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Small Azurin Derived Peptide Targets Ephrin Receptors for Radiotherapy

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Abstract

Many lung cancer treatment regimens include radiotherapy. We sought to improve the efficacy of such treatment by invoking the targeted delivery of a model radiosensitizer (nicotinamide) to malignant tissues. Ephrin receptors (Eph), which are often overexpressed in lung cancers, were selected as the target of our delivery system. Molecular targeting was achieved utilizing a small peptide derived from the C-terminal portion of azurin, a copper-containing redox protein (“cupredoxin”) that is capable of binding to ephrin receptors. We prepared and screened a sub-library of peptides derived from the C-terminal region of azurin and found several small analogues that bound ephrin receptors EphA2, EphB2, and EphB4. One such peptide, termed AzV36, was selected for conjugation with nicotinic acid via an amide bond to form AzV36-NicL. The resulting linear peptide contains 15 residues (including unusual and d-amino acids), is very stable in human serum, and can be easily manufactured. AzV36-NicL conjugate was tested in vivo for its ability to radiosensitize Lewis lung carcinoma (LCC) in artificial metastasis and solid tumor engraftment models. The compound increased the efficacy of radiotherapy with tumor colonies being ~2–13 fold lower than with radiation alone depending on experimental schedule. In contrast, equimolar amounts of unconjugated peptide (AzV36-L) or nicotinamide alone only marginally improved radiation efficacy. The targeted delivery of radiosensitizer(s) to ephrin receptors may enhance the efficacy of radiation treatment of lung cancer and of other cancers that overexpress ephrin receptor(s).

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Acknowledgments

This project was partially supported by funds from the Adams and Burnham endowments provided by the Dean’s Office of the David Geffen School of Medicine at UCLA. We also thank Robert I Lehrer, M.D. for critical reading of the manuscript and helpful discussions.

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Correspondence to Piotr Ruchala.

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Micewicz, E.D., Jung, CL., Schaue, D. et al. Small Azurin Derived Peptide Targets Ephrin Receptors for Radiotherapy. Int J Pept Res Ther 17, 247–257 (2011). https://doi.org/10.1007/s10989-011-9265-9

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  • DOI: https://doi.org/10.1007/s10989-011-9265-9

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