title: EGFR-Targeted Adenovirus Dendrimer Coating for Improved Systemic Delivery of the Theranostic NIS Gene.
abstract: We recently demonstrated tumor-selective iodide uptake and therapeutic efficacy of combined radiovirotherapy after systemic delivery of the theranostic sodium iodide symporter (NIS) gene using a dendrimer-coated adenovirus. To further improve shielding and targeting we physically coated replication-selective adenoviruses carrying the hNIS gene with a conjugate consisting of cationic poly(amidoamine) (PAMAM) dendrimer linked to the peptidic, epidermal growth factor receptor (EGFR)-specific ligand GE11. In vitro experiments demonstrated coxsackie-adenovirus receptor-independent but EGFR-specific transduction efficiency. Systemic injection of the uncoated adenovirus in a liver cancer xenograft mouse model led to high levels of NIS expression in the liver due to hepatic sequestration, which were significantly reduced after coating as demonstrated by (123)I-scintigraphy. Reduction of adenovirus liver pooling resulted in decreased hepatotoxicity and increased transduction efficiency in peripheral xenograft tumors. (124)I-PET-imaging confirmed EGFR-specificity by significantly lower tumoral radioiodine accumulation after pretreatment with the EGFR-specific antibody cetuximab. A significantly enhanced oncolytic effect was observed following systemic application of dendrimer-coated adenovirus that was further increased by additional treatment with a therapeutic dose of (131)I. These results demonstrate restricted virus tropism and tumor-selective retargeting after systemic application of coated, EGFR-targeted adenoviruses therefore representing a promising strategy for improved systemic adenoviral NIS gene therapy.Molecular Therapy-Nucleic Acids (2013) 2, e131; doi:10.1038/mtna.2013.58; published online 5 November 2013.
authors.affiliation: Department of Internal Medicine II - Campus Grosshadern, University Hospital of Munich, Munich, Germany.
authors.forename: Geoffrey K
authors.initials: GK
authors.lastname: Grünwald
authors.forename: Alexandra
authors.initials: A
authors.lastname: Vetter
authors.forename: Kathrin
authors.initials: K
authors.lastname: Klutz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Willhauck
authors.forename: Nathalie
authors.initials: N
authors.lastname: Schwenk
authors.forename: Reingard
authors.initials: R
authors.lastname: Senekowitsch-Schmidtke
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaiger
authors.forename: Christian
authors.initials: C
authors.lastname: Zach
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Per S
authors.initials: PS
authors.lastname: Holm
authors.forename: Manfred
authors.initials: M
authors.lastname: Ogris
authors.forename: Christine
authors.initials: C
authors.lastname: Spitzweg