title: Ternary complexes of folate-PEG-appended dendrimer (G4)/α-cyclodextrin conjugate, siRNA and low-molecular-weight polysaccharide sacran as a novel tumor-selective siRNA delivery system.
abstract: We previously developed a tumor-selective siRNA carrier by preparing polyamidoamine dendrimer (generation 4, G4) conjugates with α-cyclodextrin and folate-polyethylene glycol (Fol-PαC (G4)). In the present study, we developed ternary complexes of Fol-PαC (G4)/siRNA with low-molecular-weight-sacrans to achieve more effective siRNA transfer activity. Among the different molecular-weight sacrans, i.e. sacran 100, 1000 and 10,000 (MW 44,889Da, 943,692Da and 1,488,281Da, respectively), sacran 100 significantly increased the cellular uptake and the RNAi effects of Fol-PαC (G4)/siRNA binary complex with negligible cytotoxicity in KB cells (folate receptor-α positive cells). In addition, the ζ-potential and particle size of Fol-PαC (G4)/siRNA complex were decreased by the ternary complexation with sacran 100. Importantly, the in vivo RNAi effect of the ternary complex after the intravenous administration to tumor-bearing BALB/c mice was significantly higher than that of the binary complex. In conclusion, Fol-PαC (G4)/siRNA/sacran 100 ternary complex has a potential as a novel tumor-selective siRNA delivery system.
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Program for Leading Graduate Schools 'Health Life Science: Interdisciplinary and Glocal Oriented (HIGO) Program', Kumamoto University, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Ohyama
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Higashi
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Motoyama
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Program for Leading Graduate Schools 'Health Life Science: Interdisciplinary and Glocal Oriented (HIGO) Program', Kumamoto University, Japan. Electronic address: arimah@gpo.kumamoto-u.ac.jp.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Arima
mesh_terms: D000818:Animals; D001692:Biological Transport; D050091:Dendrimers / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D005492:Folic Acid / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000737:chemistry*; D011134:Polysaccharides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000235:genetics; D047391:alpha-Cyclodextrins / Q000737:chemistry*
chemical_list: D050091:Dendrimers; D004337:Drug Carriers; D011134:Polysaccharides; D034741:RNA, Small Interfering; D047391:alpha-Cyclodextrins; C571099:sacran; D011092:Polyethylene Glycols; D005492:Folic Acid; C032613:alpha-cyclodextrin
keywords: Cyclodextrin; Dendrimer; Folate; Sacran; Ternary complex; siRNA delivery