Comparative Study Of RGD PET And FDG PET Imaging And Immunohistochemical Validation In Tumor-bearing Mice

Background and Purpose: The fact that the standard radiotherapy could not match every individual tumor variation is the main cause of local failure in patients with non-small cell lung cancer?NSCLC?. The individualized radiotherapy based on personal unique features is the way to the success. Molecular imaging may be the best tool to get the dynamic and spatial biology features safely. This study is designed to build the individualized radiotherapy technique step by step with animal transplantation tumor. First, to explore the detection accuracy of ¹⁸F-Alfatide(¹⁸F-AL-NOTA-PRGD2,denoted as ¹⁸F-alfatide, shorthand for ¹⁸F-RGD) positron emission tomography?PET?imaging in LLC?Lewis lung carcinoma cell? tumor-bearing C57 mice. Second, validation the assessment of metabolic tumor volume?MTV? with ¹⁸F-RGD PET and ¹⁸F-FDG PET compared to pathologic tumor volume?Vpath?. Third, the correlation of FDG PET imaging for glucose metabolism, RGD PET imaging for angiogenesis and tumor spatial heterogeneity will be identified by imaging-specimen-molecular pathology match and compare.Materials and Methods: LLC was injected i.m.?2×105 cells/100?l/mouse? into the right hind leg muscle of C57 mice. All LLC tumor-bearing C57 mice?n=37? underwent two attenuation-corrected whole-body micro-PET scans with the radiotracers ¹⁸F-RGD and ¹⁸F-FDG within two days. ¹⁸F-RGD emission images were acquired on a 10-min micro-PET 60 min after the injection of 2.4-3.5 MBp ¹⁸F-RGD. ¹⁸F-FDG images were acquired on the same scanner 60 min after the injection of 2.6-3.6 MBp ¹⁸F-FDG. ¹⁸F-RGD metabolic tumor volume?VRGD? and ¹⁸F-FDG metabolic tumor volume?VFDG? were manually delineated slice by slice on PET images. Pathologic tumor volume?VPath? was measured in vitro after the xenografts were removed. ¹⁸F-RGD SUVs and ¹⁸F-FDG SUVs were measured by two experienced nuclear medicine physician in normal tissues, organs and overall tumor at 1 hour after injection respectively. The SUV on PET and ?v?3 and GLUT-1 expression in IHC were further measured and correlated to each other stereotactically when the xenografts were divided into outer?SUVRGD-O, SUVFDG-O?, middle?SUVRGD-M, SUVFDG-M? and inner?SUVRGD-I, SUVFDG-I? layers.Results: ¹⁸F-RGD PET imaging identified all tumors, with lower mean standardized uptake values?SUVmean? than ¹⁸F-FDG?P<0.01? in xenografts and normal organs. ¹⁸F-RGD PET SUVmean were significant lower than ¹⁸F-FDG PET in mediastinal?0.30±0.06, 3.56±0.95, P<0.01?,lung?0.20±0.04, 1.60±0.40, P<0.01? and brain?0.62±0.11, 1.52±0.27, P<0.01?. The tumor-to-lung, tumor-to-heart ratio of ¹⁸F-RGD PET?4.50±0.96, 3.03±0.70? were significant higher than those of ¹⁸F-FDG PET?1.70±0.56, 0.76±0.22, P <0.001?. The mean ± standard deviation of VPath, VRGD, and VFDG were 0.59±0.32 cm3?range, 0.13¹.64 cm3?, 0.61±0.37 cm3?range, 0.15¹.86 cm3?, and 1.24±0.53 cm3?range, 0.17².20 cm3?, respectively. VPath vs. VRGD, VPath vs. VFDG, and VRGD vs. VFDG comparisons were t=-0.145, P=0.885,t=-6.239, P<0.001,and t=-5.661, P<0.001, respectively. No significant difference was found between VPath and VRGD. VFDG was much larger than VRGD and VPath. VRGD seemed more approximate to the pathologic gross tumor volume. Furthermore, VPath was more strongly correlated with VRGD?R=0.964, P<0.001? than with VFDG?R=0.584, P<0.001?. The spatial heterogeneity of the tumor was detected and the tracers accumulation enhanced from out layer to inner layer consistently on the two tracers?SUVFDG-O, SUVFDG-M, and SUVFDG-I were 3.04±0.64, 6.33±1.16, 9.95±1.64 and SUVRGD-O, SUVRGD-M, and SUVRGD-I were 1.46±0.30, 1.96±0.37, 2.36±0.37, P<0.001?. The PET imaging was validated by IHC examination. The parameters of the tumor were significantly correlated with each other between ¹⁸F-FDG SUVmax and GLUT-1?R=0.895, P<0.001?, ¹⁸F-RGD SUVmax and ?v?3?R=0.595, P=0.019?, ¹⁸F-FDG SUVmax and ¹⁸F-RGD SUVmax?R=0.917, P<0.001?, and GLUT-1 and ?v?3?R=0.637, P=0.011?.Conclusion: ¹⁸F-RGD PET maybe a potentially effective tracer for tumor detection, spatial heterogeneity imaging and maybe an alternative supplement to ¹⁸F-FDG PET especially for patients with enhanced characteristics with brain, and chest tumors or diabetes and merit further study. ¹⁸F-RGD PET provided a better estimation of gross tumor volume than ¹⁸F-FDG PET. ¹⁸F-RGD PET is promising and effective and merits additional study in noninvasive studies that investigate the target volume margins for lung carcinoma.