title: Chimeric Antisense Oligonucleotide Conjugated to α-Tocopherol.
abstract: We developed an efficient system for delivering short interfering RNA (siRNA) to the liver by using α-tocopherol conjugation. The α-tocopherol-conjugated siRNA was effective and safe for RNA interference-mediated gene silencing in vivo. In contrast, when the 13-mer LNA (locked nucleic acid)-DNA gapmer antisense oligonucleotide (ASO) was directly conjugated with α-tocopherol it showed markedly reduced silencing activity in mouse liver. Here, therefore, we tried to extend the 5'-end of the ASO sequence by using 5'-α-tocopherol-conjugated 4- to 7-mers of unlocked nucleic acid (UNA) as a "second wing." Intravenous injection of mice with this α-tocopherol-conjugated chimeric ASO achieved more potent silencing than ASO alone in the liver, suggesting increased delivery of the ASO to the liver. Within the cells, the UNA wing was cleaved or degraded and α-tocopherol was released from the 13-mer gapmer ASO, resulting in activation of the gapmer. The α-tocopherol-conjugated chimeric ASO showed high efficacy, with hepatic tropism, and was effective and safe for gene silencing in vivo. We have thus identified a new, effective LNA-DNA gapmer structure in which drug delivery system (DDS) molecules are bound to ASO with UNA sequences.
authors.affiliation: 1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan [2] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nishina
authors.affiliation: Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Junna
authors.initials: J
authors.lastname: Numata
authors.affiliation: 1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan [2] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Nishina
authors.affiliation: 1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan [2] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan.
authors.forename: Kie
authors.initials: K
authors.lastname: Yoshida-Tanaka
authors.affiliation: Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nitta
authors.affiliation: 1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan [2] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan.
authors.forename: Wenying
authors.initials: W
authors.lastname: Piao
authors.affiliation: 1] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan [2] Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan.
authors.forename: Rintaro
authors.initials: R
authors.lastname: Iwata
authors.affiliation: Department of Pharmaceutical Microbiology, Kumamoto University, Kumamoto, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Ito
authors.affiliation: 1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan [2] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Kuwahara
authors.affiliation: 1] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan [2] Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Wada
authors.affiliation: 1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan [2] The Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Mizusawa
authors.affiliation: 1] Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan [2] Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan [3] The Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Yokota