The sodium iodide symporter (NIS) as an imaging reporter for gene, viral, and cell-based therapies

Abstract

Preclinical and clinical tomographic imaging systems increasingly are being utilized for non-invasive imaging of reporter gene products to reveal the distribution of molecular therapeutics within living subjects. Reporter gene and probe combinations can be employed to monitor vectors for gene, viral, and cell-based therapies. There are several reporter systems available; however, those employing radionuclides for positron emission tomography (PET) or singlephoton emission computed tomography (SPECT) offer the highest sensitivity and the greatest promise for deep tissue imaging in humans. Within the category of radionuclide reporters, the thyroidal sodium iodide symporter (NIS) has emerged as one of the most promising for preclinical and translational research. NIS has been incorporated into a remarkable variety of viral and non-viral vectors in which its functionality is conveniently determined by in vitro iodide uptake assays prior to live animal imaging. This review on the NIS reporter will focus on 1) differences between endogenous NIS and heterologously-expressed NIS, 2) qualitative or comparative use of NIS as an imaging reporter in preclinical and translational gene therapy, oncolytic viral therapy, and cell trafficking research, and 3) use of NIS as an absolute quantitative reporter.

Fig. (1)

A spherical phantom study to determine the partial volume losses on a Gamma-Medica (Northbridge, CA) X-SPECT System. Images for the ^99mTcO₄ phantom series were obtained with a high-sensitivity parallel-hole collimator and a 1-mm pinhole collimator. The fraction of counts displayed within CT defined spheres is plotted as a function of sphere volume.

Fig. (2)

Pinhole micro-SPECT/CT image analysis versus ex vivo quantitation of BxPC-3 tumors 3 days post-infection with an oncolytic measles virus encoding NIS. A single spherical volume of interest (VOI) was drawn around each tumor and the activity determined with PMOD imaging software. Immediately following imaging, tumors were excised and counted in a dose calibrator.

Fig. (3)

Micro-SPECT/CT image and corresponding immunohistochemistry analysis of early infection with multiple intratumoral injections of MV-NIS. A BxPC-3 xenograft was injected in three locations with a total dose of 3.5 x 10⁶ MV-NIS. On day 4 post-injection, the animal was imaged with pinhole micro-SPECT/CT. (A) The tumor was removed, aligned with the micro-SPECT/CT image, processed by IHC for measles N (brown staining), and counterstained with hematoxylin. (B) An excellent spatial correlation is seen between the live animal micro- SPECT/CT image and the three small zones of intratumoral infection.

Fig. (4)

Micro-SPECT/CT imaging of an orthotopic transplantation model of pancreatic cancer. BxPC-3-NIS xenograft fragments were transplanted to the pancreas of donor mice. Twenty days after transplantation, animals were injected with 1 mCi ^99mTc0₄ and imaged 1 h later. (A) Coronal fusion micro-SPECT/CT slice through the center of the pancreatic tumor (arrow) adjacent to the endogenous stomach activity (arrowhead). Thyroid uptake is also seen on the image. (B) The same imaging data set is displayed as a maximum intensity projection (MIP) generated from threshold-adjusted axial slices. (C) Post-mortem analysis reveals the size and location of the pancreatic tumor (arrow) relative to adjacent stomach (arrowhead) and other organs.