title: Safe and effective delivery of small interfering RNA with polymer- and liposomes-based complexes.
abstract: We developed binary and ternary complexes based on polymers and liposomes for safe and effective delivery of small interfering RNA (siRNA). Anti-luciferase siRNA was used as a model of nucleic acid medicine. The binary complexes of siRNA were prepared with cationic polymers and cationic liposomes such as polyethylenimine (PEI), polyamidoamine (PAMAM) dendrimer, poly-L-arginine (PLA), trimethyl[2,3-(dioleoxy)-propyl]ammonium chloride (DOTMA), and cholesteryl 3β-N-(dimetylaminnoethyl)carbamate hydrochloride (DC-Chol). The ternary complexes were constructed by the addition of γ-polyglutamic acid (γ-PGA) to the binary complexes. The complexes were approximately 54-153 nm in particle size. The binary complexes showed a cationic surface charge although an anionic surface charge was observed in the ternary complexes. The polymer-based complexes did not show a silencing effect in the mouse colon carcinoma cell line expressing luciferase regularly (Colon26/Luc cells). The binary complexes based on liposomes and their ternary complexes coated by γ-PGA showed a significant silencing effect. The binary complexes showed significant cytotoxicity although the ternary complexes coated by γ-PGA did not show significant cytotoxicity. The ternary complexes coated by γ-PGA suppressed luciferase activity in the tumor after their direct injection into the tumors of mice bearing Colon26/Luc cells. Thus, we have newly identified safe and efficient ternary complexes of siRNA for clinical use.
authors.affiliation: Department of Hospital Pharmacy, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Yukinobu
authors.initials: Y
authors.lastname: Kodama
authors.forename: Satoe
authors.initials: S
authors.lastname: Harauchi
authors.forename: Saki
authors.initials: S
authors.lastname: Kawanabe
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ichikawa
authors.forename: Hiroo
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Takahiro
authors.initials: T
authors.lastname: Muro
authors.forename: Norihide
authors.initials: N
authors.lastname: Higuchi
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Kitahara
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000031:analogs & derivatives / Q000737:chemistry; D005260:Female; D020868:Gene Silencing; D008081:Liposomes; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000378:metabolism*; D011108:Polymers / Q000737:chemistry; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D008081:Liposomes; D011108:Polymers; D000644:Quaternary Ammonium Compounds; D034741:RNA, Small Interfering; C054005:N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium; C070648:3-(N-(N',N'-dimethylaminoethane)carbamoyl)cholesterol; D002784:Cholesterol; D008156:Luciferases