Assessing activation of hepatic stellate cells by 99mTc-3PRGD2 scintigraphy targeting integrin αvβ3: a feasibility study

Objective: Hepatic stellate cell (HSC) activation, which is accompanied by increased expression of integrin alpha v beta 3, is an important factor in liver fibrogenesis. Molecular imaging targeting the integrin alpha v beta 3 could provide a noninvasive method for evaluating the expression and the function of the integrin alpha v beta 3 on the activated HSCs (aHSCs) in the injured liver, and then provide important prognostic information. Tc-99m-3PRGD2 is such a radiotracer specific for integrin alpha v beta 3. In this study, we aimed to compare the differences in liver uptake and retention of the Tc-99m-3PRGD2 between normal liver and injured liver to evaluate the feasibility of Tc-99m-3PRGD2 scintigraphy for this purpose. Methods: We used planar scintigraphy to assess changes in integrin alpha v beta 3 binding of intravenously-administered Tc-99m-3PRGD2 in the livers of rats with thioacetamide (TAA)-induced liver fibrosis compared with the controls. We co-injected cold c(RGDyK) with Tc-99m-3PRGD2 to assess the specific binding of the radiotracer. We performed Sirius red staining to assess liver fibrosis, immunofluorescent colocalization to identify the location of integrin alpha v beta 3 expressed in the fibrotic liver, and we measured protein and messenger RNA expression of integrin alpha v beta 3 and alpha smooth muscle actin (alpha-SMA) in the control and fibrotic livers. Results: The fibrotic livers showed enhanced Tc-99m-3PRGD2 uptake and retention. The radiotracer was demonstrated to bind specifically with the integrin alpha v beta 3 mainly expressed on the aHSCs. The liver-to-heart ratio at 30 min post-injection was higher in the fibrotic livers than in the control livers (TAA, 1.98 +/- 0.08 vs. control, 1.50 +/- 0.12, p < 0.01). The liver t(1/2) was longer than in the controls (TAA, 27.07 +/- 10.69 min vs. control, 12.67 +/- 4.10 min, p < 0.01). The difference of heart t(1/2) between the two groups was not statistically significant (TAA, 3.13 +/- 0.63 min vs. control, 3.41 +/- 0.77 min, p = 0.94). Conclusions: Tc-99m-3PRGD2 molecular imaging can provide a non-invasive method for assessing activation of HSCs. (C) 2014 Elsevier Inc. All rights reserved.