Selective sodium iodide symporter (NIS) gene therapy of glioblastoma mediated by EGFR-targeted lipopolyplexes

Spellerberg, Rebekka; Benli-Hoppe, Teoman; Kitzberger, Carolin; Berger, Simone; Schmohl, Kathrin A.; Schwenk, Nathalie; Yen, Hsi-Yu; Zach, Christian; Schilling, Franz; Weber, Wolfgang A.; Kalin, Roland E.; Glass, Rainer; Nelson, Peter J.; Wagner, Ernst und Spitzweg, Christine (2021): Selective sodium iodide symporter (NIS) gene therapy of glioblastoma mediated by EGFR-targeted lipopolyplexes. In: Molecular Therapy-Oncolytics, Bd. 23: S. 432-446

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. I-124 PET imaging allows non-invasive monitoring of the in vivo biodistribution of functional NIS expression, and application of I-131 enables cytoreduction. In our experimental design, we used epidermal growth factor receptor (EGFR)-targeted polyplexes (GE11) initially characterized in vitro using I-125 uptake assays. Mice bearing an orthotopic glioblastoma were treated subsequently with mono-dibenzocyclooctyne (DBCO)-(PEG24-)GE11/NIS or bisDBCO-PEG(24)-GE11/NIS, and 24-48 h later, I-124 uptake was assessed by positron emission tomography (PET) imaging. The best-performing polyplex in the imaging studies was then selected for I-131 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 I-124 application was characterized to be the optimal regime in the imaging studies and was therefore used for an I-131 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2372-7705
• Sprache: Englisch