Molecular Therapy: Oncolytics (Dec 2021)

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 A. Weber,
  • Roland E. Kälin,
  • Rainer Glass,
  • Peter J. Nelson,
  • Ernst Wagner,
  • Christine Spitzweg

Journal volume & issue
Vol. 23
pp. 432 – 446

Abstract

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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.

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