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

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