Polymeric Nanoparticles that Combine Dexamethasone and Naproxen for the Synergistic Inhibition of Il12b Transcription in Macrophages

Recent studies have demonstrated in vivo synergistic immunosuppressive and anti‐inflammatory capacity of dexamethasone (Dx) and naproxen (NAP) in collagen‐induced arthritis (CIA) rats. However, the molecular basis of this synergistic effect is barely understood. The low solubility of these drugs and their adverse effects hamper their efficacy on the treatment of inflammatory processes making nanoparticulated systems promising candidates to overcome these drawbacks. The aim of this work is the preparation of polymeric nanoparticles (NPs) that combine NAP and Dx in different concentrations, and the evaluation of the expression of key genes related to autoimmune diseases like CIA. To do so, self‐assembled polymeric NPs that incorporate covalently‐linked NAP and physically entrapped Dx are designed to have hydrodynamic properties that, according to bibliography, may improve retention and colocalization of both drugs at inflammation sites. The rapid uptake of NPs by macrophages is demonstrated using coumarine‐6‐loaded NPs. Dx is efficiently encapsulated and in vitro biological studies demonstrate that the Dx‐loaded NAP‐bearing NPs are noncytotoxic and reduce lipopolysaccharide‐induced NO released levels at any of the tested concentrations. Moreover, at the molecular level, a significant synergistic reduction of Il12b transcript gene expression when combining Dx and NAP is demonstrated.