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 language | English |
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Pages (from-to) | 397-408 |
Number of pages | 12 |
Journal | Molecular Therapy |
Volume | 22 |
Issue number | 2 |
DOIs | |
Publication status | Published - 2014 Feb |
Bibliographical note
Funding Information:This study was funded by the Global Research Laboratory (GRL; 2010-0019863) Project, the Fusion Technology Project (2010-50201), Regional Technology Innovation Program of the Ministry of Knowledge Economy (MEK; RTI04-01-01), National R&D Program for Cancer Control of Ministry for Health and Welfare (1020260), M.D.-Ph.D. Program (2010-0019864), Global Innovative Research Center (GiRC) program, Company-Researcher cowork program of Small & Medium Business Administration (SD122946) and the Intramural Research Program (Theragnosis, Global RNAi Carrier Initiative, and KIST Young Fellow) of KIST. The authors declared no conflict of interest.
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
- Pharmacology
- Drug Discovery