Chemotherapy; Oral mucositis; Dexamethasone; PLGA nanoparticles.

Oral mucositis (OM) is a frequent and limiting side effect of anti-cancer therapy, characterized by intense inflammatory reaction and formation of oral cavity ulcers. The aim of the present study was to evaluate the effect of Dexamethasone (Dex) incorporated into polymeric nanoparticles (Nps) of poly-(D, L-lactic-co-glycolic) acid PGLA in the experimental model of oral mucositis induced by 5-fluorouracil (5-FU) in Golden Sirianhamsters. The incorporation of Dexamethasone into the PLGA was performed by the solvent evaporation emulsification technique, followed by characterization with determination of zeta potential, polydispersity index, particle size, atomic force microscopy, stability study, determination of encapsulation efficiency and study of in vitro release. To induce the OM model, 5-FU was administered intraperitoneally (ip) on the 1st and 2nd day of the experiment (60 and 40mg/kg, respectively), with subsequent excoriations on the jugal mucosa on day 4. The following experimental groups were used: Normal, MT, 5-FU, Dex (0,25; 0,5 or 1mg/kg) and Nps PLGA/Dex (0,1; 0,5; 1mg/kg). The animals were euthanized on the 10th day of the experimental model. Macroscopic and histopathological analyzes of the jugal mucosa were performed in all groups. Subsequent analyzes were performed only on animals treated with Dex. Quantification of IL-1β and TNF-α was determined by ELISA. For the immunohistochemistry the markersMMP-2, COX-2 and TGF-β were used. For immunofluorescence, MIF, NF-κB p65,SMAD 2/3 and p-SMAD 2/3 were used. The qRT-PCR assay determined the gene expression of GILZ, MKP1, NF-κB p65 and AKT. Dexamethasone 1mg/kg and Nps PLGA/Dex 0,1mg/kg demonstrated anti-inflammatory effects in the experimental OM model, presenting a significant reduction of macroscopic and histopathological scores (*p<0,05). Treatment with Dex decreased levels of the proinflammatory cytokines TNF-α and IL-1β (*p<0,05). Immunoblotting for MMP-2, COX-2 and TGF-β (*p <0,05), as well as suppression of expression for MIF, NF-κB p65, SMAD 2/3 and p-SMAD 2/3 (*p<0.05), Dex 1mg/kg also inhibited gene expression for NF-κB p65 and AKT, and increased mRNA expression for GILZ and MKP1 (*p<0,05), compared to animals with untreated oral mucositis (5-FU). Dex improved OM induced by 5-FU. The use of pharmaceutical technology for the incorporation of Dex into PLGA Nps seems to optimize OM therapy while maintaining anti-inflammatory effects with glucocorticoid dose reduction.