18F-ML-10 PET/CT imaging in early evaluation of doxorubicin-induced cardiotoxicity

Objective To investigate the feasibility of early monitoring doxorubicin (DOX)-induced cardiotoxicity by apoptosis molecular imaging of 2-(5-[18F]fluoro-pentyl)-2-methyl-malonic acid (18F-ML-10) PET/CT. Methods Forty-seven BALB/c mice were randomly divided into the chemotherapy group (n=30) and the control group (n=17) according to the random number table. The mice in chemotherapy group were intraperitoneally injected with DOX (4 mg/kg) once a week for 3 weeks and mice in the control group were injected with the same amount of normal saline. All mice were subjected to 18F-fluorodeoxyglucose (FDG) and 18F-ML-10 PET/CT imaging at day 0, 2, 9, 16, and left ventricular ejection fraction (LVEF) was continuously monitored using cine cardiac MR (cine-CMR) imaging. The region of interest (ROI) was delineated on PET/CT images, and the maximum percentage activity of injection dose per gram of tissue (%ID/g) was calculated. The mice were sacrificed after imaging, and the heart tissue was taken for HE staining and TdT-mediated dUTP nick end labeling (TUNEL) assay. One-way analysis of variance, independent-samples t test and Pearson correlation analysis were used to analyze the data. Results In the chemotherapy group, the myocardial 18F-FDG uptake on day 0, 2, 9, 16 were (63.3±14.5), (93.7±24.0), (153.6±20.6) and (135.8±32.5) %ID/g respectively, and 18F-ML-10 uptake were (0.09±0.02), (0.18±0.03), (0.22±0.04) and (0.55±0.12) %ID/g respectively. Compared with baseline (day 0), 18F-FDG and 18F-ML-10 uptake were significantly increased in the chemotherapy group at each time point after DOX administration(F=6.823, 20.848, both P 0.05). TUNEL and HE staining indicated that the cardiomyocytes in the chemotherapy group showed obvious apoptosis and vacuolization, and the apoptotic index (AI) was positively correlated with the 18F-ML-10 uptake (r=0.950, P<0.01). The cine-CMR imaging results showed that the LVEF in the chemotherapy group continued to decrease after DOX administration (F=4.507, P<0.05), and significant difference was identified at day 16 (t=2.980, P<0.05). There was a significant negative correlation between 18F-ML-10 uptake and LVEF (r=-0.709, P=0.01). Conclusions Both 18F-FDG and 18F-ML-10 PET/CT imaging can early assess DOX-induced cardiotoxicity in vivo. Given the high targeting specificity of 18F-ML-10, it may have a greater clinical transformation advantage over 18F-FDG in early assessment of cardiotoxicity. Key words: Cardiotoxicity; Doxorubicin; Positron-emission tomography; Tomography, X-ray computed; Mice