Epidermal Growth Factor Receptor-targeted 131I-therapy of Liver Cancer Following Systemic Delivery of the Sodium Iodide Symporter Gene

Abstract

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.

Systemic Image-Guided Liver Cancer Radiovirotherapy Using Dendrimer-Coated Adenovirus Encoding the Sodium Iodide Symporter as Theranostic Gene

“…**P # 0.01. application of radioiodine (13). Our previous work convincingly demonstrated the proof of principle of the NIS gene therapy concept (3,8,9,11,12,14,15). The next step toward clinical application has to be the development of gene-transfer vehicles that are able to promote targeted and efficient systemic NIS gene transfer with the potential to reach tumor metastases.…”

“…After systemic adenovirus injection, NIS messenger RNA (mRNA) expression levels of liver, lung, spleen, kidneys, and tumors were analyzed via quantitative real-time PCR (qPCR) as described previously (12). Immunofluorescence staining of paraffin-embedded tissue sections derived from livers and HuH7 xenografts was performed using an hNIS-specific antibody directed against amino acid residues 625-643 of human NIS (Millipore) at a dilution of 1:750.…”

Establishment of an Effective Radioiodide Thyroid Ablation Protocol in Mice

“…We and others have shown the potential of NIS as a reporter gene for molecular imaging with a broad range of possible applications [13,14,15,16,17,18,19,20,21,22,23,24]. In our previous work, the role of NIS as a reporter gene allowed noninvasive multimodal imaging of functional NIS expression by 99m Tc or 123 I scintigraphy as well as SPECT and 124 I PET imaging that correlated well with the results of ex vivo gamma counter measurements as well as NIS mRNA and protein analysis.…”

Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

“…LPEI-PEG-GE11/NIS polyplexes were developed by Klutz et al 182 using linear polyethylenimine (LPEI), PEG, the synthetic EGFR-specific peptide GE11, and a sodium iodide symporter (NIS) expressing plasmid. LPEI-PEG-GE11/NIS polyplexes led to a 22-fold increase in iodide uptake in HCC HuH7 cells as well as high tumor-specific iodide accumulation, which inhibited tumor growth and increased survival in HCC xenograft bearing nude mice.…”