In Vivo Positron Emission Tomography Imaging Using the Sodium Iodide Symporter as a Reporter Gene
Information regarding the biodistribution and kinetics of spread of oncolytic viruses is crucial for safety considerations in the design of future, more efficient reagents. Although optical imaging can be used to gain this information in rodent models, im
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. Introduction Molecular imaging of gene expression has important applications in gene therapy. This technology can provide unique information on the anatomic site, level, and duration of gene transfer. This information has safety implications and can be used to improve the design of new vectors. Optical (bioluminescence, fluorescence) imaging and imaging with radioactive isotopes [scintillation camera and positron emission tomography (PET)] are the most commonly used imaging modalities by the gene therapy community. The former is highly relevant for preclinical studies in rodents (see Chapter 10), but the attenuation of light originating from deeper tissues limits its applications in large animals and humans. Imaging using
David H. Kirn et al. (eds.), Oncolytic Viruses: Methods and Protocols, Methods in Molecular Biology, vol. 797, DOI 10.1007/978-1-61779-340-0_7, © Springer Science+Business Media, LLC 2012
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radiotracers is, therefore, the method of choice to monitor gene transfer in humans. Molecular imaging of gene expression requires a reporter gene as well as a tracer (a radiotracer in the case of imaging using radioisotopes). The tracer accumulates in tissues in which the reporter gene is expressed and a camera is able to detect the accumulation of the radioactivity in these tissues. The two main modalities of detection of gene transfer are single photon emission-computed tomography (SPECT) and PET. SPECT imaging is based on the detection of individual photons emitted by the isotope (1). Detection by a PET camera requires tracers that emit positrons, the so-called beta plus emitters. The positron travels through the medium until it has lost its kinetic energy and then forms a pair with an electron. The electron–positron pair is immediately annihilated and two 511 keV photons are emitted in opposite directions (180° apart). The detector in the PET camera registers all events on a ring of detectors around the radioactivity source, but processes only events that occur simultaneously (within a very short time window) in two detectors situated 180° apart (2). Because of its potential in terms of quantification, as well as its high sensitivity, PET is the technique of choice to collect information on the anatomic location, magnitude, and kinetics of gene expression. Different reporter systems have been described in the literature: the herpes simplex thymidine kinase (HSV1-tk) gene associated with its radiolabeled substrates (3, 4) and the dopamine D2 (5), somatostatin type 2 (6), and the norepinephrine (7) receptors associated with their radioligands have all been used to monitor gene transfer by either SPECT or PET. In this chapter, we focus on another reporter system which uses the sodium/iodide symporter (NIS) as a reporter gene. NIS can be associated with different radiohalogen for either SPECT (123I or 99mTc-pertechnetate) or PET (124I) imaging (8). NIS is a transmembrane protein using the sodium gradient to concentrate iodide in cells. It is mainly expressed in the thyroid and the stomac
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