Dactolisib (NVP-BEZ235, also referred to as: 'BEZ235' or 'BEZ') is a dual mTOR/PI3K inhibitor that is of potential interest in the treatment of inflammatory disorders. This work focuses on formulation of BEZ-loaded polymeric nanoparticles composed of a blend of poly(D,L-lactide-co-glycolide) (PLGA) and poly(D,L-lactide-co-glycolide)-poly(ethylene glycol)-2000 (PLGA-PEG). The nanoparticles were prepared by an oil/water emulsion solvent evaporation method, and were subsequently characterized for yield, encapsulation efficiency, morphology, particle size, drug-polymer interaction and in vitro drug release profiles. A targeted formulation was developed by conjugation of a S-acetyl-thioacetyl (SATA)-modified mouse-anti human E-selectin antibody to the distal end of PLGA-PEG-SPDP containing nanoparticles. Our results show the successful preparation of spherical PLGA/PLGA-PEG nanoparticles loaded with BEZ. The particle size distribution showed a range from 250 to 360nm with a high (>75%) BEZ encapsulation efficiency. Approximately 35% of the loaded BEZ was released within 10days at 37°C in a medium containing 5% bovine serum albumin (BSA). Evaluation of efficacy of anti-E-selectin decorated BEZ-loaded nanoparticles was carried out in tumor necrosis factor-α (TNF-α) activated endothelial cells. Confocal microscopy analysis showed that cellular uptake of the targeted nanoparticles and subsequent internalization. Cell functional assays, including migration assay and phosphowestern blot analysis of the mTOR and pI3K signaling pathways, revealed that the E-selectin targeted nanoparticles loaded with BEZ had a pronounced effect on inflammation-activated endothelial cells as compared to the non-targeted BEZ-loaded nanoparticles. In conclusion, E-selectin targeted nanoparticles have a high potential in delivering the potent mTOR/pI3K inhibitor dactolisib to inflamed endothelial cells and are an interesting nanomedicine for anti-inflammatory therapy.
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