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Abstract
ObjectiveTo investigate the role of 188Re in human sodium iodide symporter (hNIS) theranostic gene-mediated human glioma imaging and therapy in model mice.MethodsThe human glioma cell line U87 was transfected with recombinant lentivirus encoding the hNIS gene under the control of cytomegalovirus promoter (U87-hNIS). The uptake and efflux of 188Re were determined after incubating the cells with 188Re. 188Re uptake experiments in the presence of various concentrations of sodium perchlorate were carried out. In vitro cell killing tests with 188Re were performed. U87-hNIS mediated 188Re distribution, imaging and therapy in nude mice were also tested.ResultsU87-hNIS cell line was successfully established. The uptake of 188Re in U87-hNIS cells increased up to 26-fold compared to control cells, but was released rapidly with a half-life of approximately 4 minutes. Sodium perchlorate reduced hNIS-mediated 188Re uptake to levels of control cell lines. U87-hNIS cells were selectively killed following exposure to 188Re, with a survival of 21.4%, while control cells had a survival of 92.1%. Unlike in vitro studies, U87-hNIS tumor showed a markedly increased 188Re retention even 48 hours after 188Re injection. In the therapy study, there was a significant difference in tumor size between U87-hNIS mice (317±67 mm3) and control mice (861±153 mm3) treated with 188Re for 4 weeks (P<0.01).ConclusionThe results indicate that inserting the hNIS gene into U87 cells is sufficient to induce specific 188Re uptake, which has a cell killing effect both in vitro and in vivo. Moreover, our study, based on the function of hNIS as a theranostic gene allowing noninvasive imaging of hNIS expression by 188Re scintigraphy, provides detailed characterization of in vivo vector biodistribution and level, localization, essential prerequisites for precise planning and monitoring of clinical gene therapy that aims to individualize gene therapy concept.
Highlights
Glioma remains one of the most common cancers and is a leading cause of cancer-related deaths worldwide
Lentivirus preparation, and U87 cell transfection with Lenti-CMV-human sodium iodide symporter (hNIS) We successfully developed a lentivirus-derived vector containing the hNIS gene under the control of the CMV promoter and yielded virus (Lenti-CMV-hNIS) stocks
HNIS-mediated in vitro 188Re uptake 188Re uptake in U87-hNIS cells with respect to 188Re incubation time is shown in Figure 1; the initial uptake of 188Re was dependent on incubation time. 188Re influx rapidly increased into U87-hNIS cells, with half-maximal uptake observed at about 5 minutes, reaching a maximum after about 30 minutes. 188Re uptake in U87-hNIS cells was 26-fold higher than in U87-0 cells after incubation with 188Re for 30 minutes
Summary
Glioma remains one of the most common cancers and is a leading cause of cancer-related deaths worldwide. The theranostic strategy [2,3] using radionuclide-based imaging reporter genes shows great treatment promise for various clinical fields, in the field of cancer gene therapy. The sodium iodide symporter (NIS) is a plasma membrane glycoprotein, which mediates active iodide uptake in the thyroid and other tissues [4,5]. One of the most exciting current areas of NIS research is radioiodine treatment of extrathyroidal cancers by the ectopic transfer of the NIS gene into otherwise non-NIS-expressing cancers. Many investigators have successfully obtained ectopic NIS expression by gene transfer techniques in prostate cancer [6], melanoma [7], glioma cells [8] and myeloma cells [9]
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