Sodium iodide symporter for nuclear molecular imaging and gene therapy: from bedside to bench and back

Abstract

Molecular imaging, defined as the visual representation, characterization and quantification of biological processes at the cellular and subcellular levels within intact living organisms, can be obtained by various imaging technologies, including nuclear imaging methods. Imaging of normal thyroid tissue and differentiated thyroid cancer, and treatment of thyroid cancer with radioiodine rely on the expression of the sodium iodide symporter (NIS) in these cells. NIS is an intrinsic membrane protein with 13 transmembrane domains and it takes up iodide into the cytosol from the extracellular fluid. By transferring NIS function to various cells via gene transfer, the cells can be visualized with gamma or positron emitting radioisotopes such as Tc-99m, I-123, I-131, I-124 and F-18 tetrafluoroborate, which are accumulated by NIS. They can also be treated with beta- or alpha-emitting radionuclides, such as I-131, Re-186, Re-188 and At-211, which are also accumulated by NIS. This article demonstrates the diagnostic and therapeutic applications of NIS as a radionuclide-based reporter gene for trafficking cells and a therapeutic gene for treating cancers.

Keywords: gene therapy; molecular imaging; radionuclide-based imaging; radionuclide.; sodium iodide symporter.

Figure 1

Iodide uptake function of NIS. NIS transports 2 sodium ions and 1 iodide ion into the cytoplasm together. The electrochemical sodium gradient generated by the oubaine-sensitive Na⁺/K⁺ ATPase pump provides energy for this transfer.

Figure 2

A 21-year-old female who underwent total thyroidectomy due to papillary thyroid cancer. Chest simple radiography and CT did not demonstrate any metastatic lesion of the cancer in the neck and chest regions. However, a radioiodine whole body scan revealed lymph node metastases (white arrow) in the right supraclavicular area and diffuse lung metastases (black arrows).

Figure 3

Cells without NIS gene expression obtain the function of iodine uptake with NIS gene transduction by viral or non-viral vector delivery. The cells can be imaged by radionuclide-based molecular imaging techniques using gamma ray or positron-emitting radiotracers and be cleared by beta or alpha particle-emitting radionuclides.

Figure 4

Visualization of macrophages expressing NIS with radionuclide-based molecular imaging. Inflammation at the right thigh (yellow arrow) was well visualized in F-18 FDG microPET imaging. Migration of microphages expressing NIS to the inflammation site (white arrow) was clearly visualized on I-124 microPET imaging .

Figure 5

Visualization of tumor cells expressing NIS with optical molecular imaging using I-124. Tumor xenografts of anaplastic thyroid cancer cells expressing NIS were well visualized on both microPET imaging (white arrows) and Cerenkov luminescence imaging (black arrows) after intravenous administration of I-124 .

Figure 6

A 26-year-old female who underwent total thyroidectomy due to papillary thyroid cancer. (A) Chest simple radiograph did not demonstrate any observable metastatic lesions of the cancer. (B) CT scan of the chest demonstrated several metastatic lesions of the cancer in both lung fields (white arrows). TSH-stimulated serum thyroglobulin was 65.0 ng/mL. The patient was diagnosed with metastatic thyroid cancer of the lung. (C) A post initial high dose I-131 treatment (150 mCi) scan revealed numerous metastatic lung lesions. (D) A post 2^nd high dose I-131 treatment (200 mCi) scan revealed fewer but still several metastatic lung lesions (black arrows). (E, F) A post 3^rd high dose I-131 treatment (200 mCi) scan revealed no remarkable radioiodine uptake in both lung fields and chest CT showed only tiny lung nodules having no clinical significance. TSH-stimulated serum thyroglobulin was 1.4 ng/mL after the third treatment. The patient had achieved complete remission with three times of high dose I-131 treatment and her status still remains disease-free at 7 years follow-up.