Chemotherapy; Oral mucositis; Dexamethasone; PLGA nanoparticles.

Oral mucositis (OM) is a frequent and limiting adverse reaction to cancer therapy, characterized by an intense inflammatory reaction and cumulative ulcer formation in the oral cavity. This study aimed to evaluate the effect of dexamethasone (DEX) incorporated into the polymeric nanoparticles (NPs) of poly (lactic-co-glycolic acid) - PGLA - in the experimental model of oral mucositis induced by 5-fluorouracil (5-FU) in Golden Sirian hamsters. The incorporation of DEX into the PLGA was performed using the solvent evaporation emulsification technique, followed by characterization with the determination of the 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 (60mg / kg) and 2nd (40mg / kg) days of the experiment, with subsequent abrasions on the oral mucosa performed on the 4th day under anesthetic effect. The animals were distributed in the experimental groups: Normal, Mechanical Trauma, 5-FU, DEX (0.25; 0.5 or 1mg / kg) and NPs PLGA-DEX (0.1; 0.5 or 1mg / kg). On the 10th day of the experimental model, the animals were euthanized. Macroscopic, histopathological analyzes, IL-1β and TNF-α quantification by ELISA, immunohistochemistry for MMP2, COX-2, TGF-β, and NF-κB p65, immunofluorescence for markers NF-κB p65, MIF, SMAD 2/3 and p-SMAD 2/3 were performed, qRT-PCR assay to determine 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, with a significant reduction in macroscopic and histopathological scores (*p<0.05). Treatment with DEX or NP PLGA-DEX attenuated the levels of the proinflammatory cytokines TNF-α and IL-1β (*p<0.05), reduced the immunostaining for MMP-2, COX-2, TGF-β, and NF- κB p65 (*p<0.05), suppressed protein expression of MIF, NF-κB p65, SMAD 2/3 and p-SMAD 2/3 (*p <0.05), inhibited gene expression for NF-κB p65 and AKT, and raised the mRNA to GILZ and MKP1 (* p <0.05) compared to animals with untreated OM (group 5-FU). DEX improved OM-induced by 5-FU. The use of an innovative formulation, developed with the aid of pharmaceutical technology for the incorporation of DEX into PLGA NPs, seems to optimize OM therapy while maintaining anti-inflammatory effects with reduced glucocorticoid dose.