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.
Bibliographical noteFunding 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.