In situ mucoadhesive hydrogel capturing tripeptide KPV: the anti-inflammatory, antibacterial and repairing effect on chemotherapy-induced oral mucositis.

Abstract

The self-healing of chemotherapy-induced oral mucositis is difficult in practice because of both local bacterial infection and severe inflammation. Herein, in situ mucoadhesive hydrogels (PPP_E) were successfully prepared by using temperature-sensitive PLGA-PEG-PLGA (PPP) as a matrix and epigallocatechin-3-gallate (EGCG) with inherent antibacterial activity as an adhesion enhancer. A series of PPP_E precursor solutions with various EGCG concentrations (1%, 2% and 5%) were prepared by fixing the PPP concentration at 25%. EGCG slightly decreased the sol-gel transition temperature and shortened the sol-gel transition time of the PPP hydrogel. Moreover, the incorporation of EGCG could significantly increase the tissue adhesion properties of the PPP hydrogel at 37 °C. PPP_2%E displayed a suitable gelation temperature (36.2 °C), gelation time (100 s) and storage modulus (48 Pa). Tripeptide KPV as a model drug was easily dissolved in cold PPP_2%E precursor solution to prepare KPV@PPP_2%E hydrogel. The anti-inflammatory activity and promotion of cell migration potential by KPV in PPP-2% E hydrogel were well maintained. Moreover, KPV@PPP_2%E exhibited strong antibacterial efficacy against S. aureus. PPP_2%E precursor solution rapidly transformed to a hydrogel and adhered to the wound surface for 7 hours when administrated to the gingival mucosa of rats. Treatment with KPV@PPP_2%E hydrogel greatly improved the food intake and body weight recovery of rats with chemotherapy-induced oral mucositis. Moreover, the tissue morphology of the ulcerated gingiva after application of KPV@PPP_E hydrogel was also well repaired by promoting CK10 and PCNA expression. In addition, the inflammatory cytokines including IL-1β and TNF-α were significantly inhibited by KPV@PPP_2%E hydrogel while IL-10 was up-regulated. KPV@PPP_2%E hydrogel also had an anti-bacterial effect on MRSA-infected gingival ulcer wounds, which resulted in the obvious inhibition of infiltration by inflammatory cells into submucosal tissues. Conclusively, KPV@PPP_E may be a promising practical application for cancer patients with chemotherapy-induced oral mucositis.