TNF-α Gene Silencing Using Polymerized siRNA/Thiolated Glycol Chitosan Nanoparticles for Rheumatoid Arthritis

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.

Peptide-siRNA nanocomplexes targeting NF-κB subunit p65 suppress nascent experimental arthritis

“…However, the potential use of siRNA therapy in RA has not progressed beyond the preclinical models. These studies range from local electroporation to deliver siRNA directly into joint tissue of arthritic mice to several studies of systemic delivery of liposome-or polymer-based nanoparticles delivering anti-cytokine or anti-cytokine receptor siRNA (25)(26)(27)(28)(29)(30). Although these preclinical studies all showed efficacy, potential off-target effects and immune responses were rarely fully addressed.…”

Optimization of multifunctional chitosan–siRNA nanoparticles for oral delivery applications, targeting TNF-α silencing in rats

“…[8,10,13,[21][22][23]25,38,39]. MTC conjugates were rationally designed in our previous investigation and were demonstrated to overcome the intestinal absorption barrier as well as the transfection barrier in macrophages [13].…”

Molecular targets in arthritis and recent trends in nanotherapy

“…83 Downregulation of TNF-α-induced inflammatory responses by these NPs led to inhibition of joint swelling in CIA mice also leading to minimal cartilage destruction and inflammatory cell infiltration in mice. Modified forms of CS such as thiolated glycol chitosan NPs have also been used for delivery of polymerized siRNA targeting TNF-α 84 for the treatment of RA. Other polymer-based self-assembling NPs such as cyclodextrin NPs for delivery of α-methylprednisolone 85 have also been used intravenously to treat mice with CIA.…”