Dexamethasone-loaded injectable silk-polyethylene glycol hydrogel alleviates cisplatin-induced ototoxicity

Abstract

Yuming Chen,1–3 Jiayi Gu,1–3 Jian Liu,4 Ling Tong,1 Fuxin Shi,5 Xiaoqin Wang,4 Xueling Wang,1–3 Dehong Yu,1–3 Hao Wu1–31Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, People’s Republic of China; 2Ear Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, People’s Republic of China; 3Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases (14DZ2260300), Shanghai 200011, People’s Republic of China; 4National Engineering Laboratory for Modern Silk, Soochow University, Suzhou 215123, People’s Republic of China; 5Department of Otology and Laryngology, Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Decibel Therapeutics, Boston, MA, 02215, USABackground: Cisplatin is an extensively used anti-neoplastic agent for the treatment of various solid tumors. However, a high incidence of severe ototoxicity is accompanied by its use in the clinic. Currently, no drugs or therapeutic strategies have been approved for the treatment of cisplatin-induced ototoxicity by the FDA.Purpose: The purpose of this study was to investigate the otoprotective effects of dexamethasone (DEX)-loaded silk-polyethylene hydrogel (DEX-SILK) following round window membrane administration in the cisplatin-induced ototoxicity mouse model.Methods: The morphology, gelation kinetics, viscosity and secondary structure of the DEX-SILK hydrogel were analyzed. DEX concentration in the perilymph was tested at different time points following hydrogel injection on the RWM niche. Cultured cells (HEI-OC1), organ of Corti explants (C57/BL6, P0-2), and cisplatin-induced hearing loss mice model (C57/BL6) were used as in vitro and in vivo models for investigating the otoprotective effects of DEX-SILK hydrogel against cisplatin.Results: Encapsulation of DEX with a loading of 8% (w/v) did not significantly change the silk gelation time, and DEX was evenly distributed in the Silk-PEG hydrogel as visualized by scanning electron microscopy (SEM). The concentration of Silk majorly influenced DEX distribution, morphological characteristics, viscosity, and gelation time. The optimized DEX-SILK hydrogel (8% w/v loading, 15% silk concentration, 10 μl) was administered directly onto the RWM of the guinea pigs. The DEX concentration in the perilymph was maintained above 1 μg/ml for at least 21 days for the DEX-SILK, while it was maintained for less than 6 h in the control sample of free DEX. DEX-SILK (5-60 ng/ml) exhibited significant protective effects against cisplatin-induced cellular ototoxicity and notably reduced the production of reactive oxygen species (ROS). Eventually, pretreatment with DEX-SILK effectively preserved outer hair cells in the cultured organ of Corti explants and demonstrated significant hearing protection at 4, 8, and 16 kHz in the cisplatin-induced hearing loss mice as compared to the effects noted following pretreatment with DEX.Conclusion: These results demonstrated the clinical value of DEX-SILK for the therapy of cisplatin-induced ototoxicity.Keywords: silk-polyethyleneglycol hydrogel, cisplatin-induced hearing loss, dexamethasone, round window membrane

Keywords

• silk-polyethyleneglycolhydrogel
• cisplatin-induced hearing loss
• dexamethasone
• round window membrane