EGFR-targeted nonviral NIS gene transfer for bioimaging and therapy of disseminated colon cancer metastases

// Sarah Urnauer 1 , Andrea M. Muller 1 , Christina Schug 1 , Kathrin A. Schmohl 1 , Mariella Tutter 1 , Nathalie Schwenk 1 , Wolfgang Rodl 2 , Stephan Morys 2 , Michael Ingrisch 3 , Jens Bertram 4 , Peter Bartenstein 5 , Dirk-Andre Clevert 3 , Ernst Wagner 2 and Christine Spitzweg 1 1 Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany 2 Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, LMU Munich, Munich, Germany 3 Department of Clinical Radiology, University Hospital of Munich, LMU Munich, Munich, Germany 4 Department of Nuclear Medicine, Radiopharmacy, Klinikum rechts der Isar der Technischen Universitat Munchen, Munich, Germany 5 Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany Correspondence to: Christine Spitzweg, email: Christine.Spitzweg@med.uni-muenchen.de Keywords: sodium iodide symporter, gene therapy, theranostic application, nonviral EGFR-targeted gene transfer, colon cancer metastases Received: April 26, 2017      Accepted: August 04, 2017      Published: September 16, 2017 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 131 I. 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 18 F-tetrafluoroborate ( 18 F-TFB) as novel NIS PET tracer. Mice that were injected with LPEI-PEG-GE11/NIS 48 h before 18 F-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 131 I 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.