Lipophilic 2′‐O‐Acetal Ester RNAs: Synthesis, Thermal Duplex Stability, Nuclease Resistance, Cellular Uptake, and siRNA Activity after Spontaneous Naked Delivery. (29th September 2016)

• Record Type: Journal Article
• Authors: Biscans, Annabelle; Bertrand, Jean‐Rémi; Dubois, Josephine; Rüger, Jacqueline; Vasseur, Jean‐Jacques; Sczakiel, Georg; Dupouy, Christelle; Debart, Françoise
• Is Part Of: Chembiochem. Volume 17:Number 21(2016)
• Page Start: 2054
• Page End: 2062
• Publication Date: 2016-09-29
• Subjects: acetal ester modifications -- cellular uptake -- lipophilicity -- RNA -- siRNA; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201600317
• Languages: English
• ISSNs: 1439-4227

Abstract

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 (P i BuOM)‐modified siRNAs and their impact on biological activity. In the case of spontaneous cellular uptake of naked P i BuOM‐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 P i BuOM‐modified siRNA and of substantial target suppression in human cells in serum‐containing medium. Abstract : Gymnotic oligonucleotide delivery : We provide evidence for improved spontaneous cellular uptake of naked P i BuOM‐modified siRNA and for substantial target suppression in human cells in serum‐containing medium. This study demonstrates the wide usefulness of P i BuOM modifications for naked delivery of oligonucleotides in biological studies.