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 131I. 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 18F-tetrafluoroborate (18F-TFB) as novel NIS PET tracer. Mice that were injected with LPEI-PEG-GE11/NIS 48 h before 18F-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 131I 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.