Dual EGFR- and TfR-targeted gene transfer for sodium iodide symporter gene therapy of glioblastoma
Rebekka Spellerberg, Teoman Benli‐Hoppe, Carolin Kitzberger, Mara Hageneier, Nathalie Schwenk, Özgür Öztürk, Katja Steiger, Gabriele Multhoff, Matthias Eiber, Franz Schilling, Wolfgang Weber, Roland E. Kälin, Rainer Glaß, Peter J. Nelson, Ernst Wagner, Christine Spitzweg
Abstract
Sodium iodide symporter (NIS) gene transfer for active accumulation of iodide in tumor cells is a powerful theranostic strategy facilitating both diagnostic and therapeutic application of radioiodide. In glioblastoma (GBM), the blood-brain barrier (BBB) presents an additional delivery barrier for nucleic acid nanoparticles. In the present study, we designed dual-targeted NIS plasmid DNA complexes containing targeting ligands for the transferrin receptor (TfR) and the epidermal growth factor receptor (EGFR), thus providing the potential for active transport across the BBB followed by targeting of tumor cells. In vitro 125 I transfection studies confirmed TfR-and EGFR-dependent transfection efficiency and NIS-specific iodide uptake of dual-targeted polyplexes. In vivo gene transfer in mice bearing orthotopic U87 GBM xenografts was assessed at 48 h after intravenous polyplex injection by positron emission tomography (PET) imaging using 18 F-labeled tetrafluoroborate (TFB) as tracer. The tumoral 18 F-TFB uptake of mice treated with dual-targeted polyplexes (0.56% 0.08% ID/mL) was significantly higher compared with mice treated with EGFR-mono-targeted (0.33% 0.03% ID/mL) or TfR-monotargeted (0.27% 0.04% ID/mL) polyplexes. In therapy studies, application of 131 I induced a superior therapeutic effect of the dual-targeted therapy, demonstrated by a significant delay in tumor growth and prolonged survival.