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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.
AuthorsGeoffrey K Grünwald, Alexandra Vetter, Kathrin Klutz, Michael J Willhauck, Nathalie Schwenk, Reingard Senekowitsch-Schmidtke, Markus Schwaiger, Christian Zach, Ernst Wagner, Burkhard Göke, Per S Holm, Manfred Ogris, Christine Spitzweg
JournalMolecular therapy. Nucleic acids (Mol Ther Nucleic Acids) Vol. 2 Pg. e131 (Nov 05 2013) ISSN: 2162-2531 [Print] United States
PMID24193032 (Publication Type: Journal Article)

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