Molecules 2011, 16(2), 1559-1578; doi:10.3390/molecules16021559
Article

Challenges in Optimizing a Prostate Carcinoma Binding Peptide, Identified through the Phage Display Technology

1 Department of Radiooncology and Radiation Therapy, University of Heidelberg, INF 400, 69120, Heidelberg, Germany 2 Research Laboratories, Bayer Schering Pharma AG, Berlin, Germany 3 Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, INF 260, 69120, Heidelberg, Germany 4 Department of Nuclear Medicine, University of Heidelberg, INF 400, 69120 Heidelberg, Germany
* Author to whom correspondence should be addressed.
Received: 15 December 2010; in revised form: 9 February 2011 / Accepted: 11 February 2011 / Published: 14 February 2011
(This article belongs to the Special Issue Phage Display of Combinatorial Libraries)
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Abstract: The transfer of peptides identified through the phage display technology to clinical applications is difficult. Major drawbacks are the metabolic degradation and label instability. The aim of our work is the optimization of DUP-1, a peptide which was identified by phage display to specifically target human prostate carcinoma. To investigate the influence of chelate conjugation, DOTA was coupled to DUP-1 and labeling was performed with 111In. To improve serum stability cyclization of DUP-1 and targeted D-amino acid substitution were carried out. Alanine scanning was performed for identification of the binding site and based on the results peptide fragments were chemically synthesized. The properties of modified ligands were investigated in in vitro binding and competition assays. In vivo biodistribution studies were carried out in mice, carrying human prostate tumors subcutaneously. DOTA conjugation resulted in different cellular binding kinetics, rapid in vivo renal clearance and increased tumor-to-organ ratios. Cyclization and D-amino acid substitution increased the metabolic stability but led to binding affinity decrease. Fragment investigation indicated that the sequence NRAQDY might be significant for target-binding. Our results demonstrate challenges in optimizing peptides, identified through phage display libraries, and show that careful investigation of modified derivatives is necessary in order to improve their characteristics.
Keywords: phage display; peptide; prostate carcinoma; radiolabeling; affinity

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MDPI and ACS Style

Askoxylakis, V.; Zitzmann-Kolbe, S.; Zoller, F.; Altmann, A.; Markert, A.; Rana, S.; Marr, A.; Mier, W.; Debus, J.; Haberkorn, U. Challenges in Optimizing a Prostate Carcinoma Binding Peptide, Identified through the Phage Display Technology. Molecules 2011, 16, 1559-1578.

AMA Style

Askoxylakis V, Zitzmann-Kolbe S, Zoller F, Altmann A, Markert A, Rana S, Marr A, Mier W, Debus J, Haberkorn U. Challenges in Optimizing a Prostate Carcinoma Binding Peptide, Identified through the Phage Display Technology. Molecules. 2011; 16(2):1559-1578.

Chicago/Turabian Style

Askoxylakis, Vasileios; Zitzmann-Kolbe, Sabine; Zoller, Frederic; Altmann, Annette; Markert, Annette; Rana, Shoaib; Marr, Annabell; Mier, Walter; Debus, Jürgen; Haberkorn, Uwe. 2011. "Challenges in Optimizing a Prostate Carcinoma Binding Peptide, Identified through the Phage Display Technology." Molecules 16, no. 2: 1559-1578.

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