, A.M., Rosenfeld, M., Reisfeld, R.A., Hu, T., Klier, G., et al. 1994. Integrin αvβ3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79: 1157–1164.
Brooks, P.C., Stromblad S., Klemle R., Visscher D., Sarkar F.H., and Cheresh, D.A. 1995. Anti-integrin αvβ3 blocks human breast cancer growth and angiogenesis in human skin. J. Clin. Invest. 96: 1815–1822.
Hammes, H.-P., Brownlee, M., Joonczyk, A., Sutter, A., and Preissner, K.T. 1996. Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularization. Nature. Med. 5: 529–533.
Conforti, G., Dominguew-Jimenez, C., Zanetti, A., Gimbrone, M.A., Cremona, O., Marchisio, P.C., et al. 1992. Human endothelial cells express integrin receptors on the luminal aspect of their membrane. Blood 80: 437–446.
Smith, G.P. and Scott, J.K. 1993. Libraries of peptides and proteins displayed in filamentous phage. Methods Enzymol. 21: 228–257.
Ruoslahti, E. 1996. RGD and other recognition sequences for integrins. Annu. Rev. Cell Dev. Biol. 12: 697–715.
Koivunen, E., Wang, B., and Ruoslahti, E. 1995. Phage libraries displaying cyclic peptides with different ring sizes: ligand specificities of the RGD-directed integrins. Bio/Technology 13: 265–270.
Geter, M.R., Trigg, M.E., and Merril, C.R. 1973. Fate of bacteriophage lambda in non-immune germ-free mice. Nature 246: 221–223.
Shockley, T.R., Lin, K., Nagy, J.A., Tompkins, R.G., Dvorak, H.F., and Yarmush, M.L 1991. Penetration of tumor tissue by antibodies and other immunoproteins. Ann. N.Y. Acad. Sci. 618: 367–382.
Dvorak, H.F., Nagy, J.A., and Dvorak, A.M. 1991. Structure of solid tumors and their vasculature: implications for therapy with monoclonal antibodies. Cancer Cells 3: 77–85.
Folkman, J. 1995. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Med. 1: 27–31.
Hanahan, D. and Folkman, J. 1996. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353–364.
Rak, J.W., St. Croix, B.D., and Kerbel, R.S. 1995. Consequences of angiogenesis for tumor progression, metastasis and cancer. Anticancer Drugs 6: 3–18.
Price, J.E., Polyzos, A., Zhang, R.D., and Daniels, L.M. 1990. Tumorigenicity and metastasis of human breast carcinoma cell lines in nude mice. Cancer Res. 50: 717–721.
Nicolson, G.L., Inoue, T., Van Pelt, C.S., and Cavanaugh, P.G. 1990. Differential expression of a Mr. approximately 90,000 cell surface transferrin receptor-related glycoprotein on murine B16 metastatic melanoma sublines selected for enhanced brain or ovary colonization. Cancer Res. 50: 515–520.
Welch, D.R., Bisi, J.E., Miller, B.E., Conaway, D., Seftor, E.A., Yohem, K.H., et al. 1991. Characterization of a highly invasive and spontaneously metastatic human malignant melanoma cell line. Int. J. Cancer 47: 227–237.
Montesano, R., Pepper, M.S., Möhle-Steinlein, U., Risau, W., Wagner, E.F., and Orci, L. 1990. Increased proteolytic activity is responsible for the aberrant morphogenetic behavior of endothelial cells expressing the middle T oncogene. Cell 62: 435–445.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Pasqualini, R., Koivunen, E. & Ruoslahti, E. αv Integrins as receptors for tumor targeting by circulating ligands. Nat Biotechnol 15, 542–546 (1997). https://doi.org/10.1038/nbt0697-542
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nbt0697-542
This article is cited by
-
Tissue factor (coagulation factor III): a potential double-edge molecule to be targeted and re-targeted toward cancer
Biomarker Research (2023)
-
Theranostic RGD@Fe3O4-Au/Gd NPs for the targeted radiotherapy and MR imaging of breast cancer
Cancer Nanotechnology (2023)
-
Antineoplastic Effects and Mechanisms of a New RGD Chimeric Peptide from Bullfrog Skin on the Proliferation and Apoptosis of B16F10 Cells
The Protein Journal (2021)
-
Brain-invasive meningiomas: molecular mechanisms and potential therapeutic options
Brain Tumor Pathology (2021)
-
Marriage of black phosphorus and Cu2+ as effective photothermal agents for PET-guided combination cancer therapy
Nature Communications (2020)