Inhibitors of p38 mitogen‐activated protein kinase (MAPK) are currently being pursued as therapeutics in inflammatory conditions, but many candidates have demonstrated limited efficacy or toxicity issues to date. Nanoformulation of p38 MAPK inhibitors may overcome these challenges, by enabling controlled release and targeted delivery. Thus, the aim of this study was to develop a nanoformulation of the p38 MAPK inhibitor GSK 678361A and subsequently validate its anti‐inflammatory efficacy in vitro, versus the drug in its free format. Poly(lactic‐co‐glycolic acid) nanoparticles encapsulating GSK 678361A were prepared via a salting‐out method and characterised by photon correlation spectroscopy, scanning electron microscopy and high‐performance liquid chromatography. The anti‐inflammatory effect of both free and nanoformulated GSK 678361A was evaluated in cultures of lipopolysaccharide‐stimulated macrophages, with subsequent enzyme‐linked immunosorbent assay analysis of TNF‐α and IL‐6 providing readouts of efficacy. A controlled release nanoformulation of GSK 678361A was successfully developed, with physicochemical characterisation revealing an average particle diameter of 115.5 ± 3.5 nm and polydispersity index of 0.13 ± 0.03, indicative of a homogeneous size distribution. GSK 678361A loading was quantified at 10.1 ± 0.4 µg per mg of poly(lactic‐co‐glycolic acid), equating to an entrapment efficiency of approximately 50%. When tested in cultures of lipopolysaccharide‐stimulated macrophages, GSK 678361A nanoparticles inhibited the production of pro‐inflammatory cytokines to an extent that was largely comparable with the free drug, although superior efficacy of the nanoformulation was observed at selected doses. These studies indicate that GSK 678361A may be successfully nanoformulated without loss of drug activity, warranting further evaluation in models of inflammation in vivo.
- p38 MAPK inhibitor