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

Abstract

Recent studies have demonstrated in vivo synergistic immunosuppressive and antiinflammatory 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, selfassembled 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 co-localization 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 non-cytotoxic 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.

Dexamethasone: Insights into Pharmacological Aspects, Therapeutic Mechanisms, and Delivery Systems

“…Polymeric NPs represent additional drug delivery systems with a vast potential for targeted and localized delivery of drugs/genes. − Natural polymers such as chitosan, arginine, dextrin, poly­(glycolic acid), polysaccharides, poly­(lactic acid), and hyaluronic acid have been used for developing polymeric drug delivery systems . Some synthetic polymers, including poly­(2-hydroxyethyl methacrylate), poly­(ethylenimine)­s, poly­( N -isopropylacrylamide)­s, and dendritic polymers, have also been used for polymeric-based NPs’ development .…”

Could Nanotheranostics be the Answer to the Coronavirus Crisis?

“…[ 48 ] Furthermore, previous studies showed a more remarkable, targeted reduction of inflammatory cytokines and recovery in comparison with pristine Dex [ 49 ] or when synergistically combined with naproxen (i.e., nonsteroidal anti‐inflammatory drug (NSAID)). [ 50 ]…”

Ketoprofen-Based Polymer-Drug Nanoparticles Provide Anti-Inflammatory Properties to HA/Collagen Hydrogels

“…The use of non-steroidal anti-inflammatory drugs (NSAIDs) offers an additional anti-inflammatory treatment by influencing macrophage polarity and improving the healing of chronic wounds [ 33 , 34 ]. The NSAIDs are effective because of their inhibition of cyclooxygenase-2 (COX-2), which is responsible for the synthesis of prostaglandins (PG) in pathological processes, such as inflammation [ 35 ].…”

“…Unfortunately, most NSAIDs are hydrophobic, which results in low bioavailability. To address this problem, hydrophilic nanoparticles (NPs) with NSAID moieties have been developed [ 33 , 34 ]. Previously, in vitro experiments with ketoprofen (KT)-based NPs and macrophages showed low toxicity, as well as a reduction in nitric oxide (NO) and other pro-inflammatory markers, such as Il-12b and TNF-α in inflammatory conditions [ 34 ].…”