title: Potential use of lactosylated dendrimer (G3)/α-cyclodextrin conjugates as hepatocyte-specific siRNA carriers for the treatment of familial amyloidotic polyneuropathy.
abstract: To reveal the potential use of lactosylated-dendrimer (G3) conjugates with α-cyclodextrin (Lac-α-CDE (G3)) as novel hepatocyte-specific siRNA carriers in order to treat transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP), we evaluated the RNAi effect of siRNA complexes with Lac-α-CDE (G3) both in vitro and in vivo. Herein, we targeted TTR gene expression because TTR-related FAP was often caused by amyloidogenic TTR (ATTR), which mainly expresses in hepatocytes. Lac-α-CDE (G3, average degree of substitution of lactose (DSL) 1.2)/siRNA complex had a potent RNAi effect against TTR gene expression through adequate physicochemical properties, asialoglycoprotein receptor (ASGP-R)-mediated cellular uptake, efficient endosomal escape and the delivery of the siRNA complex to cytoplasm, but not nucleus, with negligible cytotoxicity. Lac-α-CDE (G3, DSL 1.2)/siRNA complex had the potential to induce the in vivo RNAi effect after intravenous administration in the liver of mice. The blood chemistry values in the α-CDE (G3) and Lac-α-CDE (G3, DSL 1.2) systems were almost equivalent to those in the control system (5% mannitol solution). Taken together, these results suggest that Lac-α-CDE (G3, DSL 1.2) has the potential for a novel hepatocyte-selective siRNA carrier in vitro and in vivo, and has a possibility as a therapeutic tool for FAP to the liver transplantation.
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Mori
authors.forename: Shogo
authors.initials: S
authors.lastname: Yamashita
authors.forename: Keiichi
authors.initials: K
authors.lastname: Motoyama
authors.forename: Taishi
authors.initials: T
authors.lastname: Higashi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ando
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Arima
mesh_terms: D028227:Amyloid Neuropathies, Familial / Q000378:metabolism / Q000628:therapy*; D000818:Animals; D015153:Blotting, Western; D050091:Dendrimers / Q000737:chemistry*; D005434:Flow Cytometry; D005822:Genetic Vectors / Q000008:administration & dosage / Q000737:chemistry*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007785:Lactose / Q000737:chemistry*; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D047391:alpha-Cyclodextrins / Q000737:chemistry*
chemical_list: D050091:Dendrimers; D011228:Prealbumin; D034741:RNA, Small Interfering; D047391:alpha-Cyclodextrins; D007785:Lactose; C032613:alpha-cyclodextrin