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Urnauer, Sarah; Müller, Andrea M.; Schug, Christina; Schmohl, Kathrin A.; Tutter, Mariella; Schwenk, Nathalie; Rödl, Wolfgang; Morys, Stephan; Ingrisch, Michäl; Bertram, Jens; Bartenstein, Peter; Clevert, Dirk-André; Wagner, Ernst; Spitzweg, Christine (2017): EGFR-targeted nonviral NIS gene transfer for bioimaging and therapy of disseminated colon cancer metastases. In: Oncotarget, Vol. 8, No. 54: pp. 92195-92208
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Abstract

Liver metastases present a serious problem in the therapy of advanced colorectal cancer (CRC), as more than 20% of patients have distant metastases at the time of diagnosis with less than 5% being cured. Consequently, new therapeutic approaches are of major need together with high-resolution imaging methods that allow highly specific detection of small metastases. The unique combination of reporter and therapy gene function of the sodium iodide symporter (NIS) may represent a promising theranostic strategy for CRC liver metastases allowing non-invasive imaging of functional NIS expression and therapeutic application of I-131. For targeted NIS gene transfer polymers containing linear polyethylenimine (LPEI), polyethylene glycol (PEG) and the epidermal growth factor receptor (EGFR)specific ligand GE11 were complexed with human NIS DNA (LPEI-PEG-GE11/NIS). Tumor specificity and transduction efficiency were examined in high EGFR-expressing LS174T metastases by non-invasive imaging using F-18-tetrafluoroborate (F-18-TFB) as novel NIS PET tracer. Mice that were injected with LPEI-PEG-GE11/NIS 48 h before F-18-TFB application showed high tumoral levels (4.8 +/- 0.6% of injected dose) of NIS-mediated radionuclide uptake in comparison to low levels detected in mice that received untargeted control polyplexes. Three cycles of intravenous injection of EGFR-targeted NIS polyplexes followed by therapeutic application of 55.5 MBq I-131 resulted in marked delay in metastases spread, which was associated with improved animal survival. In conclusion, these preclinical data confirm the enormous potential of EGFR-targeted synthetic polymers for systemic NIS gene delivery in an advanced multifocal CRC liver metastases model and open the exciting prospect of NIS-mediated radionuclide therapy in metastatic disease.