Selective sodium iodide symporter (NIS) genetherapy of glioblastoma mediatedby 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

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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. 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.

Original languageEnglish
Pages (from-to)432-446
Number of pages15
JournalMolecular Therapy - Oncolytics
Volume23
DOIs
StatePublished - 17 Dec 2021
Externally publishedYes

Keywords

  • DNA nanoparticle
  • EGFR-targeting
  • GBM
  • NIS
  • gene therapy
  • glioblastoma
  • polyplexes
  • radioiodine
  • sodium iodide symporter

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