Targeting of human renal tumor-derived endothelial cells with peptides obtained by phage display.
The phenotypic and molecular diversity of tumor-associated vasculature provides a basis for the development of targeted diagnostics and therapeutics. In the present study, we have developed a peptide-based targeting of human tumor endothelial cells (TEC) derived from renal carcinomas. We used a murine model of human tumor angiogenesis, in which TEC injected subcutaneously in severe combined immunodeficiency (SCID) mice organized in vascular structures connected with the mouse circulation, to screen in vivo a phage display library of random peptides. Using this approach, we identified cyclic peptides showing specific binding to TEC and not to normal human endothelial cells or to murine tumor endothelial cells. In particular, the peptide CVGNDNSSC (BB1) bound to TEC in vitro and in vivo. Using BB1 peptide conjugated with the ribosome-inactivating toxin saporin, we targeted TEC in vivo. Injection of BB1-saporin but not saporin alone or control modified BB-1ala saporin induced a selective cell apoptosis and disruption of the TEC vessel network. No increase in cell apoptosis was found in other murine organs. In conclusion, the identification of peptide sequences able to bind selectively human tumor-derived endothelial cells may represent a tool to deliver antiangiogenic or antitumor agents within the neoplastic vessels.
Bussolati
Benedetta
B
Cattedra di Nefrologia, Dipartimento di Medicina Interna, Università di Torino, Turin, Italy.
Grange
Cristina
C
Tei
Lorenzo
L
Deregibus
Maria Chiara
MC
Ercolani
Mauro
M
Aime
Silvio
S
Camussi
Giovanni
G
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D016253:Microscopy, Immunoelectron; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D011485:Protein Binding; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D019151:Peptide Library; D010455:Peptides