| [Objective] ①To investigate the feasibility to image hypoxia in tumor with a new hypoxia imaging agent 99Tcm-EC-metronodazole ( (99)~Tc~m-EC-MNZ ).To investigate the in vivo distribution and detect the pharmacokinetic parameters of (99)~Tc~m-EC-MNZ with mice bearing S180 sarcoma tumor . ②To evaluate the correlation between T/M (the radioactivity ratio of tumor to the opposite muscle ) by SPECT hypoxic imaging with (99)~Tc~m-EC-MNZ and the expression of hypoxia induce factor-1α(HIF-1α)in S180 sarcoma tumor and in Lewis lung cancer animal mode . [Methods] ①EC-MNZ is labeled with(99)~Tc~m. ②99Tcm-EC-MNZ with the dose of 370MBq/kg are injected into 64 Kunming mice bearing S180 sarcoma via tail vein and the radioactivity in heart, lung, kidney and other organs are measured at 0,1/6,1/2,1,2,4,8,24h after injection. The in vivo distribution of 99Tcm-EC –MNZ in mice and its pharmacokinetic parameters are calculated by DAS 1.0 soft ware. ③12 Kunming mice bearing S180 sarcoma and 12 mice bearing Lewis lung cancer are used for SPECT imaging and ROI technique is adopted to measure the T/M. ④Tumor biopsies are collected immediately after SPECT imaging. The expression of HIF-1αand VEGF, which is regulated by HIF-1α, are detected by immunohistochemistry. [Results] ①The distribution of 99Tcm-EC-MNZ in mice bearing S180 sarcoma shows the liver and kidneys uptake the most of 99Tcm-EC-MNZ after injection. The radioactivities decrease with the time in all organs and in tumor, while radioactivity ratios of tumor to non-tumor(T/NT) increase with the time and reach the peak value at 4h~8h after injection. At 24h after administration 99Tcm-EC-MNZ is cleared to 10-7~10-8 of the injection dose. ②The concentration of 99Tcm-EC-MNZ in blood plasma of mice bearing S180 sarcoma is cleared as a two-component model with the T1/2α=0.44h and T1/2β=18.97h. ③The T/M value of S180 sarcoma at 3h after injection of 99Tcm-EC-MNZ ranges from 1.93 to 4.46 with average value of 3.04±0.74. The expression of HIF-1αof S180 sarcoma is 31.2%~60.8% with the median of 50.4% and the expression of VEGF is 33.8%~57.5% with the median of 53.1%, respectively. ④There is a significant linear correlation between HIF-1αexpression and T/M(t=2.732,P=0.021), also there is a significant linear correlationbetween HIF-1αexpression and VEGF(t=3.011, P =0.0131)for the mice bearing S180 sarcoma . ⑤The T/M ratios of Lewis lung cancer range from 1.42 ~2.06(1.78±0.22). HIF-1αexpression of Lewis lung cancer is 0.1%~1.75% and VEGF expression is 0.25%~2.05%. No statistical correlation is observed between the T/M ratio and HIF-1αexpression (t=1.161,P=0.272),neither between HIF-1αexpression and VEGF expression(t=0.066,P=0.949) in Lewis cancer . Furthermore, The difference of T/M ratio and HIF-1αexpression between two tumor models exists statistical significance with P<0.01( t'=5.69) and P<0.05(t'=9.49),respectively. [Conclusion] There is a correspondence between T/M value by SPECT and the expression of HIF-1αand VEGF by immunohistochemistry. 99Tcm-EC-MNZ is a promising hypoxia imaging agent, it can image tumor hypoxia . |
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