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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 α_vβ₆- Integrin: Two Approaches to the Multivalent Effect

Ajay N. Singh¹, Michael J. McGuire², Shunzi Li², Guiyang Hao¹, Amit Kumar¹, Xiankai Sun^1,3,4✉, Kathlynn C. Brown^2,4✉

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.

✉ Corresponding author: Kathlynn C. Brown, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8807. Tel: 214-645-6348 Fax: 214-645-6347Kathlynn.Brownedu. Xiankai Sun, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8542. Tel: 214-645-5978 Fax: 214-645-2885. Xiankai.Sunedu. More

Abstract

The integrin α_vβ₆ is an emerging biomarker for non-small cell lung cancer (NSCLC). An α_vβ₆-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 α_vβ₆⁺ 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 α_vβ₆⁺ tumors. By contrast, no significant accumulation was observed in α_vβ₆^- 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 α_vβ₆-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.

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