title: Enteral siRNA delivery technique for therapeutic gene silencing in the liver via the lymphatic route.
abstract: An efficient targeting delivery technology is needed for functional oligonucleotides to exert their potential effect on the target gene without an adverse effect in vivo. Development of enteral delivery systems for nucleic acids is a major challenge because of their large molecular size and instability. Here, we describe a new enteral delivery technique that enables small interfering RNA (siRNA) selectively delivered to the liver to silence its target Apolipoprotein B gene expression. A nuclease-resistant synthetic siRNA was conjugated with α-tochopherol and administered as lipid nanoparticle to the large intestine of the mice in a postprandial state. The selective transport into the liver, effective gene silence, and consequently significant reduction in serum low density lipoprotein-cholesterol level, were demonstrated. The chylomicron-mediated pathway via the lymphatic route was suggested as major mechanism. This unique approach may provide a basis for developing oral and rectal delivery systems for nucleic acids targeting liver.
authors.affiliation: Laboratory of Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nisikiori-Kita, Tondabayashi-shi, Osaka 584-8540, Japan.|Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.|Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Nishina
authors.affiliation: Laboratory of Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nisikiori-Kita, Tondabayashi-shi, Osaka 584-8540, Japan.|Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Watanabe
authors.affiliation: Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.|Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Kie
authors.initials: K
authors.lastname: Yoshida-Tanaka
authors.affiliation: Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.|Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Wenying
authors.initials: W
authors.lastname: Piao
authors.affiliation: Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.|Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Kuwahara
authors.affiliation: Laboratory of Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nisikiori-Kita, Tondabayashi-shi, Osaka 584-8540, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Horikiri
authors.affiliation: Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors.forename: Kanjiro
authors.initials: K
authors.lastname: Miyata
authors.affiliation: Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.|Polymer Chemistry Division, Chemical Resources Laboratory, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama-shi, Kanagawa 226-8503, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishiyama
authors.affiliation: Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.|Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Department of Life Science and Medical Ethics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.|Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.|National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi-machi, Kodaira-shi, Tokyo 187-8551, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Mizusawa
authors.affiliation: Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.|Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.|Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Yokota
mesh_terms: D000285:Administration, Rectal; D000818:Animals; D001055:Apolipoproteins B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport; D002914:Chylomicrons / Q000097:blood; D016503:Drug Delivery Systems / Q000379:methods*; D020868:Gene Silencing; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D042601:Lymphatic Vessels / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D019518:Postprandial Period / Q000502:physiology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism
chemical_list: D001055:Apolipoproteins B; D002914:Chylomicrons; D008077:Lipoproteins, LDL; D009943:Organophosphorus Compounds; D034741:RNA, Small Interfering; C434331:phosphoramidite; D024502:alpha-Tocopherol