title: Ligand density at the surface of a nanoparticle and different uptake mechanism: two important factors for successful siRNA delivery to liver endothelial cells.
abstract: The specific delivery of a gene to liver sinusoidal endothelial cells (LSEC) could become a useful strategy for treating various liver diseases associated with such cells. We previously reported that the accumulation of KLGR peptide modified liposomes through liver sinusoidal blood vessels was enhanced after an intravenous administration. Here, we report on an attempt to develop an LSEC targeted nanocarrier system to deliver siRNA for the successful knockdown of LSEC specific gene expression. The system involved the development of a multifunctional envelop-type nano device (MEND) modified with the KLGR peptide for siRNA delivery targeting LSEC. Our developed carrier successfully lowered specific gene expression in LSEC. An in vivo study showed that at a lower density of ligand at the surface of the MEND resulted in the highest knockdown of gene expression in LSEC. This is the first report of the successful delivery of siRNA to LSECs. Further experiments suggest that not only a higher endosomal escape efficiency into the cytosol but also the uptake mechanism as a function of ligand density are two important factors to be considered for targeting LSEC.
authors.affiliation: Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Afsana
authors.initials: A
authors.lastname: Akhter
authors.affiliation: Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sakurai
authors.affiliation: Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Ohga
authors.affiliation: Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hida
authors.affiliation: Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan; Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan. Electronic address: harasima@pharm.hokudai.ac.jp.
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
mesh_terms: D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism*; D018014:Gene Transfer Techniques; D006801:Humans; D008024:Ligands; D008081:Liposomes / Q000008:administration & dosage / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D053758:Nanoparticles / Q000008:administration & dosage* / Q000378:metabolism*; D010455:Peptides / Q000008:administration & dosage / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000378:metabolism*
chemical_list: D008024:Ligands; D008081:Liposomes; D010455:Peptides; D034741:RNA, Small Interfering
keywords: ApoB 100; KLGR peptide; Liver sinusoidal endothelial cell; siRNA