title: TNF-α gene silencing using polymerized siRNA/thiolated glycol chitosan nanoparticles for rheumatoid arthritis.
abstract: Among various proinflammatory cytokines involved in the pathogenesis of rheumatoid arthritis (RA), tumor necrosis factor (TNF)-α plays a pivotal role in the release of other cytokines and induction of chronic inflammation. Even though siRNA has the therapeutic potential, they have a challenge to be delivered into the target cells because of their poor stability in physiological fluids. Herein, we design a nanocomplex of polymerized siRNA (poly-siRNA) targeting TNF-α with thiolated glycol chitosan (tGC) polymers for the treatment of RA. Poly-siRNA is prepared through self-polymerization of thiol groups at the 5' end of sense and antisense strand of siRNA and encapsulated into tGC polymers, resulting in poly-siRNA-tGC nanoparticles (psi-tGC-NPs) with an average diameter of 370 nm. In the macrophage culture system, psi-tGC-NPs exhibit rapid cellular uptake and excellent in vitro TNF-α gene silencing efficacy. Importantly, psi-tGC-NPs show the high accumulation at the arthritic joint sites in collagen-induced arthritis (CIA) mice. Treatment monitoring data obtained by the matrix metalloproteinase 3-specific nanoprobe and microcomputed tomography show that intravenous injection of psi-tGC-NPs significantly inhibits inflammation and bone erosion in CIA mice, comparable to methotrexate (5 mg/kg). Therefore, the availability of psi-tGC-NP therapy that target specific cytokines may herald new era in the treatment of RA.
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, South Korea.
authors.forename: So Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, South Korea; Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, South Korea.
authors.forename: Aeju
authors.initials: A
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chosun University, Gwangju, South Korea.
authors.forename: Seung Rim
authors.initials: SR
authors.lastname: Hwang
authors.affiliation: College of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
authors.forename: Jong-Sung
authors.initials: JS
authors.lastname: Park
authors.affiliation: College of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Jang
authors.affiliation: Korean Intellectual Property Office, Daejeon, South Korea.
authors.forename: Myung Sook
authors.initials: MS
authors.lastname: Huh
authors.affiliation: College of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
authors.affiliation: Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, South Korea.
authors.forename: Soo-Young
authors.initials: SY
authors.lastname: Yoon
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, South Korea.
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, South Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, South Korea.
authors.forename: Ick Chan
authors.initials: IC
authors.lastname: Kwon
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, South Korea. Electronic address: kim@kist.re.kr.
authors.forename: Inchan
authors.initials: I
authors.lastname: Youn
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, South Korea. Electronic address: iyoun@kist.re.kr.
authors.forename: Kwangmeyung
authors.initials: K
authors.lastname: Kim
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D002460:Cell Line; D048271:Chitosan / Q000737:chemistry; D004195:Disease Models, Animal; D015870:Gene Expression; D020868:Gene Silencing; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics*; D013438:Sulfhydryl Compounds / Q000737:chemistry; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics*
chemical_list: D034741:RNA, Small Interfering; D013438:Sulfhydryl Compounds; D014409:Tumor Necrosis Factor-alpha; C118638:glycol-chitosan; D048271:Chitosan