| Objective:The purpose of this study is to explore the feasibility of applying the radioactive molecular probe 99 m Tc-3PRGD2 in primary hepatic carcinoma, thus supplying a new method of early diagnosis of HCC.Methods:The xenograft model of the human hepatocarcinoma in Balb/c nunu nude mice was established.16 mice with the tumor maximum diameter of 1.0cm were randomly divided into4 groups and injected intravenously with 10 u Ci of 99 m Tc-3PRGD2. At 30 min, 1h, 2h and 4h after administration, mice were sacrificed by humane euthanasia, the important organs(tumor, heart, liver, spleen, lungs, kidneys, stomach, intestine, muscle and blood) were excised and counted on a γ-counter. The percentage activity of injection dose per gram of tissue(%ID/g) and ratio of target/ non-target were calculated for evaluating the biological distribution characteristics of 99 m Tc-3PRGD2 in the nude mice.12 mice with various tumor sizes were injected intravenously with 10 uCi of99mTc-3PRGD2. At 1h after injection, mice were sacrificed by humane euthanasia,each tumor was tested the weight and counted on a γ-counter for calculating the tumor uptakes of 99 m Tc-3PRGD2(%ID, %ID/g), the tumor size and the tumor uptake were used to draw scatter diagram and make regression analysis. The integrin αvβ3expression levels were determined by immunohistochemical staining, in order to analyze the correlation between the tumor uptake(%ID/g) and receptor expression.Imaging study in the nude mice bearing hepatic carcinoma was performed by using micro SPECT/PET/CT equipment(Versatile Emission Computed Tomography System, Milabs, Utrecht, the Netherlands).Multiphase imaging study: 4 animal models were injected intravenously with 1.5m Ci of 99 m Tc-3PRGD2, at 30 min after administration, list-mode was used to complete data acquisition of 30 min ~ 3h and 4h ~ 4.5h post injection. Multiphase images were obtained by the list-mode raw data reconstruction, with setting the beginning scan time as 0.5h, 1h, 2h, 4h after administration(a 30-min scanning time) and the scan time as 30min、60min、90min,.thus provides the best beginning scan time and the best scan time.Mutilmodal imaging study: On the 8th, 12 th, 16 th, 20 th and 24 th days after the inoculation of Hep G2, 4 animal models were injected intravenously with 1.5m Ci of99mTc-3PRGD2 and 1.0m Ci of 18F-FDG. At 1h after administration, a 45-min SPECT/PET acquisition was obtained to monitor the development of tumor. The tumor uptakes of 99 m Tc-3PRGD2 and 18F-FDG were quantified by PMOD software(PMOD Technologies,Zurich,Switzerland), the difference between 99 m Tc-3PRGD2SPECT/CT images and 18F-FDG PET/CT imags during growth of tumor was compared in order to assess the value of 99 m Tc-3PRGD2 and 18F-FDG in early diagnosis of HCC.Results:1. Biodistribution results indicated that 99 m Tc-3PRGD2 was mainly excreted through urinary system, partly metabolized by liver or intestine. The tumor uptakes in different time were 4.301±0.313 %ID/g(0.5h), 6.902±0.717 %ID/g(1h),5.045±0.193 %ID/g(2h) and 2.099±0.388% ID/g(4h) respectively, with a significant statistically difference between each group(F=78.864,P<0.05), suggesting the highest tumor uptakes were obtained at 1h post injection. The highest uptake ratios of tumor to muscle were obtained at 2h after administration, but there was no significant difference between 1h and 2h(t=1.905, P>0.05). The relationship between the tumor size(g)and the tumor uptake(%ID) was modeled as quadratic polynomial fitting curve( R2=0.821, y=-5.216x2+5.905x+0.386), suggesting the uptakes of99mTc-3PRGD2 increased with the growth of tumor when tumors were <0.42 g and peaked when tumor size was 0.42 g, then the uptakes of99mTc-3PRGD2 decreased because of tumor tissue necrosis.There was a good Linear relationship(r=0.928,P<0.05) between the tumor uptake and the integrin αvβ3 expression levels by immunohistochemistry.2. Subcutaneous tumor was visualized clearly under micro SPECT/CT fusion images,and the contrast between tumor and muscle was quite good. Multiphase images were obtained by setting the beginning scan time as 0.5h, 1h, 2h, 4h after administration with a 30-min scanning time, the highest tumor uptakes of 99 m Tc-3PRGD2 were4.61±1.17 %ID/cm3 at 0.5h post injection, so the best beginning scan time was between half an hour to an hour after administration. Another multiphase images were obtained by setting the scan time as 30 min, 60 min and 90 min, starting 30 min post injection. There was no obvious difference among three groups by visual inspection,and the tumor uptake peaked when scan time was 30min(4.20±1.02 %ID/cm3),suggesting the best scan time was 30 min.3. On the 8 th, 12 th, 16 th days after inoculation of Hep G2, subcutaneous tumor was visualized clearly under 99 m Tc-3PRGD2 SPECT/CT fusion images, and the uptakes of99mTc-3PRGD2(%ID)increased with the growth of tumor. On the contray, there was only a small amount of uptakes in the subcutaneous tumor under 18F-FDG PET/CT fusion images, the uptakes of 18F-FDG(%ID) was obviously below the uptakes of99mTc-3PRGD2. From the 20 th day to 24 th day, tumor began necrosis with further increasing, 99 m Tc-3PRGD2 SPECT/CT images and 18F-FDG PET/CT imags both showed uneven distribution in the tumor, the uptakes of 18F-FDG were higher than the uptakes of 99 m Tc-3PRGD2. The uptakes of 99 m Tc-3PRGD2 and 18F-FDG were divided into five groups according to the day which mutilmodal image was performed. Proved by independent-samples t test, there was a significant statistically difference among different groups except for the 24 th day(P<0.05).Conclusion:99mTc-3PRGD2 could be applied in the diagnosis of primary hepatic carcinoma to make up the insufficient sensitivity of 18F-FDG PET/CT imaging alone in small liver cancer or early stage of liver cancer, the combine image of 99 m Tc-3PRGD2SPECT/CT and 18F-FDG PET/CT might improve the positive detection rate of HCC. |
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