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

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 51fold increase in perchlorate-sensitive iodide uptake activity in Neuro2A cells in vitro. Through I-scintigraphy and ex vivo gamma counting Neuro2A tumors in syngeneic A/J mice were shown to accumulate 8% to 13% ID/g I with a biological half-life of 13 hours, resulting in a tumor-absorbed dose of 247 mGy/MBq I after i.v. application of G2-HD-OEI/NIS. Nontarget organs, including liver, lung, kidneys, and spleen revealed no significant iodide uptake. Moreover, two cycles of systemic NIS gene transfer followed by I application (55.5 MBq) resulted in a significant delay in tumor growth associated with markedly improved survival. Conclusions: In conclusion, our data clearly show the high potential of novel pseudodendritic polymers for tumor-specific NIS gene delivery after systemic application, opening the prospect of targeted NIS-mediated radionuclide therapy of nonthyroidal tumors even in metastatic disease. (Clin Cancer Res 2009;15(19):6079–86) 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 Re and At (6–9). We have proven the feasibility of extrathyroidal radioiodine therapy after induction of iodide uptake by ex vivo Authors' Affiliations: Departments of Internal Medicine II and Nuclear Medicine, Ludwig-Maximilians-University, and Department of Pharmacy, Center of Drug Research, Pharmaceutical Biology-Biotechnology and Center for NanoScience (CeNS), Ludwig-Maximilians-University, Munich, Germany Received4/5/09; revised5/22/09; accepted 6/16/09; publishedOnlineFirst 9/29/09. Grant support: Grants Sp 581/4-1, Sp 581/4-2 (DFG Forschergruppe FOR411 ‘Radionuklidtherapie’) as well as SFB 824 (DFG Sonderforschungsbereich 824) from the Deutsche Forschungsgemeinschaft, Bonn, Germany, and by a grant from the Wilhelm-Sander-Stiftung (2008.037.1) to C. Spitzweg, as well as the DFG-funded Nanosystems initiative Munich and EG-funded Project GIANT to M. Ogris and E. Wagner. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: K. Klutz and V. Russ contributed equally to this study. Requests for reprints: Christine Spitzweg, Klinikum Grosshadern, Medizinische Klinik II, Marchioninistrasse 15, 81377 Munich, Germany. Phone: 49-89-7095-0; Fax: 49-89-7095-8887; E-mail: [email protected] or Manfred Ogris, Department of Pharmacy, Center of Drug Research, Pharmaceutical Biology-Biotechnology, Butenandtstrasse 5-13, 81377 Munich, Germany. Phone: 49-89-2180-77842; Fax: 49-89-218077791; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0851 6079 Clin Cancer Res 2009;15(19) October 1, 2009 www.aacrjournals.org Research. on January 6, 2018. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst September 29, 2009; DOI: 10.1158/1078-0432.CCR-09-0851