title: Lipophilic 2'-O-Acetal Ester RNAs: Synthesis, Thermal Duplex Stability, Nuclease Resistance, Cellular Uptake, and siRNA Activity after Spontaneous Naked Delivery.
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.
authors: IBMM, UMR 5247 CNRS, Université Montpellier, ENSCM, Campus Triolet, Place Eugène Bataillon, 34095, Montpellier Cedex 05, France.
authors: Annabelle
authors: A
authors: Biscans
authors: UMR 8203 CNRS, Université Paris-Sud, Gustave Roussy, Université Paris-Saclay, 114 rue Edouard Vaillant, 94805, Villejuif Cedex, France.
authors: Jean-Rémi
authors: JR
authors: Bertrand
authors: Institut für Molekulare Medizin, Universitätsklinikum Schleswig-Holstein, Universität zu Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors: Josephine
authors: J
authors: Dubois
authors: Institut für Molekulare Medizin, Universitätsklinikum Schleswig-Holstein, Universität zu Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
authors: Jacqueline
authors: J
authors: Rüger
authors: IBMM, UMR 5247 CNRS, Université Montpellier, ENSCM, Campus Triolet, Place Eugène Bataillon, 34095, Montpellier Cedex 05, France.
authors: Jean-Jacques
authors: JJ
authors: Vasseur
authors: Institut für Molekulare Medizin, Universitätsklinikum Schleswig-Holstein, Universität zu Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany. sczakiel@imm.uni-luebeck.de.
authors: Georg
authors: G
authors: Sczakiel
authors: IBMM, UMR 5247 CNRS, Université Montpellier, ENSCM, Campus Triolet, Place Eugène Bataillon, 34095, Montpellier Cedex 05, France.
authors: Christelle
authors: C
authors: Dupouy
authors: IBMM, UMR 5247 CNRS, Université Montpellier, ENSCM, Campus Triolet, Place Eugène Bataillon, 34095, Montpellier Cedex 05, France. francoise.debart@umontpellier.fr.
authors: Françoise
authors: F
authors: Debart
mesh_terms: D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D004952:Esters / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020871:RNA Stability; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D012260:Ribonucleases / Q000378:metabolism*; D013696:Temperature
chemical_list: D004952:Esters; D034741:RNA, Small Interfering; D012260:Ribonucleases
keywords: RNA; acetal ester modifications; cellular uptake; lipophilicity; siRNA