Qin Shi, Yuyun Sun, Sheng Cao, Jian Zhang, Jianping Zhan, Yongping Zhang, Shaoli Song, Yingjian Zhang, Mingwei Wang
Abstract
ObjectiveTo 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.
MethodsForty-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.
ResultsIn 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<0.01). The myocardial 18F-ML-10 and 18F-FDG uptake were essentially unchanged at all time points in the control group(F=2.036, 1.155, 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).
ConclusionsBoth 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
Contributor Information
Qin Shi
Department of Nuclear Medicine, Fudan University Shanghai Cancer Center
Department of Oncology, Shanghai Medical College, Fudan University
Center for Molecular Imaging, Fudan University
Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China
Yuyun Sun
Department of Nuclear Medicine, Fudan University Shanghai Cancer Center
Department of Oncology, Shanghai Medical College, Fudan University
Center for Molecular Imaging, Fudan University
Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China
Sheng Cao
Department of Nuclear Medicine, Fudan University Shanghai Cancer Center
Department of Oncology, Shanghai Medical College, Fudan University
Center for Molecular Imaging, Fudan University
Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China
College of Life and Environmental Sciences, Shanghai Normal University
Key Laboratory of Resource Chemistry, Ministry of Education
Shanghai Key Laboratory of Rare Earth Functional Materials
Key Laboratory of Molecular Imaging Probes and Sensors, Shanghai Normal University, Shanghai 200234, China
Jian Zhang
Department of Nuclear Medicine, Fudan University Shanghai Cancer Center
Department of Oncology, Shanghai Medical College, Fudan University
Center for Molecular Imaging, Fudan University
Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China
College of Life and Environmental Sciences, Shanghai Normal University
Key Laboratory of Resource Chemistry, Ministry of Education
Shanghai Key Laboratory of Rare Earth Functional Materials
Key Laboratory of Molecular Imaging Probes and Sensors, Shanghai Normal University, Shanghai 200234, China
Jianping Zhan
Department of Nuclear Medicine, Fudan University Shanghai Cancer Center
Department of Oncology, Shanghai Medical College, Fudan University
Center for Molecular Imaging, Fudan University
Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China
Yongping Zhang
Department of Nuclear Medicine, Fudan University Shanghai Cancer Center
Department of Oncology, Shanghai Medical College, Fudan University
Center for Molecular Imaging, Fudan University
Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China
Shaoli Song
Department of Nuclear Medicine, Fudan University Shanghai Cancer Center
Department of Oncology, Shanghai Medical College, Fudan University
Center for Molecular Imaging, Fudan University
Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China
Yingjian Zhang
Department of Nuclear Medicine, Fudan University Shanghai Cancer Center
Department of Oncology, Shanghai Medical College, Fudan University
Center for Molecular Imaging, Fudan University
Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China
Mingwei Wang
Department of Nuclear Medicine, Fudan University Shanghai Cancer Center
Department of Oncology, Shanghai Medical College, Fudan University
Center for Molecular Imaging, Fudan University
Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai 200032, China
