期刊
THERANOSTICS
卷 4, 期 7, 页码 745-760出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.7811
关键词
Lung Cancer; Molecular Imaging; Positron Emission Tomography; Integrin; Peptide
资金
- small animal imaging research program grant (SAIRP) from the National Institute of Cancer [U24 CA126608]
- Welch Foundation [I-1622]
- National Institute of Biomedical Imaging and Bioengineering [1R01EB014244-01]
The integrin alpha(v)beta(6) is an emerging biomarker for non-small cell lung cancer (NSCLC). An alpha(v)beta(6)-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 alpha(v)beta(+)(6) 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 (H-2-D10) and direct presentation of two copies of the peptide on the chelator scaffold (H-2-(M10)(2)). Binding affinities of the divalent peptide conjugates are four-fold higher than their monovalent counterpart (H-2-M10), suggestive of multivalent binding. PET imaging using the bivalent Cu-64-labeled conjugates showed rapid and persistent accumulation in alpha(v)beta(+)(6) tumors. By contrast, no significant accumulation was observed in alpha(v)beta(-)(6)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, Cu-64-AcD10, showed drastic decrease of kidney accumulation while maintaining tumor uptake. In conclusion, we developed an alpha(v)beta(6)-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.
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