Selective sodium iodide symporter (NIS) gene therapy of glioblastoma mediated by EGFR-targeted lipopolyplexes
Rebekka Spellerberg, Teoman Benli‐Hoppe, Carolin Kitzberger, Simone Berger, Kathrin A. Schmohl, Nathalie Schwenk, Hsi-Yu Yen, Christian Zach, Franz Schilling, Wolfgang Weber, Roland E. Kälin, Rainer Glaß, Peter J. Nelson, Ernst Wagner, Christine Spitzweg
Abstract
Lipo-oligomers, post-functionalized with ligands to enhance targeting, represent promising new vehicles for the tumor-specific delivery of therapeutic genes such as the sodium iodide symporter ( NIS ). Due to its iodide trapping activity, NIS is a powerful theranostic tool for diagnostic imaging and the application of therapeutic radionuclides. 124 I PET imaging allows non-invasive monitoring of the in vivo biodistribution of functional NIS expression, and application of 131 I enables cytoreduction. In our experimental design, we used epidermal growth factor receptor (EGFR)-targeted polyplexes (GE11) initially characterized in vitro using 125 I uptake assays. Mice bearing an orthotopic glioblastoma were treated subsequently with mono-dibenzocyclooctyne (DBCO)-PEG 24 -GE11/NIS or bisDBCO-PEG 24 -GE11/NIS, and 24–48 h later, 124 I uptake was assessed by positron emission tomography (PET) imaging. The best-performing polyplex in the imaging studies was then selected for 131 I therapy studies. The in vitro studies showed EGFR-dependent and NIS-specific transfection efficiency of the polyplexes. The injection of monoDBCO-PEG 24 -GE11/NIS polyplexes 48 h before 124 I application was characterized to be the optimal regime in the imaging studies and was therefore used for an 131 I therapy study, showing a significant decrease in tumor growth and a significant extension of survival in the therapy group. These studies demonstrate the potential of EGFR-targeted polyplex-mediated NIS gene therapy as a new strategy for the therapy of glioblastoma.