Targeted Radioiodine Therapy of Neuroblastoma Tumors following Systemic Nonviral Delivery of the Sodium Iodide Symporter Gene

Abstract

Purpose: We recently reported the significant therapeutic efficacy of radioiodine therapy in various tumor mouse models following transcriptionally targeted sodium iodide symporter (NIS) gene transfer. These studies showed the high potential of NIS as a novel diagnostic and therapeutic gene for the treatment of extrathyroidal tumors. As a next crucial step towards clinical application of NIS-mediated radionuclide therapy we aim at systemic delivery of the NIS gene to target extrathyroidal tumors even in the metastatic stage. Experimental Design: In the current study, we used synthetic polymeric vectors based on pseudodendritic oligoamines with high intrinsic tumor affinity (G2-HD-OEI) to target a NIS-expressing plasmid (CMV-NIS-pcDNA3) to neuroblastoma (Neuro2A) cells. Results: Incubation with NIS-containing polyplexes (G2-HD-OEI/NIS) resulted in a 51-fold increase in perchlorate-sensitive iodide uptake activity in Neuro2A cells in vitro. The exact mechanism by which iodide is actively transported across the basolateral membrane of thyroid follicular cells was clarified by the cloning and characterization of the sodium iodide symporter (NIS) 13 years ago (1-3). NIS, an intrinsic transmembrane glycoprotein with 13 putative transmembrane domains, is responsible for the ability of the thyroid gland to concentrate iodide, the first and rate-limiting step in the process of thyroid hormonogenesis (4, 5). Moreover, due to its expression in follicular cell-derived thyroid cancer cells, NIS provides the molecular basis for the diagnostic and therapeutic application of radioiodine, which has been successfully used for more than 60 years in the treatment of thyroid cancer patients and therefore represents the most effective form of systemic anticancer radiotherapy available to the clinician today (6). Since its cloning in 1996 NIS has been identified and characterized as a novel promising target gene for the treatment of extrathyroidal tumors following selective NIS gene transfer into tumor cells that allows diagnostic and therapeutic application of radioiodine and alternative radionuclides, such as 188 Re and 211 At (6-9). We have proven the feasibility of extrathyroidal radioiodine therapy after induction of iodide uptake by ex vivo

Systemic Image-Guided Liver Cancer Radiovirotherapy Using Dendrimer-Coated Adenovirus Encoding the Sodium Iodide Symporter as Theranostic Gene

“…**P # 0.01. application of radioiodine (13). Our previous work convincingly demonstrated the proof of principle of the NIS gene therapy concept (3,8,9,11,12,14,15). The next step toward clinical application has to be the development of gene-transfer vehicles that are able to promote targeted and efficient systemic NIS gene transfer with the potential to reach tumor metastases.…”

Establishment of an Effective Radioiodide Thyroid Ablation Protocol in Mice

“…We and others have shown the potential of NIS as a reporter gene for molecular imaging with a broad range of possible applications [13,14,15,16,17,18,19,20,21,22,23,24]. In our previous work, the role of NIS as a reporter gene allowed noninvasive multimodal imaging of functional NIS expression by 99m Tc or 123 I scintigraphy as well as SPECT and 124 I PET imaging that correlated well with the results of ex vivo gamma counter measurements as well as NIS mRNA and protein analysis.…”

Mesenchymal Stem Cell–Mediated, Tumor Stroma–Targeted Radioiodine Therapy of Metastatic Colon Cancer Using the Sodium Iodide Symporter as Theranostic Gene

“…Total RNA was isolated from the liver and other tissues using the RNeasy Mini Kit (Qiagen) according to the manufacturer's recommendations, and quantitative real-time PCR was performed as described previously (21).…”