TNF-α gene silencing using polymerized siRNA/Thiolated glycol chitosan nanoparticles for rheumatoid arthritis

So Jin Lee, Aeju Lee, Seung Rim Hwang, Jong Sung Park, Jiyeon Jang, Myung Sook Huh, Dong Gyu Jo, Soo-Young Yoon, Youngro Byun, Sun Hwa Kim, Ick Chan Kwon, Inchan Youn, Kwangmeyung Kim

Research output: Contribution to journalArticlepeer-review

95 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)397-408
Number of pages12
JournalMolecular Therapy
Volume22
Issue number2
DOIs
Publication statusPublished - 2014 Feb

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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