title: Systemic delivery of small interfering RNA targeting nuclear factor κB in mice with collagen-induced arthritis using arginine-histidine-cysteine based oligopeptide-modified polymer nanomicelles.
abstract: This study aimed to build an innovative system to deliver a systemic small interfering RNA (siRNA) treatment for rheumatoid arthritis. We combined arginine-histidine-cysteine based oligopeptide-modified polymer micelles with siRNA targeting the nuclear factor κB subunit, RelA (siRelA). This is a key molecule in the control of inflammation. We tested the cellular uptake of siRNA and its effects on inflammatory cytokine levels in vitro using synoviocytes, and siRNA distribution and therapeutic effects in vivo in mice with collagen-induced arthritis (CIA). These studies showed that arginine-histidine based oligopeptide modified micelles produced effective cellular siRNA uptake and suppressed inflammatory cytokine levels in synoviocytes. In vivo, these micelles produced marked accumulation of siRNAs in arthritic paws in CIA mice, with much less accumulation in healthy mice. The siRelA-polymer micelle complexes also produced more effective suppression of RelA mRNA expression and inflammatory cytokine levels in the arthritic paws of CIA mice and reduced their clinical symptom scores and paw thickness.
authors.affiliation: School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. Electronic address: kanazawa@toyaku.ac.jp.
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanazawa
authors.affiliation: School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Endo
authors.affiliation: School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Arima
authors.affiliation: School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Ibaraki
authors.affiliation: School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Takashima
authors.affiliation: School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Seta
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D003545:Cysteine / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006639:Histidine / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008823:Micelles; D016328:NF-kappa B / Q000378:metabolism*; D053758:Nanoparticles / Q000737:chemistry*; D009842:Oligopeptides / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism; D000070918:Synoviocytes / Q000187:drug effects / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D016207:Cytokines; D008823:Micelles; D016328:NF-kappa B; D009842:Oligopeptides; D011108:Polymers; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D006639:Histidine; D003094:Collagen; D001120:Arginine; D003545:Cysteine
keywords: Functional peptides; Nuclear factor κB; Polymeric micelles; RelA; Rheumatoid arthritis; Systemic siRNA delivery