Injectable glycol chitosan-dexamethasone prodrug thermogel for otoprotective therapy against radiation-induced middle ear injury.

Radiation therapy for head and neck cancer often causes otologic complications due to inflammation and mucosal damage in the middle ear. To address this problem, an injectable glycol chitosan-dexamethasone prodrug thermogel (HGC-Su-DEX) was developed for localized and sustained otoprotective therapy. Dexamethasone (DEX) was covalently linked to hexanoyl glycol chitosan (HGC) via a biodegradable succinate linker, yielding an amphiphilic conjugate capable of sol-gel transition near physiological temperature. The HGC-Su-DEX formulations exhibited tunable thermogelling behavior and comparable release kinetics, ensuring in situ gelation, prolonged local retention, and self-degradation after drug release. In vivo studies demonstrated that a single intratympanic injection of HGC-Su-DEX effectively prevented radiation-induced thickening of the middle ear and Eustachian tube mucosa, providing protection equivalent to multiple doses of free dexamethasone phosphate solution. In vitro assays further revealed that the thermogel significantly attenuated radiation-induced oxidative stress, DNA damage, and apoptosis by modulating mitochondrial function and stress-related signaling pathways. These findings establish HGC-Su-DEX as a single-dose, self-degradable prodrug thermogel with sustained anti-inflammatory efficacy, providing a promising strategy for preventing radiation-induced ototoxicity.