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PET imaging of acute and chronic inflammation in living mice

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

In this study, we evaluated the 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced acute and chronic inflammation in living mice by PET imaging of TNF-α and integrin αvβ3 expression.

Methods

TPA was topically applied to the right ear of BALB/c mice every other day to create the inflammation model. 64Cu-DOTA-etanercept and 64Cu-DOTA-E{E[c(RGDyK)]2}2 were used for PET imaging of TNF-α and integrin αvβ3 expression in both acute and chronic inflammation. Hematoxylin and eosin staining, ex vivo autoradiography, direct tissue sampling, and immunofluorescence staining were also performed to confirm the non-invasive PET imaging results.

Results

The ear thickness increased significantly and the TNF-α level more than tripled after a single TPA challenge. MicroPET imaging using 64Cu-DOTA-etanercept revealed high activity accumulation in the inflamed ear, reaching 11.1 ± 1.3, 13.0 ± 2.0, 10.9 ± 1.4, 10.2 ± 2.2%ID/g at 1, 4, 16, and 24 h post injection, respectively (n = 3). Repeated TPA challenges caused TPA-specific chronic inflammation and reduced 64Cu-DOTA-etanercept uptake due to lowered TNF-α expression. 64Cu-DOTA-E{E[c(RGDyK)]2}2 uptake in the chronically inflamed ears (after four and eight TPA challenges) was significantly higher than in the control ears and those after one TPA challenge. Immunofluorescence staining revealed increased integrin β3 expression, consistent with the non-invasive PET imaging results using 64Cu-DOTA-E{E[c(RGDyK)]2}2 as an integrin αvβ3-specific radiotracer. Biodistribution and autoradiography studies further confirmed the quantification capability of microPET imaging.

Conclusion

Successful PET imaging of TNF-α expression in acute inflammation and integrin αvβ3 expression in chronic inflammation provides the rationale for multiple target evaluation over time to fully understand the inflammation processes.

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Acknowledgements

This work was supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) (R21 EB001785), the National Cancer Institute (NCI) (R21 CA102123, P50 CA114747, U54 CA119367, and R24 CA93862), the Department of Defense (DOD) (W81XWH-04-1-0697, W81XWH-06-1-0665, W81XWH-06-1-0042, W81XWH-07-1-0374, and DAMD17-03-1-0143), and a Benedict Cassen Postdoctoral Fellowship from the Education and Research Foundation of the Society of Nuclear Medicine (to W. Cai). We thank Drs. Gang Niu, Hui Wang, and Zhanhong Wu for their help with the biodistribution studies. We also thank the cyclotron team at the University of Wisconsin, Madison for 64Cu production.

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Authors and Affiliations

  1. The Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Rd, P095, Stanford, CA, 94305-5484, USA

    Qizhen Cao, Weibo Cai, Zi-Bo Li, Kai Chen, Lina He & Xiaoyuan Chen

  2. AmProtein Corporation, Camarillo, CA, USA

    Hui-Cheng Li & Mizhou Hui

Authors
  1. Qizhen Cao
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  2. Weibo Cai
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  3. Zi-Bo Li
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  6. Hui-Cheng Li
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  7. Mizhou Hui
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  8. Xiaoyuan Chen
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Corresponding author

Correspondence to Xiaoyuan Chen.

Additional information

Qizhen Cao and Weibo Cai contributed equally to this work.

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Cao, Q., Cai, W., Li, ZB. et al. PET imaging of acute and chronic inflammation in living mice. Eur J Nucl Med Mol Imaging 34, 1832–1842 (2007). https://doi.org/10.1007/s00259-007-0451-0

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  • DOI: https://doi.org/10.1007/s00259-007-0451-0

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