A mucoadhesive thermosensitive hydrogel containing erythropoietin as a potential treatment in oral mucositis: in vitro and in vivo studies

Oral mucositis (OM) represents a therapeutic challenge frequently encountered in cancer patients undergoing chemotherapy or radiotherapy. Erythropoietin (EPO) has anti-inflammatory, antioxidant, and wound-healing properties and therefore has important roles in the prevention and treatment of OM. In the current study, we developed a thermally sensitive mucoadhesive gel based on trimethyl chitosan (TMC) containing EPO for the treatment of OM. TMCs with various degrees of substitution (DS) were synthesized and mixed with beta-glycerophosphate (GP) and characterized for gelation properties by means of theological analysis. The effects of DS of TMCs and different concentrations of GP on gelation temperature and time were investigated. The mucoadhesive property of the mixtures was also assessed using cattle buccal mucosa. The optimized mixture was loaded with EPO and subjected to in vitro drug release, wash away, in vitro antimicrobial, and wound-healing tests. The effect of EPO-loaded formulation was also investigated in vivo in Sprague-Dawley rats with chemotherapy-induced mucositis. The best properties were obtained with the blend of TMC of 9.8% DS (5%) and GP (20%). EPO was released from the hydrogel during 8 h, and more than 30% of the drug still remained on the mucosa after 3 h of washing the buccal mucosa with phosphate buffer. TMC/GP mixture was characterized by antimicrobial properties. The EPO hydrogel demonstrated in vitro/in vivo wound-healing properties. Therefore, EPO-loaded hydrogel has the potential to be used in the treatment of OM and other oral or subcutaneous wounds.