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Mechanisms of cellular uptake and endosomal escape of calcium-siRNA nanocomplexes.
International Journal of Pharmaceutics 2016 December 31
Ca(2+)-siRNA nanocomplexes represent a simple yet an effective platform for siRNA delivery into the cell cytoplasm, with subsequent successful siRNA-induced target gene silencing. Herein, we aimed to elucidate the roles played by calcium ions in siRNA nanocomplex formation, cell uptake, and endosomal escape. We investigated whether the replacement of Ca(2+)in the nanocomplex by other bivalent cations would affect their cell entry and subsequent gene silencing. Our results indicate that Mg(2+) and Ba(2+) lead to the formation of nanocomplexes of similar physical features (size=100nm, surface charge ζ=-8mV) as the Ca(2+)-siRNA nanocomplexes. Yet, these nanocomplexes were not uptaken by the cells to the same extent as those prepared with Ca(2+), and siRNA-induced target gene silencing was not obtained. Cell internalization of Ca(2+-)-siRNA nanocomplexes, examined by employing chemical inhibitors to clathrin-, caveolin- and dynamin-mediated endocytosis pathways, indicated the involvement of all mechanisms in the process. Inhibition of endosome acidification by bafilomycin completely abolished the siRNA-mediated silencing by Ca(2+)-siRNA nanocomplexes. Collectively, our results indicate that Ca(2+) promotes cell internalization and rapid endosomal escape, thus leading to the efficient siRNA-induced target gene silencing elicited by the Ca(2+)-siRNA nanocomplexes.
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