Suppression of human arthritis synovial fibroblasts inflammation using dexamethasone-carbon nanotubes via increasing caveolin-dependent endocytosis and recovering mitochondrial membrane potential

Abstract

Yeon Kyung Lee,1,* Sang-Woo Kim,1,* Jun-Young Park,1 Woong Chol Kang,2 Youn Joo Kang,3 Dongwoo Khang1,4 1Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 2Department of Cardiology, Gil Medical Center, Gachon University, Incheon, 3Department of Rehabilitation Medicine, Eulji Hospital, Eulji University School of Medicine, Seoul, 4Department of Physiology, College of Medicine, Gachon University, Incheon, South Korea *These authors contributed equally to this work Abstract: Dexamethasone (DEX), a non-particulate glucocorticoid (GC) to inhibit anti-inflammatory response, has been widely used for the treatment of various diseases such as arthritis, cancer, asthma, chronic obstructive pulmonary disease, cerebral edema, and multiple sclerosis. However, prolonged and/or high-dose GC therapy can cause various serious adverse effects (adrenal insufficiency, hyperglycemia, Cushing’s syndrome, osteoporosis, Charcot arthropathy, etc). In this study, developed DEX-carbon nanotube (CNT) conjugates improved intracellular drug delivery via increased caveolin-dependent endocytosis and ultimately suppressed the expression of major pro-inflammatory cytokines in tumor necrosis factor-α (TNF-α)-stimulated human fibroblast-like synoviocytes (FLS) at low drug concentrations. Specifically, DEX on polyethylene-glycol (PEG)-coated CNTs induced caveolin uptake, recovered mitochondrial disruption, and inhibited reactive oxygen species production by targeting mitochondria that was released from the early endosome in TNF-α-stimulated FLS. The obtained results clearly demonstrated that DEX-PEG-coated CNTs significantly inhibited the inflammation by FLS in rheumatoid arthritis (RA) by achieving greater drug uptake and efficient intracellular drug release from the endosome, thus suggesting a mechanism of effective low-dose GC therapy to treat inflammatory diseases, including RA and osteoarthritis. Keywords: carbon nanotubes, polyethylene-glycol, dexamethasone, arthritis, fibroblast-like synoviocytes, caveolin-dependent endocytosis 

Keywords

• Carbon nanotubes
• Polyethylene-glycol
• Dexamethasone
• Arthritis
• Fibroblast-like synoviocytes
• Caveolin-dependent endocytosis