The encapsulation of glucocorticoids such as dexamethasone in nanoparticles faces two main issues: a low drug loading and the destabilization of the nanoparticle suspension due to drug crystallization. Here, we successfully formulated a prodrug of dexamethasone, dexamethasone palmitate (DXP), into nanoparticles stabilized by the sole presence of DSPE-PEG 2000 . Two formulation processes, nanoprecipitation, and emulsion-evaporation allowed the formation of stable nanoparticles. By adjusting the

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... rug/lipid ratio and the DXP concentration nanoparticles of DXP (DXP-NPs) with a size comprised between 130 and 300nm can be obtained. Owing to the presence of DSPE-PEG 2000 , a high drug entrapment efficiency of 98%w/w was reached for both processes, corresponding to a very high equivalent dexamethasone drug loading around 50%w/w with the absence of crystallization upon storage at 4°C. The anti-inflammatory activity of DXP-NPs was preserved when incubated with macrophages activated with lipopolysaccharide. Pharmacokinetics parameters were evaluated after intravenous (IV) injection of DXP-NPs to healthy mice. The release of DXM from DXP-NPs in plasma was clearly controlled up to 18 hours compared to the free drug which was rapidly eliminated from plasma after administration. In conclusion, a novel type of nanoparticle combining the advantages of prodrugs and nanoparticles was designed, easy to produce with a high loading efficiency and leading to modified pharmacokinetics and tissue distribution after IV administration.