PET imaging of acute and chronic inflammation in living mice |
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Authors: | Qizhen Cao Weibo Cai Zi-Bo Li Kai Chen Lina He Hui-Cheng Li Mizhou Hui Xiaoyuan Chen |
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Institution: | (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;(2) AmProtein Corporation, Camarillo, CA, USA |
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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{Ec(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{Ec(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{Ec(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.
Qizhen Cao and Weibo Cai contributed equally to this work. |
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Keywords: | Acute and chronic inflammation TNF-α Integrin α vβ 3 Positron emission tomography Etanercept |
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