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

Abstract

Background: 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.

• Authors: Yuming Chen, Jiayi Gu, Jian Liu, Ling Tong, Fuxin Shi, Xiaoqin Wang, Xueling Wang, Dehong Yu, Hao Wu
• Journal: International journal of nanomedicine (Int J Nanomedicine) Vol. 14 Pg. 4211-4227 ( 2019) ISSN: 1178-2013 [Electronic] New Zealand
• PMID: 31239676 (Publication Type: Journal Article)

Chemical References

• Biocompatible Materials
• Hydrogels
• Protective Agents
• Reactive Oxygen Species
• Silk
• Polyethylene Glycols
• Dexamethasone
• Cisplatin

Topics

• Animals
• Biocompatible Materials (adverse effects)
• Bombyx
• Cell Line
• Cisplatin (adverse effects)
• Cochlea (drug effects, pathology)
• Dexamethasone (pharmacology, therapeutic use)
• Disease Models, Animal
• Drug Liberation
• Ear (pathology)
• Guinea Pigs
• Hearing Loss (chemically induced, drug therapy)
• Hydrogels (chemistry)
• Injections
• Mice, Inbred C57BL
• Polyethylene Glycols (chemistry)
• Protective Agents (pharmacology)
• Reactive Oxygen Species (metabolism)
• Silk (chemistry)