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RNAi-mediated gene-targeting through systemic application of polyethylenimine (PEI)-complexed siRNA in vivo

Abstract

RNA interference (RNAi) represents a powerful, naturally occurring biological strategy for inhibition of gene expression. It is mediated through small interfering RNAs (siRNAs), which trigger specific mRNA degradation. In mammalian systems, however, the application of siRNAs is severely limited by the instability and poor delivery of unmodified siRNA molecules into the cells in vivo. In this study, we show that the noncovalent complexation of synthetic siRNAs with low molecular weight polyethylenimine (PEI) efficiently stabilizes siRNAs and delivers siRNAs into cells where they display full bioactivity at completely nontoxic concentrations. More importantly, in a subcutaneous mouse tumor model, the systemic (intraperitoneal, i.p.) administration of complexed, but not of naked siRNAs, leads to the delivery of the intact siRNAs into the tumors. The i.p. injection of PEI-complexed, but not of naked siRNAs targeting the c-erbB2/neu (HER-2) receptor results in a marked reduction of tumor growth through siRNA-mediated HER-2 downregulation. Hence, we establish a novel and simple system for the systemic in vivo application of siRNAs through PEI complexation as a powerful tool for future therapeutic use.

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Acknowledgements

We are grateful to Dr J Platz for providing the NF-kB/luciferase plasmid. We acknowledge Silke Kaske, Lige Dai, Beate Junk, Helga Radler, and Andrea Wüstenhagen for expert technical assistance.

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Urban-Klein, B., Werth, S., Abuharbeid, S. et al. RNAi-mediated gene-targeting through systemic application of polyethylenimine (PEI)-complexed siRNA in vivo. Gene Ther 12, 461–466 (2005). https://doi.org/10.1038/sj.gt.3302425

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  • DOI: https://doi.org/10.1038/sj.gt.3302425

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