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Establishment of a Human Hepatocellular Carcinoma Cell Line Highly Expressing Sodium Iodide Symporter for Radionuclide Gene Therapy

¹ Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea
² Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

To evaluate the possibility of radionuclide gene therapy and imaging in hepatocellular carcinoma cancer, we investigated the iodine accumulation of a human hepatocellular carcinoma cell line, SK-Hep1, by transfer of human sodium iodide symporter (hNIS) gene. By targeting NIS expression in SK-Hep1, we could also investigate whether these cells concentrate ^99mTc-pertechnetate and ¹⁸⁸Re-perrhenate as well as ¹²⁵I in vitro and in vivo. Methods: The hNIS gene was transfected to human hepatocellular carcinoma SK-Hep1 cell lines using lipofectamine plus reagent. The uptake and efflux of ¹²⁵I, ^99mTc-pertechnetate, and ¹⁸⁸Re-perrhenate were measured in the transfected and parental cells. Biodistribution was studied in nude mice bearing SK-Hep1 and SK-Hep1-NIS at 10 and 30 min and at 1, 2, 6, 16, and 23 h after injection of ¹²⁵I, ^99mTc- pertechnetate, or ¹⁸⁸Re-perrhenate. In tumor imaging studies, the nude mice were intravenously injected with ¹⁸⁸Re-perrhenate and imaged with a -camera equipped with a pinhole collimator at 30 and 60 min after injection. The survival rate (%) was determined by the clonogenic assay after 37 MBq/10 mL (1 mCi/10 mL) ¹³¹I and ¹⁸⁸Re-perrhenate treatment. Results: SK-Hep1-NIS, stably expressing the NIS gene, accumulated ¹²⁵I up 150 times higher than that of SK-Hep1. Iodine uptake of SK-Hep1-NIS is completely blocked by perchlorate. NIS gene transfection into SK-Hep1 also resulted in 112- and 87-fold increases of ^99mTc-pertechnetate and ¹⁸⁸Re-perrhenate uptake, respectively. Iodide efflux from SK-Hep1-NIS was relatively slow, with only 10% released during the initial 5 min, and 60% remained at 25 min. In the biodistribution study using SK-Hep1-NIS–xenographed mice, the tumor uptake of ¹²⁵I, ¹⁸⁸Re-perrhenate, and ^99mTc-pertechnetate was 68.0 ± 15.0, 46.2 ± 9.1, and 59.6 ± 16.2 %ID/g (percentage injected dose per gram) at 2 h after injection, respectively. After ¹⁸⁸Re-perrhenate injection in SK-Hep1 and SK-Hep1-NIS–xenographed nude mice, whole-body images clearly visualized the SK-Hep1-NIS tumor, whereas the control tumor was not visualized. The survival rate (%) of SK-Hep1-NIS was markedly reduced to 46.3% ± 10.1% and 28.9% ± 5.2% after 37 MBq/mL (1 mCi/10 mL) ¹³¹I and ¹⁸⁸Re-perrhenate treatment compared with the survival rates of the parental cells. These results demonstrated that SK-Hep1-NIS could be selectively killed by the induced ¹³¹I and ¹⁸⁸Re-perrhenate accumulation through NIS gene expression. Conclusion: NIS-based gene therapy using ß-emitting radionuclides has the potential to be used in hepatocellular carcinoma management.

Key Words: sodium iodide symporter (NIS) • radionuclide gene therapy • hepatocellular carcinoma • ¹⁸⁸Re-perrhenate

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