title: Application of biodegradable dendrigraft poly-l-lysine to a small interfering RNA delivery system.
abstract: Dendrigraft poly-l-lysine (DGL), including its central core, consists entirely of lysine, hence it is completely biodegradable. We applied DGL in a small interfering RNA (siRNA) delivery system. Binary complexes with siRNA and DGL had particle sizes of 23-73 nm and ζ-potentials of 34-42 mV. The siRNA-DGL complexes showed significant silencing effects in a mouse colon carcinoma cell line expressing luciferase (Colon26/Luc cells). The siRNA-DGL complexes induced slight cytotoxicity and hematological toxicity at a high charge ratio of DGL to siRNA, probably because of their cationic charges. Therefore, we recharged the siRNA-DGL complexes with γ-polyglutamic acid (γ-PGA), a biodegradable anionic compound, which was reported to reduce the cytotoxicity of cationic complexes. The ternary complexes showed particle sizes of 35-47 nm at a charge ratio of greater than 14 to siRNA with negative charges. Strong silencing effects of the ternary complexes were observed in Colon26/Luc cells without cytotoxicity or hematological toxicity. The cellular uptake and degradation of the binary and ternary complexes were confirmed by fluorescence microscopy. The ternary complexes suppressed luciferase activity in the tumor after direct injection into the tumors of mice bearing Colon26/Luc cells. Thus, a potentially important siRNA delivery system was constructed using biodegradable DGL.
authors.affiliation: a Department of Hospital Pharmacy , Nagasaki University Hospital , Nagasaki , Japan.
authors.forename: Yukinobu
authors.initials: Y
authors.lastname: Kodama
authors.affiliation: a Department of Hospital Pharmacy , Nagasaki University Hospital , Nagasaki , Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Kuramoto
authors.affiliation: a Department of Hospital Pharmacy , Nagasaki University Hospital , Nagasaki , Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Mieda
authors.affiliation: a Department of Hospital Pharmacy , Nagasaki University Hospital , Nagasaki , Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Muro
authors.affiliation: a Department of Hospital Pharmacy , Nagasaki University Hospital , Nagasaki , Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: a Department of Hospital Pharmacy , Nagasaki University Hospital , Nagasaki , Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kurosaki
authors.affiliation: b Institute of Tropical Medicine, Nagasaki University , Nagasaki , Japan.
authors.forename: Miako
authors.initials: M
authors.lastname: Sakaguchi
authors.affiliation: a Department of Hospital Pharmacy , Nagasaki University Hospital , Nagasaki , Japan.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: a Department of Hospital Pharmacy , Nagasaki University Hospital , Nagasaki , Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kitahara
authors.affiliation: a Department of Hospital Pharmacy , Nagasaki University Hospital , Nagasaki , Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D050091:Dendrimers / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D009374:Neoplasms, Experimental / Q000235:genetics / Q000628:therapy; D011107:Polylysine / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics
chemical_list: D001672:Biocompatible Materials; D050091:Dendrimers; D004337:Drug Carriers; D034741:RNA, Small Interfering; D011107:Polylysine
keywords: biodegradable; dendrigraft poly-l-lysine; nanoparticles; siRNA delivery; γ-polyglutamic acid