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 journalArticle

65 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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  • Cite this

    Lee, S. J., Lee, A., Hwang, S. R., Park, J. S., Jang, J., Huh, M. S., Jo, D. G., Yoon, S. Y., Byun, Y., Kim, S. H., Kwon, I. C., Youn, I., & Kim, K. (2014). TNF-α gene silencing using polymerized siRNA/Thiolated glycol chitosan nanoparticles for rheumatoid arthritis. Molecular Therapy, 22(2), 397-408. https://doi.org/10.1038/mt.2013.245