Preclinical applications of imaging for cancer gene therapy

Abstract

Gene therapy is a very attractive strategy in experimental cancer therapy. Ideally, the approach aims to deliver therapeutic genes selectively to cancer cells. However, progress in the improvement of gene therapy formulations has been hampered by difficulties in measuring transgene delivery and in quantifying transgene expression in vivo. In clinical trials, endpoints rely almost exclusively on the analysis of biopsies by molecular and histopathological methods, which provide limited information. Therefore, to ensure the rational development of gene therapy, a crucial issue is the utilisation of technologies for the non-invasive monitoring of spatial and temporal gene expression in vivo upon administration of a gene delivery vector. Such imaging technologies would allow the generation of quantitative information about gene expression and the assessment of cancer gene therapy efficacy. In the past decade, progress has been made in the field of in vivo molecular imaging. This review highlights the various methods currently being developed in preclinical models.

Cancer-Specific Transgene Expression Mediated by Systemic Injection of Nanoparticles

“…In the thyroid, NIS promotes iodide concentration, and radio-iodide uptake is used in the detection and, in some specific cases, in the treatment of disseminated thyroid carcinomas (9). In gene therapy experiments, ectopic expression of NIS has been shown to allow accumulation of radioactive iodide in tissues for noninvasive imaging (10)(11)(12). Moreover, ectopic NIS expression is unlikely to interfere with the cell biochemistry.…”

“…[13][14][15][16]. The imaging of NIS-expressing tissues is particularly versatile because NIS can promote cellular uptake of different radioisotopes: 123 8,11). This imaging method has very recently been validated in humans (17).…”

SPECT/CT imaging of oncolytic adenovirus propagation in tumours in vivo using the Na/I symporter as a reporter gene

“…hNIS uses the sodium gradient generated from the Na + /K À ATPase to co-transport two Na + and one I À ions across the basolateral membrane of thyroid follicular cells 15 and is also key to the successful treatment of differentiated thyroid carcinomas with 131 I. 16 hNIS has been shown to allow accumulation of radioactive iodide endogenously and transduced exogenously expressing tissues for non-invasive imaging [17][18][19][20] and is unlikely to interfere with the cell biochemistry. 21 Different modalities have been reported to image hNISexpressing tissues, including positron emission tomography (PET), [22][23][24] scintigraphic imaging 25 and single photon emission computed tomography (SPECT).…”

“…26 The imaging of hNIS-expressing tissues is particularly versatile since hNIS can promote cellular uptake of different radioisotopes 123 I (SPECT), 124 I (PET), 99m Tc (SPECT), 131 I (scintigraphic imaging). 19,[25][26][27][28] In the present study, we have generated two replication-competent adenoviruses (AdIP1 and AdAM6) encoding the hNIS cDNA. AdIP1 is a 'wild-type' virus based on the Ad-5 serotype in which the only modification is the replacement of the gp19k gene in the E3 region by the hNIS cDNA.…”

Human Breast Tumor Cells Express Multimodal Imaging Reporter Genes

“…The main application of molecular imaging in preclinical tumor models is to evaluate the outcomes of drug treatments and therapies by noninvasively monitoring the growth and metastasis of tumors on animals using various imaging platforms [3][4][5][6]. To directly compare imaging results across multiple modalities requires the use of reporter genes that are transfected in cells or animals, and the expression of reporter genes is measured by their corresponding imaging tools [6,7].…”