Lipophilic 2′‐O‐Acetal Ester RNAs: Synthesis,Thermal Duplex Stability,Nuclease Resistance,Cellular Uptake,and siRNA Activity after Spontaneous Naked Delivery |
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| Authors: | Dr. Annabelle Biscans Dr. Jean‐Rémi Bertrand Josephine Dubois Jacqueline Rüger Dr. Jean‐Jacques Vasseur Prof. Georg Sczakiel Dr. Christelle Dupouy Dr. Françoise Debart |
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| Affiliation: | 1. IBMM, UMR 5247 CNRS, Université Montpellier, ENSCM, Campus Triolet, Montpellier Cedex 05, France;2. UMR 8203 CNRS, Université Paris-Sud, Gustave Roussy, Université Paris-Saclay, Villejuif Cedex, France;3. Institut für Molekulare Medizin, Universit?tsklinikum Schleswig-Holstein, Universit?t zu Lübeck, Lübeck, Germany |
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| Abstract: | The in vivo application of siRNA depends on its cellular uptake and intracellular release, and this is an unsatisfactorily resolved technical hurdle in medicinal applications. Promising concepts directed towards providing efficient cellular and intracellular delivery include lipophilic chemical modification of siRNA. Here we describe chemistry for the production of modified siRNAs designed to display improved transmembrane transport into human cells while preserving the potency of the RNAi‐based inhibitors. We report the synthesis and the biochemical and biophysical characteristics of 2′‐O‐phenylisobutyryloxymethyl (PiBuOM)‐modified siRNAs and their impact on biological activity. In the case of spontaneous cellular uptake of naked PiBuOM‐modified siRNA, we observed increased target suppression in human cells relative to unmodified or pivaloyloxymethyl (PivOM)‐modified siRNA. We provide evidence of improved spontaneous cellular uptake of naked PiBuOM‐modified siRNA and of substantial target suppression in human cells in serum‐containing medium. |
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| Keywords: | acetal ester modifications cellular uptake lipophilicity RNA siRNA |
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