Theranostics 2014; 4(7):745-760. doi:10.7150/thno.7811 This issue Cite

Research Paper

Dimerization of a Phage-Display Selected Peptide for Imaging of αvβ6- Integrin: Two Approaches to the Multivalent Effect

Ajay N. Singh1, Michael J. McGuire2, Shunzi Li2, Guiyang Hao1, Amit Kumar1, Xiankai Sun1,3,4✉, Kathlynn C. Brown2,4✉

1. Department of Radiology,
2. Department of Internal Medicine,
3. Advanced Imaging Research Center, and
4. The Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.

Citation:
Singh AN, McGuire MJ, Li S, Hao G, Kumar A, Sun X, Brown KC. Dimerization of a Phage-Display Selected Peptide for Imaging of αvβ6- Integrin: Two Approaches to the Multivalent Effect. Theranostics 2014; 4(7):745-760. doi:10.7150/thno.7811. https://www.thno.org/v04p0745.htm
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Abstract

Graphic abstract

The integrin αvβ6 is an emerging biomarker for non-small cell lung cancer (NSCLC). An αvβ6-binding peptide was previously selected from a phage-displayed peptide library. Here, we utilize a multivalent design to develop a peptidic probe for positron emission tomography (PET) imaging of αvβ6+ NSCLC tumors. Multimeric presentation of this peptide, RGDLATLRQL, on a bifunctional copper chelator was achieved using two approaches: dimerization of the peptide followed by conjugation to the chelator (H2-D10) and direct presentation of two copies of the peptide on the chelator scaffold (H2-(M10)2). Binding affinities of the divalent peptide conjugates are four-fold higher than their monovalent counterpart (H2-M10), suggestive of multivalent binding. PET imaging using the bivalent 64Cu-labeled conjugates showed rapid and persistent accumulation in αvβ6+ tumors. By contrast, no significant accumulation was observed in αvβ6- tumors. Irrespective of the dimerization approach, all divalent probes showed three-fold higher tumor uptake than the monovalent probe, indicating the role of valency in signal enhancement. However, the divalent probes have elevated uptake in non-target organs, especially the kidneys. To abrogate nonspecific uptake, the peptide's N-terminus was acetylated. The resultant bivalent probe, 64Cu- AcD10, showed drastic decrease of kidney accumulation while maintaining tumor uptake. In conclusion, we developed an αvβ6-integrin specific probe with optimized biodistribution for noninvasive PET imaging of NSCLC. Further, we have demonstrated that use of multivalent scaffolds is a plausible method to improve library selected peptides, which would be suboptimal or useless otherwise, for imaging probe development.

Keywords: Lung Cancer, Molecular Imaging, Positron Emission Tomography, Integrin, Peptide.


Citation styles

APA
Singh, A.N., McGuire, M.J., Li, S., Hao, G., Kumar, A., Sun, X., Brown, K.C. (2014). Dimerization of a Phage-Display Selected Peptide for Imaging of αvβ6- Integrin: Two Approaches to the Multivalent Effect. Theranostics, 4(7), 745-760. https://doi.org/10.7150/thno.7811.

ACS
Singh, A.N.; McGuire, M.J.; Li, S.; Hao, G.; Kumar, A.; Sun, X.; Brown, K.C. Dimerization of a Phage-Display Selected Peptide for Imaging of αvβ6- Integrin: Two Approaches to the Multivalent Effect. Theranostics 2014, 4 (7), 745-760. DOI: 10.7150/thno.7811.

NLM
Singh AN, McGuire MJ, Li S, Hao G, Kumar A, Sun X, Brown KC. Dimerization of a Phage-Display Selected Peptide for Imaging of αvβ6- Integrin: Two Approaches to the Multivalent Effect. Theranostics 2014; 4(7):745-760. doi:10.7150/thno.7811. https://www.thno.org/v04p0745.htm

CSE
Singh AN, McGuire MJ, Li S, Hao G, Kumar A, Sun X, Brown KC. 2014. Dimerization of a Phage-Display Selected Peptide for Imaging of αvβ6- Integrin: Two Approaches to the Multivalent Effect. Theranostics. 4(7):745-760.

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