title: A lipid nanoparticle for the efficient delivery of siRNA to dendritic cells.
abstract: Applying small interfering RNA (siRNA) to dendritic cell (DC) based therapy represents a potential candidate for cancer immunotherapy. However, delivering siRNA to DCs is a challenging issue for non-viral vectors. To date, only viral vectors have achieved efficient gene silencing in DCs. We report herein that a novel cationic lipid, YSK12-C4, when loaded in a nanoparticle with siRNA (YSK12-C4 multifunctional envelope type nano device [YSK12-MEND]), greatly facilitated gene silencing in mouse DCs. The use of the YSK12-MEND resulted in a gene silencing efficiency in excess of 90%, with a median effective dose (ED50) of 1.5nM, whereas the maximum gene silencing efficiency of Lipofectamine RNAiMAX was less than 60% and the ED50 was 25nM. Furthermore, suppressor of cytokine signaling 1, an immune suppressive molecule in DCs, silenced in the mouse DC by the YSK12-MEND showed a drastic enhancement in cytokine production, resulting in the significant suppression of tumor growth when it was applied to DC-based therapy against a mouse lymphoma. These results clearly indicate that YSK12-MEND overcomes the obstacle associated with non-viral vectors and can be considered to be a promising non-viral vector for siRNA delivery to DCs, thus accelerating DC-based therapies with siRNA.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Warashina
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Applied Chemistry, Faculty of Engineering, Aichi Institute of Technology, 1247 Yachigusa, Yakusa-Cho, Toyota 470-0392, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hyodo
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Hatakeyama
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan. Electronic address: harasima@pharm.hokudai.ac.jp.
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005822:Genetic Vectors; D006461:Hemolysis; D007167:Immunotherapy; D008055:Lipids / Q000008:administration & dosage* / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009369:Neoplasms / Q000473:pathology / Q000628:therapy; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry; D051122:Scavenger Receptors, Class B / Q000235:genetics; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000235:genetics; D047368:Tumor Burden
chemical_list: D008055:Lipids; D034741:RNA, Small Interfering; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein
keywords: Cancer immunotherapy; Dendritic cell; Dendritic cell-based vaccine; Endosomal escape; SOCS1; siRNA nanoparticle