Evaluation of 99mTc-3PRGD2 integrin receptor imaging in hepatocellular carcinoma tumour-bearing mice: comparison with 18F-FDG metabolic imaging

Abstract

ObjectiveOur study was designed to explore the utility of 99mTc-HYNIC-PEG4-E[PEG4-c(RGDfK)]2 (99mTc-3PRGD2) for the detection of hepatocellular carcinoma (HCC) and specifically to compare the diagnostic performance of 99mTc-3PRGD2 integrin receptor imaging and 2-18-fluoro-2-deoxy-d-glucose (18F-FDG) metabolic imaging in a nude mouse model.Methods 99mTc-3PRGD2 was synthesized using a HYNIC-3PRGD2 lyophilized kit with 99mTcO4 labelling. The nude mouse animal model was established by subcutaneously injecting 5 × 107/ml HepG2 cells into the shoulder flank of each mouse. Biodistribution studies were performed at 0.5, 1, 2 and 4 h after intravenous administration of 0.37 MBq of 99mTc-3PRGD2. Immunohistochemistry was performed to evaluate the expression level of integrin αvβ3 in the HCC tissues. Dynamic imaging was performed using list-mode after the administration of 55.5 MBq of 99mTc-3PRGD2, to reconstruct the multiphase images and acquire the best initial scan time. At 8, 12, 16, 20 and 24 days after inoculation with HepG2 cells, 55.5 MBq of 99mTc-3PRGD2 and 37 MBq of 18F-FDG were injected successively into the nude mouse model, subsequently, simultaneous SPECT/PET imaging was performed to calculate the tumour volume and tumour uptake of 99mTc-3PRGD2 and 18F-FDG.ResultsThe biodistribution study first validated that the tumour uptake of 99mTc-3PRGD2 at the different time points was higher than that of all the other organs tested in the experiment, except for the kidney. Integrin αvβ3 expressed highly in early stage HCC and declined for further necrosis of the tumour tissue. Subcutaneous tumours were visualized clearly with excellent contrast under 99mTc-3PRGD2 SPECT/CT imaging, and the multiphase imaging comparison showed the tumours were prominent at 0.5 h, suggesting that the best initial scan time is 0.5 h post-injection. The comparison of the imaging results of the two methods showed that 99mTc-3PRGD2 integrin receptor imaging was more sensitive than 18F-FDG metabolic imaging for the detection of early stage HCC, meanwhile the tumour uptake of 99mTc-3PRGD2 was consistently higher than that of 18F-FDG. However, as tumour necrosis further increased in HCC tissues, the uptake of 18F-FDG was higher than that of 99mTc-3PRGD2.ConclusionOur study demonstrated that 99mTc-3PRGD2 is a valuable tumour molecular probe for the detection of early stage HCC compared with 18F-FDG, meriting further investigation of 99mTc-3PRGD2 as a novel SPECT tracer for tumour imaging.

Molecular Imaging of Tumor Microenvironment to Assess the Effects of Locoregional Treatment for Hepatocellular Carcinoma

“…(33) angiogenesis Several targets of tumor angiogenesis, such as integrin α v β 3 and VEGF, are being intensively investigated to evaluate tumor angiogenesis in HCC by molecular imaging. For instance, the radiolabeled tracers, 64 Cu-cyclam-RAFT-c(-RGDfK-)4 (34) and 99m Tc-3PRGD2, (35) were studied for monitoring integrin α v β 3 by PET and SPECT, whereas 99m Tc-NGR (36) was prepared for targeting CD13 by SPECT. The vascular MRI techniques can be generally divided into two groups: (1) direct detection of angiogenesis with extrinsic contrast agents, such as DCE-MRI and MRI with targeted agents; and (2) indirect detection of angiogenesis without contrast agents, such as arterial spin labeling (ASL) and BOLD-MRI.…”