Abstract
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Objectives: To differentiate hypoxia from proliferation, we compared the imaging characteristics and hypoxia selectivity of hypoxia PET radiotracers ([18F] fluoromisonidazole (18F-FMISO), [18F] flortanidazole (18F-HX4)) in vivo, and in a human breast tumor-bearing mouse model using micro PET/CT. We further investigated the relationships between hypoxia radiotracers uptake and cell proliferation with [18F] fluorodeoxyglucose (18F-FDG).
Methods: Experiment in vitro: cells were divided into normal oxygen group and hypoxia group. Each group was divided into three sub-groups by the time of exposure to FMISO or HX4. Each sub-group was separately cultivated for another one hour after added with 2 uCi of 18F-FMISO or 18F-HX4 at l,2,3h. Radioactivity was detected by a gamma counter. The results were expressed as a ratio of intracellular radioactivity with total fluid radioactivity (Ccell/Ctotal). Experiment in vivo: twenty-four nude mice bearing human breast cancer(MDA231 cell line) xenograft tumors were administered with 1 of the 3 PET tracers (18F-FMISO, 18F-HX4, 18F-FDG). The animal numbers for each PET tracer were 8 equally and mice were sacrificed after PET/CT imaging. Immunohistochemical staining was conducted to assess HIF-1α and Ki67 expression. We investigated the correlations between PET tracer uptakes and HIF-1α (or Ki67) expression.Results The Ccell/Ctotal of 18F-FMISO and 18F-HX4 uptake of cells in hypoxia group was significantly higher than the normal oxygen group and increased continuously by hypoxia aggravated. Both the 18F-FMISO and18F-HX4 uptake were significantly correlated with HIF-1α(r = 0.67, P < 0.05, r = 0.82, P < 0.05, respectively), a slight correlation was detected between 18F-FMISO uptake and Ki67 expression(r = 0.59, P < 0.05). 18F-FDG uptake was correlated with Ki-67(r = 0.70, P < 0.05), but not with HIF-1α. Conclusions Both in vitro and in vivo studies showed that 18F-FMISO and 18F-HX4 were significantly correlated with hypoxic cells, and both of the 18F-FMISO and 18F-FDG were correlated with cell proliferation.