Molecular imaging of mesothelioma by detection of manganese‐superoxide dismutase activity using manganese‐enhanced magnetic resonance imaging

Abstract

Malignant mesothelioma (MM) is a fatal malignancy with a rapidly increasing incidence in industrialized countries because of the widespread use of asbestos in the past centuries. Early diagnosis of MM is critical for a better prognosis, but this is often difficult because of the lack of disease-specific diagnostic imaging. Here, we report that manganese-enhanced magnetic resonance imaging (MEMRI) represents a promising approach for a more selective mesothelioma imaging by monitoring a high-level expression of manganese-superoxide dismutase (Mn-SOD), which is observed in many MM. We found that most human MM cells overexpressed Mn-SOD protein compared with human mesothelial cells and that NCI-H226 human MM cells highly expressed Mn-SOD and augmented Mn accumulation when loaded with manganese chloride (MnCl 2 ). The cells showed marked T 1 -signal enhancement on in vitro MRI after incubation with MnCl 2 because of the T 1 shortening effect of Mn 21 . H226subcutaneous tumor was preferentially enhanced compared with a lung adenocarcinoma cell tumor and another human MM cell tumor in MnCl 2 -enhanced T 1 -weighted MR image (T 1 WI), correlating with their respective Mn-SOD expression levels. Moreover, in a more clinically relevant setting, H226 xenografted pleural tumor was markedly enhanced and readily detected by MEMRI using manganese dipyridoxyl diphosphate (MnDPDP), a clinically used contrast agent, as well as MnCl 2 . Therefore, we propose that MEMRI can be a potentially powerful method for noninvasive detection of MM, with high spatial resolution and marked signal enhancement, by targeting Mn-SOD.Malignant mesothelioma (MM) is an asbestos-related malignant tumor originating from mesothelial cells lining pleural and peritoneal cavities. There is a long latency period (more than 30 years) between the asbestos exposure and the onset of the disease, and the number of patients is now rapidly increasing in industrialized countries because of the widespread use and installation of asbestos fibers in the past centuries. Epidemiological studies indicate that the incidence is rapidly increasing worldwide.

In vivo MEMRI characterization of brain metastases using a 3D Look-Locker T1-mapping sequence

“…Several studies have measured the T1 in tumors after the injection of MnCl2. The limitation of these studies was the acquisitions of T1 maps in 2D on a limited number of slices through the tumors212223. Only a few studies acquired T1 maps in 3D, with the main drawback of long acquisition times: from 40 min24 to ~2 h25.…”

Tumor Enhancement Effect of Overexpressed Manganese-superoxide Dismutase in Manganese-enhanced MR Imaging

“…Our results here agreed well with our previous results of greater enhancement by MEMRI of mesotheliomas with higher levels of Mn-SOD-expression. 5 In addition, because we have shown comparable results between MEMRI using manganese dipyridoxyldiphosphate (MnDPDP), a Mnchelating contrast agent used clinically, and MEMRI using MnCl 2 , 5 our studyˆndings have clinical implications.…”

“…Our recent report that MEMRI could be used to detect mesothelioma with high expression of Mn-SOD suggested the possible preferential enhancement of tumors overexpressing Mn-SOD by MEMRI. 5 Here, we further evaluate the usefulness of MEMRI in tumor detection and investigate the eŠects of Mn-SOD expression in tumor enhancement by MEMRI.…”

CHAPTER 17. Magnetic Resonance Imaging in Respiratory Diseases: From Diagnosis to Pharmaceutical Research and Development

“…Regarding exposure to asbestos, MRI could be regarded as suitable for potentially repeated examinations following initial screening by CT. 138,139 In an experimental model of malignant mesothelioma, Hasegawa et al 140 reported the use of manganese-enhanced MRI (MEMRI) for selective mesothelioma imaging in vivo. The authors made use of the high-level expression of manganese-superoxide dismutase (Mn-SOD) observed in malignant mesotheliomas to induce accumulation of manganese (Mn 21 ) ions in tumors, resulting in significant T 1 signal enhancement in vitro and in vivo in xenografted pleural tumors (Figure 17.10).…”