Inflammation imaging of atherosclerosis in Apo-E-deficient mice using a 99mTc-labeled dual-domain cytokine ligand

Interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) play a critical role in initiating and accelerating atherosclerosis. This study evaluated the imaging properties of Tc-99m-TNFR2-Fc-IL-1RA (Tc-99m-TFI), a dual-domain cytokine radioligand that targets TNF-alpha and IL-1 beta pathways, in assessing atherosclerosis development in apolipoprotein-E-deficient (ApoE(-/-)) mice. Methods: The feasibility and specificity of detecting atherosclerosis with Tc-99m-TFI SPECT imaging were investigated in ApoE(-/-) and ApoE(+/+) mice. Fifty-four ApoE(-/-) mice were fed either an atherogenic diet (AGD) or a normal diet (ND) beginning at 5 weeks of age. Eighteen Apo-E wild-type (ApoE(+/+)) mice were fed an ND. Two groups of ApoE(-/-) mice (n = 12 each group) on AGD and ND were imaged three times with Tc-99m-TFI and a high-resolution SPECT system at 20-25, 30-40, and 48-52 weeks to study the evolution of atherosclerotic plaque. Results: Focal radioactive accumulations in the aortic arch region were observed in the ApoE(-/-) mice (n = 12) on AGD but not in the ApoE(+/+) mice on ND (n = 10). Apo-E-/- mice on ND (n = 11) exhibited lower radioactive uptake than ApoE(-/-) mice on AGD (P < 0.05). Co-injection of an excess of cold ligand with Tc-99m-TFI resulted in significant reduction of Tc-99m-TFI uptake in the ApoE(-/-) mice on AGD. Longitudinal studies showed that Tc-99m-TFI uptake in the aortas of ApoE(-/-) mice progressively increased from 20 to 48 weeks. Real-time PCR assays demonstrated that atherosclerotic aortas expressed significantly higher IL-1 beta and TNF-alpha than the aortas from wild-type controls. Conclusions: Atherosclerotic plaques were detected by Tc-99m-TFI imaging in ApoE(-/-) mice. Tc-99m-TFI is promising for specific detection of inflammatory response in atherosclerotic plaques. (c) 2014 Elsevier Inc. All rights reserved.