Enteral siRNA delivery technique for therapeutic gene silencing in the liver via the lymphatic route

Masahiro Murakami; Kazutaka Nishina; Chie Watanabe; Kie Yoshida-Tanaka; Wenying Piao; Hiroya Kuwahara; Yuji Horikiri; Kanjiro Miyata; Nobuhiro Nishiyama; Kazunori Kataoka; Masayuki Yoshida; Hidehiro Mizusawa; Takanori Yokota

doi:10.1038/srep17035

Enteral siRNA delivery technique for therapeutic gene silencing in the liver via the lymphatic route

Sci Rep. 2015 Nov 23:5:17035. doi: 10.1038/srep17035.

Authors

Masahiro Murakami^{1

2}, Kazutaka Nishina^{2

3}, Chie Watanabe^{1

2}, Kie Yoshida-Tanaka^{2

3}, Wenying Piao^{2

3}, Hiroya Kuwahara^{2

3}, Yuji Horikiri¹, Kanjiro Miyata⁴, Nobuhiro Nishiyama^{4

5}, Kazunori Kataoka^{4

6}, Masayuki Yoshida⁷, Hidehiro Mizusawa^{3

8

9}, Takanori Yokota^{2

3

8}

Affiliations

¹ Laboratory of Pharmaceutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nisikiori-Kita, Tondabayashi-shi, Osaka 584-8540, Japan.
² 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.
³ 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.
⁴ 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.
⁵ Polymer Chemistry Division, Chemical Resources Laboratory, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama-shi, Kanagawa 226-8503, Japan.
⁶ Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan.
⁷ 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.
⁸ Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
⁹ National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi-machi, Kodaira-shi, Tokyo 187-8551, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Rectal
Animals
Apolipoproteins B / antagonists & inhibitors*
Apolipoproteins B / genetics
Apolipoproteins B / metabolism
Biological Transport
Chylomicrons / blood
Drug Delivery Systems / methods*
Gene Silencing*
Jejunum / drug effects
Jejunum / metabolism
Lipoproteins, LDL / blood
Liver / drug effects
Liver / metabolism
Lymphatic Vessels / physiology
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Nanoparticles / administration & dosage*
Nanoparticles / chemistry
Nanoparticles / metabolism
Organophosphorus Compounds / administration & dosage*
Organophosphorus Compounds / chemistry
Organophosphorus Compounds / metabolism
Postprandial Period / physiology
RNA, Small Interfering / administration & dosage
RNA, Small Interfering / genetics*
RNA, Small Interfering / metabolism
alpha-Tocopherol / administration & dosage
alpha-Tocopherol / chemistry
alpha-Tocopherol / metabolism

Substances

Apolipoproteins B
Chylomicrons
Lipoproteins, LDL
Organophosphorus Compounds
RNA, Small Interfering
phosphoramidite
alpha-Tocopherol