Gymnotic delivery and gene silencing activity of reduction-responsive siRNAs bearing lipophilic disulfide-containing modifications at 2'-position.
Modified oligoribonucleotides used as siRNAs bearing biolabile disulfide-containing groups at some 2'-positions were synthesized following a post-synthesis transformation of solid-supported 2'-O-acetylthiomethyl RNA, previously described. Thus, the reduction-responsive and lipophilic benzyldithiomethyl (BnSSM) modification was introduced at different locations into siRNAs targeting the Ewing sarcoma EWS-Fli1 protein. Thermal stability, serum stability and response to glutathione treatment of modified siRNAs were thoroughly investigated. Among 17 modified siRNAs, significant gene silencing activities were demonstrated for the 8 most stable siRNAs in serum (half-life > 1 h) when using a transfection reagent. Of special interest, two naked 2'-O-BnSSM siRNAs transfection exhibited a remarkable gene silencing activity after 24 h incubation. These inhibitions are consistent with an efficient gymnotic delivery demonstrated by the presence of the corresponding fluorescent siRNAs within cells.
['Gauthier|Florian|F|', 'Claveau|Sandra|S|', 'Bertrand|Jean-Rémi|JR|', 'Vasseur|Jean-Jacques|JJ|', 'Dupouy|Christelle|C|', 'Debart|Françoise|F|']
D000818:Animals D001483:Base Sequence D002417:Cattle D045744:Cell Line, Tumor D004220:Disulfides D005978:Glutathione D006207:Half-Life D006801:Humans D008856:Microscopy, Fluorescence D009690:Nucleic Acid Conformation D009841:Oligonucleotides D010084:Oxidation-Reduction D051789:Proto-Oncogene Protein c-fli-1 D034622:RNA Interference D020871:RNA Stability D034741:RNA, Small Interfering D013696:Temperature
Gymnotic delivery Gene silencing Reduction-responsive siRNA Disulfide-containing groups