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

Abstract

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 β-glycerophosphate (GP) and characterized for gelation properties by means of rheological 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.

Effect of freeze drying on stability, thermo-responsive characteristics, and in vivo wound healing of erythropoietin-loaded trimethyl chitosan/glycerophosphate hydrogel

“…GP solution was then added to the mixture to obtain EPO-loaded hydrogel containing final concentrations of TMC (5% w/v) and GP (20% w/v). The mixture was prepared at 4 °C and under constant stirring(8). The rheological behavior and mucoadhesive property of EPO-loaded TMC/GP system was evaluated using digital rotary viscometer (RVDV-III U, Daiki Sciences Co. USA) and tensile stress tester (TA.…”

“…The rheological behavior and mucoadhesive property of EPO-loaded TMC/GP system was evaluated using digital rotary viscometer (RVDV-III U, Daiki Sciences Co. USA) and tensile stress tester (TA. XT plus Texture Analyzer, Stable Micro system, Godalming, UK), respectively following procedure described previously(8). To evaluate the release profile of EPO, 1 mL of the hydrogel solution containing EPO was placed in 25-mL flat-bottomed glass beakers and allowed to thicken in an incubator at 37 °C for 5 min.…”

“…reported that systemic EPO treatment is beneficial in cutaneous ulcers in patients with systemic ulceration(7). Recently we developed a novel thermosensitive hydrogel containing EPO for prevention and treatment of oral mucositis (OM)(8). OM is inflammation of oral mucosa of cancer patients as a result of radiotherapy and/or chemotherapy(9).…”

“…OM is inflammation of oral mucosa of cancer patients as a result of radiotherapy and/or chemotherapy(9). Our developed formulation successfully decreased the severity of OM in animal chemotherapy-induced OM model(8). Thermosensitive hydrogels exhibit solution to gel transition when the ambient temperature changes to physiological level.…”

Novel and revisited approaches in nanoparticle systems for buccal drug delivery

“…Chitosan based thermosensitive gels for the delivery of erythropoietin have also been developed, and showed a good formulation and protein stability over time [62,63].…”