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Targeting of human renal tumor-derived endothelial cells with peptides obtained by phage display
Benedetta Bussolati1, Cristina Grange, Lorenzo Tei
1Cattedra di Nefrologia, Dipartimento di Medicina Interna, Università di Torino, Turin, Italy.
Abstract:
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.
Insights
Researchers developed a peptide (BB1) that specifically targets human tumor endothelial cells (TEC). This peptide, when linked to a toxin, selectively induced cancer cell death and disrupted tumor blood vessels in mice.
Area of Science:
- Oncology
- Vascular Biology
- Drug Discovery
Background:
- Tumor vasculature exhibits diverse phenotypes, offering targets for cancer therapy.
- Targeting tumor endothelial cells (TEC) is a strategy to inhibit tumor growth and angiogenesis.
Purpose of the Study:
- To identify and characterize peptide ligands that selectively bind to human TEC.
- To evaluate the therapeutic potential of a TEC-targeting peptide conjugated to a toxin.
Main Methods:
- Screening a phage display library in a SCID mouse model with human renal carcinoma TEC.
- In vitro and in vivo binding assays using the identified peptide (BB1).
- Assessment of BB1-saporin conjugate efficacy in inducing apoptosis and disrupting tumor vasculature.
Main Results:
- Identified cyclic peptide BB1 with specific binding to human TEC, not normal human or murine endothelial cells.
- BB1-saporin conjugate selectively induced apoptosis in TEC and disrupted the tumor vessel network in vivo.
- No significant apoptosis observed in other murine organs, indicating target specificity.
Conclusions:
- Peptide BB1 is a specific targeting agent for human tumor endothelial cells.
- BB1-saporin conjugate demonstrates potential as a targeted therapeutic for delivering antiangiogenic or antitumor agents.
