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, Kwang Meyung Kim

Research output: Contribution to journalArticle

54 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 1

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Gene Silencing
Nanoparticles
Small Interfering RNA
Rheumatoid Arthritis
Tumor Necrosis Factor-alpha
Experimental Arthritis
Cytokines
Polymers
Therapeutics
glycol-chitosan
Osteitis
X-Ray Microtomography
Matrix Metalloproteinase 3
Sulfhydryl Compounds
Methotrexate
Intravenous Injections
Polymerization
Arthritis
Macrophages
Inflammation

ASJC Scopus subject areas

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

Cite this

TNF-α gene silencing using polymerized siRNA/Thiolated glycol chitosan nanoparticles for rheumatoid arthritis. / Lee, So Jin; Lee, Aeju; Hwang, Seung Rim; Park, Jong Sung; Jang, Jiyeon; Huh, Myung Sook; Jo, Dong Gyu; Yoon, Soo-Young; Byun, Youngro; Kim, Sun Hwa; Kwon, Ick Chan; Youn, Inchan; Kim, Kwang Meyung.

In: Molecular Therapy, Vol. 22, No. 2, 01.02.2014, p. 397-408.

Research output: Contribution to journalArticle

Lee, SJ, Lee, A, Hwang, SR, Park, JS, Jang, J, Huh, MS, Jo, DG, Yoon, S-Y, Byun, Y, Kim, SH, Kwon, IC, Youn, I & Kim, KM 2014, 'TNF-α gene silencing using polymerized siRNA/Thiolated glycol chitosan nanoparticles for rheumatoid arthritis', Molecular Therapy, vol. 22, no. 2, pp. 397-408. https://doi.org/10.1038/mt.2013.245
Lee, So Jin ; Lee, Aeju ; Hwang, Seung Rim ; Park, Jong Sung ; Jang, Jiyeon ; Huh, Myung Sook ; Jo, Dong Gyu ; Yoon, Soo-Young ; Byun, Youngro ; Kim, Sun Hwa ; Kwon, Ick Chan ; Youn, Inchan ; Kim, Kwang Meyung. / TNF-α gene silencing using polymerized siRNA/Thiolated glycol chitosan nanoparticles for rheumatoid arthritis. In: Molecular Therapy. 2014 ; Vol. 22, No. 2. pp. 397-408.
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