title: siRNA-lipid nanoparticles with long-term storage stability facilitate potent gene-silencing in vivo.
abstract: Considerable efforts have been directed towards discovering and developing delivery vehicles for RNA therapeutics. While most studies emphasize the efficacy and safety of these delivery vehicles, few reports conduct a comprehensive assessment of their storage stability, a critical property for practical applications. Here, we report a potent and safe lipid nanoparticle with long-term storage stability. Through chemical synthesis and screening of cationic lipids, a formulation has been identified that enables potent knockdown of hepatocyte proteins in mice upon intravenous administration (siRNA ED50 ~0.02 mg/kg). Toxicity studies revealed that a dose of 2mg/kg was well tolerated in rats, the most sensitive rodent model. We identified that a cyclic chemical structure in cationic lipids improved particle stability. The nanoparticles showed over 1.5 year storage stability as a liquid, with over 90% siRNA encapsulation without any changes in particle size. This novel delivery material has promising potential as a drug product that could bring RNA therapeutics to the treatment of liver-related disorders.
authors.affiliation: DDS Research, Global Formulation Research Japan, Pharmaceutical Science and Technology Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. Electronic address: y14-suzuki@hhc.eisai.co.jp.
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: DDS Research, Global Formulation Research Japan, Pharmaceutical Science and Technology Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hyodo
authors.affiliation: Fukuoka Development & Technical Group, Sogo Pharmachemical Co., Ltd., 408-1 Sonegasaki, Kamisokoino, Nakama, Fukuoka 809-0003, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: DDS Research, Global Formulation Research Japan, Pharmaceutical Science and Technology Unit, Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ishihara
mesh_terms: D000818:Animals; D020868:Gene Silencing; D008055:Lipids / Q000737:chemistry*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000737:chemistry*; D013997:Time Factors
chemical_list: D008055:Lipids; D034741:RNA, Small Interfering
keywords: Drug delivery; Gene silencing; Lipid nanoparticles; RNA therapeutics; siRNA