Dimerization of a phage-display selected peptide for imaging of αvβ6- integrin: Two approaches to the multivalent effect

Ajay N. Singh, Michael J. McGuire, Shunzi Li, Guiyang Hao, Amit Kumar, Xiankai Sun, Kathlynn C. Brown

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)745-760
Number of pages16
JournalTheranostics
Volume4
Issue number7
DOIs
StatePublished - 2014

Fingerprint

Dimerization
Integrins
Bacteriophages
Peptides
Chelating Agents
Non-Small Cell Lung Carcinoma
Positron-Emission Tomography
Peptide Library
Neoplasms
Kidney
Copper
Biomarkers

Keywords

  • Integrin
  • Lung cancer
  • Molecular imaging
  • Peptide
  • Positron emission tomography

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
  • Medicine(all)

Cite this

Dimerization of a phage-display selected peptide for imaging of αvβ6- integrin : Two approaches to the multivalent effect. / Singh, Ajay N.; McGuire, Michael J.; Li, Shunzi; Hao, Guiyang; Kumar, Amit; Sun, Xiankai; Brown, Kathlynn C.

In: Theranostics, Vol. 4, No. 7, 2014, p. 745-760.

Research output: Contribution to journalArticle

Singh, Ajay N. ; McGuire, Michael J. ; Li, Shunzi ; Hao, Guiyang ; Kumar, Amit ; Sun, Xiankai ; Brown, Kathlynn C. / Dimerization of a phage-display selected peptide for imaging of αvβ6- integrin : Two approaches to the multivalent effect. In: Theranostics. 2014 ; Vol. 4, No. 7. pp. 745-760.
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