title: Potential use of glucuronylglucosyl-β-cyclodextrin/dendrimer conjugate (G2) as a siRNA carrier for the treatment of familial amyloidotic polyneuropathy.
abstract: We previously reported that 6-O-α-(4-O-α-D-glucuronyl)-D-glucosyl-β-cyclodextrin (GUG-β-CyD) conjugate with polyamidoamine dendrimer (dendrimer, generation 2; G2) (GUG-β-CDE (G2)) is useful as a gene transfer carrier. In the present study, to investigate the potentials of GUG-β-CDE (G2) as a siRNA carrier, we evaluated the RNAi effect of its complex with siRNA against transthyretin (TTR) mRNA (siTTR) for the treatment of familial amyloidotic polyneuropathy (FAP). Among the various GUG-β-CDEs (G2) having the different degrees of substitution of GUG-β-CyD (degree of substation (DS) 1.8, 2.5, 3.0 and 5.0), GUG-β-CDE (G2, DS 1.8) showed the highest siTTR transfer activity. GUG-β-CDE (G2, DS 1.8)/siTTR complex showed no cytotoxicity in HepG2 cells. After intravenous administration of GUG-β-CDE (G2, DS 1.8)/siTTR complex to BALB/c mice, TTR mRNA expression was tended to reduce with negligible change of blood chemistry data. Particle size, ζ-potential and cellular association of the GUG-β-CDE (G2, DS 1.8) complex were almost the same as those of the other CDEs complexes. Meanwhile, GUG-β-CDE (G2, DS 1.8)/siTTR complex showed high endosomal escaping ability of siTTR in cytoplasm. These findings suggest the potential of GUG-β-CDE (G2, DS 1.8) as a siRNA carrier for the FAP treatment.
authors: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University , Chuo-ku, Kumamoto , Japan .
authors: Takayuki
authors: T
authors: Anno
authors: Taishi
authors: T
authors: Higashi
authors: Yuya
authors: Y
authors: Hayashi
authors: Keiichi
authors: K
authors: Motoyama
authors: Hirofumi
authors: H
authors: Jono
authors: Yukio
authors: Y
authors: Ando
authors: Hidetoshi
authors: H
authors: Arima
mesh_terms: D061605:Administration, Intravenous; D028227:Amyloid Neuropathies, Familial / Q000235:genetics / Q000628:therapy*; D000818:Animals; D050091:Dendrimers / Q000737:chemistry*; D011992:Endosomes / Q000378:metabolism; D018014:Gene Transfer Techniques; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009844:Oligosaccharides / Q000737:chemistry*; D010316:Particle Size; D011073:Polyamines / Q000737:chemistry*; D011228:Prealbumin / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage*
chemical_list: D050091:Dendrimers; D009844:Oligosaccharides; C531249:Poly(amidoamine); D011073:Polyamines; D011228:Prealbumin; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C438085:cyclomaltoheptaosyl-(6-1)-glucopyranosyl-(4-1)-glucopyranosiduronic acid
keywords: Conjugate; PAMAM dendrimer; familial amyloidotic polyneuropathy; glucuronylglucosyl-β-cyclodextrin; siRNA; transthyretin