title: Quick nuclear transportation of siRNA and in vivo hepatic ApoB gene silencing with galactose-bearing polymeric carrier.
abstract: Since previous studies have linked the genetic mutations of Apolipoprotein B (ApoB) to the low density lipoprotein (LDL) cholesterol levels, it can be believed that the knockdown of ApoB by siRNA silencing is a useful method to reduce the cardiovascular disease. However, the spontaneous uptake of siRNA is hindered, and thus vectors are necessary to aid its transfer into the cells. Among the synthetic non-viral vectors, cationic polymers are extensively investigated as possible candidates for efficient and specific gene delivery, because they can be easily modified to get different set of properties. Therefore, in this work a set of random copolymers with different molecular weight and composition were synthesized. These vectors present 2-(dimethylamino)ethyl methacrylate, as cationic monomer, and galactose units as liver-targeting moieties. From in vitro experiments, copolymers with monomer ratio and molecular weight about 0.1 and 80kDa, respectively, showed adequate transfection capabilities and displaying good cell viability, independently of the nature of the saccharides units. However, in the in vivo experiments in C57BL/6 high-fat-fed mice, a better blood compatibility and protection against degradation leading to better transfection by the random copolymers bearing galactose units was confirmed.
authors: Department of Biomedical Engineering, National Cerebral and Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita, Osaka 565-8565, Japan.
authors: Yoichi
authors: Y
authors: Tachibana
authors: Department of Biomedical Engineering, National Cerebral and Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita, Osaka 565-8565, Japan.
authors: Maria Chiara
authors: MC
authors: Munisso
authors: Department of Biomedical Engineering, National Cerebral and Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita, Osaka 565-8565, Japan; Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadao, Suita, Osaka 565-0861, Japan.
authors: Wakako
authors: W
authors: Kamata
authors: Biotechnology Development Department, Toyobo Co. Ltd., 2-8. Dojima Hama 2, Kita-ku, Osaka 530-8230, Japan.
authors: Masaru
authors: M
authors: Kitagawa
authors: Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita, Osaka 565-8565, Japan.
authors: Mariko
authors: M
authors: Harada-Shiba
authors: Department of Biomedical Engineering, National Cerebral and Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita, Osaka 565-8565, Japan. Electronic address: yamtet@ri.ncvc.go.jp.
authors: Tetsuji
authors: T
authors: Yamaoka
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D059305:Diet, High-Fat; D005690:Galactose / Q000378:metabolism*; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D008099:Liver / Q000378:metabolism*; D008689:Methacrylates / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011108:Polymers / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000378:metabolism*
chemical_list: C415826:Apob protein, mouse; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D008689:Methacrylates; D011108:Polymers; D034741:RNA, Small Interfering; C049840:2-(dimethylamino)ethyl methacrylate; D005690:Galactose
keywords: Complexes; Liver targeting; Suppression; siRNA