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A Cystine Knot Peptide Targeting Integrin ?v?6 for Photoacoustic and Fluorescence Imaging of Tumors in Living Subjects.

ABSTRACT: Photoacoustic imaging is a nonionizing biomedical imaging modality with higher resolution and imaging depth than fluorescence imaging, which has greater sensitivity. The combination of the 2 imaging modalities could improve the detection of cancer. Integrin ?_v?₆ is a cell surface marker overexpressed in many different cancers. Here, we report the development and evaluation of a dye-labeled cystine knot peptide, which selectively recognizes integrin ?_v?₆ with high affinity, for photoacoustic and fluorescence imaging. The new dual-modality probe may find clinical application in cancer diagnosis and intraoperative imaging of integrin ?_v?₆-positive tumors.

Methods

An engineered cystine knot peptide, R₀1, that recognizes integrin ?_v?₆ was labeled with Atto 740 (A740) and evaluated for its specific cell uptake and its sensitivity threshold. A740-R₀1 was injected via the tail vein into nude mice xenografted with A431 (integrin ?_v?₆-positive) or 293T (integrin ?_v?₆-negative) tumors. Photoacoustic and fluorescence scans of tumors were acquired before and at 0.5, 1, 2, and 4 h after injection of A740-R₀1. Dynamic photoacoustic scans of various normal organs were also acquired. Ex vivo fluorescence imaging of tissues was performed 1 h after injection.

Results

The A740-R₀1 demonstrated integrin ?_v?₆-dependent binding to A431 cells in culture. Sensitivity studies indicated that the probe may potentially detect lesions as small as 1 or 6 mm³ by fluorescence or photoacoustic imaging, respectively. The photoacoustic and fluorescence signals of A431 xenografts at 1 h after injection were 1.87 ± 0.25 arbitrary units (AU) and 8.27 ± 0.87 AU, respectively. Target specificity was confirmed by low tumor uptake in 293T tumors at 1 h after injection (1.07 ± 0.15 AU and 1.10 ± 0.14 AU for photoacoustic and fluorescence signals, respectively). A740-R₀1 exhibited hepatobiliary clearance marked by high uptake in the liver, spleen, and intestine but low uptake in the kidneys.

Conclusion

A740-R₀1 specifically targeted integrin ?_v?₆ with low nanomolar affinity. A740-R₀1 was able to detect integrin ?_v?₆ both in vitro and in vivo by photoacoustic and fluorescence imaging. A740-R₀1 is able to detect ?_v?₆-positive tumors in living subjects and may have clinical application in cancer diagnosis and real-time image-guided surgery.

SUBMITTER: Zhang C

PROVIDER: S-EPMC5367447 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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A Cystine Knot Peptide Targeting Integrin αvβ6 for Photoacoustic and Fluorescence Imaging of Tumors in Living Subjects.

Zhang Chao C Kimura Richard R Abou-Elkacem Lotfi L Levi Jelena J Xu Lingyun L Gambhir Sanjiv Sam SS

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20160526 10

Photoacoustic imaging is a nonionizing biomedical imaging modality with higher resolution and imaging depth than fluorescence imaging, which has greater sensitivity. The combination of the 2 imaging modalities could improve the detection of cancer. Integrin αvβ6 is a cell surface marker overexpressed in many different cancers. Here, we report the development and evaluation of a dye-labeled cystine knot peptide, which selectively recognizes integrin αvβ6</sub ...[more]

PMID: 27230926

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