We recently demonstrated
tumor-selective
iodide uptake and therapeutic efficacy of radioiodine in
neuroblastoma tumors after systemic nonviral polyplex-mediated
sodium iodide symporter (NIS) gene delivery. In the present study, we used novel polyplexes based on linear
polyethylenimine (LPEI),
polyethylene glycol (PEG), and the synthetic
peptide GE11 as an
epidermal growth factor receptor (EGFR)-specific
ligand to target a NIS-expressing plasmid to
hepatocellular carcinoma (HCC) (HuH7). Incubation of HuH7 cells with LPEI-PEG-GE11/NIS polyplexes resulted in a 22-fold increase in
iodide uptake, which was confirmed in other
cancer cell lines correlating well with EGFR expression levels. Using (123)I-scintigraphy and ex vivo γ-counting, HuH7 xenografts accumulated 6.5-9% injected dose per gram (ID/g) (123)I, resulting in a
tumor-absorbed dose of 47 mGray/Megabecquerel (mGy/MBq) (131)
Iodide ((131)I) after intravenous (i.v.) application of LPEI-PEG-GE11/NIS. No
iodide uptake was observed in other tissues. After pretreatment with the EGFR-specific antibody
cetuximab, tumoral
iodide uptake was markedly reduced confirming the specificity of EGFR-targeted polyplexes. After three or four cycles of polyplex/(131)I application, a significant delay in
tumor growth was observed associated with prolonged survival. These results demonstrate that systemic NIS gene transfer using polyplexes coupled with an EGFR-targeting
ligand is capable of inducing
tumor-specific
iodide uptake, which represents a promising innovative strategy for systemic NIS gene therapy in metastatic
cancers.