Dexamethasone-loaded injectable silk-polyethylene glycol hydrogel alleviates cisplatin-induced ototoxicity
Dexamethasone-loaded injectable silk-polyethylene glycol hydrogel alleviates cisplatin-induced ototoxicity
复制标题
地塞米松可注射丝聚乙二醇水凝胶减轻顺铂引起的耳毒性
DOI：
10.2147/ijn.s195336
复制
发表时间：
2019-01-01
影响因子：
8
通讯作者：
Wu, Hao
中科院分区：
文献类型：
--
作者：
Chen, Yuming;Gu, Jiayi;Wu, Hao
背景：顺铂是一种广泛用于治疗各种实体瘤的抗肿瘤药物。然而，严重耳毒性的高发生率伴随着其在临床中的使用。目前，尚无药物或治疗方案被FDA批准用于治疗顺铂引起的耳毒性。目的：研究地塞米松（dexamethasone，DEX）丝聚乙烯水凝胶的耳保护作用在顺铂诱导的耳毒性小鼠模型中，圆窗膜给药后，使用DEX-SILK。分析了DEX-SILK水凝胶的形态、凝胶化动力学、粘度和二级结构。在RWM龛上注射水凝胶后的不同时间点测试外淋巴中的DEX浓度。培养细胞（HEI-OC 1），Corti器官外植体以C57/BL6，P0 - 2）和顺铂诱导的听力损失小鼠模型（C57/BL6）作为研究DEX-SILK水凝胶对顺铂的耳保护作用的体外和体内模型。以8%（w/v）的负载包封DEX没有显著改变丝凝胶化时间，扫描电子显微镜（SEM）显示，DEX均匀分布在Silk-PEG水凝胶中。丝素浓度主要影响DEX分布、形态特征、粘度和凝胶化时间。将优化的DEXSILK水凝胶（8%w/v负载，15%丝浓度，10 μ l）直接施用到豚鼠的RWM上。对于DEX-SILK，外淋巴液中的DEX浓度保持在1 μ g/ml以上至少21天，而在游离DEX的对照样品中保持不到6小时。DEX-SILK（5 - 60 ng/ml）对顺铂诱导的细胞耳毒性表现出显著的保护作用，并显著减少活性氧（ROS）的产生。最后，预处理DEX-SILK有效地保存外毛细胞培养器官的Corti外植体，并表现出显着的听力保护在4，8，和16 kHz的顺铂诱导的听力损失小鼠相比，注意到以下的影响与DEX.Conclusion：这些结果表明，DEX-SILK的治疗顺铂诱导的耳毒性的临床价值。
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 DEXSILK hydrogel (8% w/v loading, 15% silk concentration, 10 mu l) was administered directly onto the RWM of the guinea pigs. The DEX concentration in the perilymph was maintained above 1 mu g/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.