Abstract
The first-line treatment of osteoarthritis is based on anti-inflammatory drugs, the most currently used being nonsteroidal anti-inflammatory drugs, selective cyclooxygenase 2 (COX-2) inhibitors and corticoids. Most of them present cytotoxicity and low bioavailability in physiological conditions, making necessary the administration of high drug concentrations causing several side effects. The goal of this work was to encapsulate three hydrophobic anti-inflammatory drugs of different natures (celecoxib, tenoxicam and dexamethasone) into core-shell terpolymer nanoparticles with potential applications in osteoarthritis. Nanoparticles presented hydrodynamic diameters between 110 and 130 nm and almost neutral surface charges (between -1 and -5 mV). Encapsulation efficiencies were highly dependent on the loaded drug and its water solubility, having higher values for celecoxib (39-72%) followed by tenoxicam (20-24%) and dexamethasone (14-26%). Nanoencapsulation reduced celecoxib and dexamethasone cytotoxicity in human articular chondrocytes and murine RAW264.7 macrophages. Moreover, the three loaded systems did not show cytotoxic effects in a wide range of concentrations. Celecoxib and dexamethasone-loaded nanoparticles reduced the release of different inflammatory mediators (NO, TNF-α, IL-1β, IL-6, PGE2 and IL-10) by lipopolysaccharide (LPS)-stimulated RAW264.7. Tenoxicam-loaded nanoparticles reduced NO and PGE2 production, although an overexpression of IL-1β, IL-6 and IL-10 was observed. Finally, all nanoparticles proved to be biocompatible in a subcutaneous injection model in rats. These findings suggest that these loaded nanoparticles could be suitable candidates for the treatment of inflammatory processes associated with osteoarthritis due to their demonstrated in vitro activity as regulators of inflammatory mediator production.