A666-conjugated nanoparticles target prestin of outer hair cells preventing cisplatin-induced hearing loss
A666-conjugated nanoparticles target prestin of outer hair cells preventing cisplatin-induced hearing loss
复制标题
结合 a666 的纳米粒子靶向外毛细胞的 prestin，预防顺铂引起的听力损失
DOI：
10.2147/ijn.s170130
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发表时间：
2018-01-01
影响因子：
8
通讯作者：
Wu, Hao
中科院分区：
文献类型：
--
作者：
Wang, Xueling;Chen, Yuming;Wu, Hao
背景：为了克服常规治疗药物在治疗或减轻顺铂耳毒性方面的局限性，研究了利用药物给药系统（DDS）给药内耳的方法。方法：本研究构建了一种新型靶向地塞米松（DEX）负载DDS A666-DEX-NP，用于预防顺铂性听力损失。A666-(CLEPRWGFGWWLH)肽特异性结合prestin， prestin仅限于外毛细胞（ohc）。采用HEI-OC1和顺铂处理豚鼠（12 mg/kg，腹腔）作为体外和体内模型，研究其对顺铂的靶向性和保护作用。结果：与A666-unconjugated nanoparticles （NP）相比，A666-conjugated香豆素6-labeled NP对OHCs表现出积极的靶向性。此外，a666 -香豆素6标记的NP可以通过A666-prestin相互作用被HEI-OC1细胞显著内化。这有利于A666-DEX-NP预处理的细胞摄取，其次是顺铂处理组，与顺铂治疗前4小时用DEX或DEX- np预处理的细胞相比，这导致细胞活力增强，凋亡特性降低，活性氧水平降低。在顺铂处理的豚鼠中，与生理盐水、DEX或DEX- np制剂预处理相比，A666-DEX-NP预处理有效地保存了ohc，并在4、8和16 kHz时显示出显著的听力保护。结论：这种靶向ohc的DDS为DEX的应用提供了一种新的策略，可以潜在地用于对抗顺铂耳毒性。
Background: The delivery of treatment agents to inner ear with drug delivery system (DDS) has been under investigation to overcome the limitations of the conventional therapeutic agents in curing or alleviating the cisplatin ototoxicity.Methods: In the present study, a novel targeted dexamethasone (DEX)-loaded DDS, A666-DEX-NP, was constructed for prevention from cisplatin-induced hearing loss. A666-(CLEPRWGFGWWLH) peptides specifically bind to prestin, which is limited to the outer hair cells (OHCs). HEI-OC1 and cisplatin-treated guinea pigs (12 mg/kg, intraperitoneal) were used as in vitro and in vivo models for investigating the targeting and protective efficiency against cisplatin.Results: As expected, compared to A666-unconjugated nanoparticles (NP), A666-conjugated coumarin 6-labeled NP showed active targeting to OHCs. Furthermore, A666-coumarin 6-labeled NP could be significantly internalized by HEI-OC1 cells via the A666-prestin interaction. This facilitated the uptake of cells pretreated with A666-DEX-NP, followed by the cisplatin-treated group, which led to enhanced cell viability, reduced apoptotic properties, and decreased reactive oxygen species levels as compared to cells pretreated with DEX or DEX-NP, 4 hours in advance of cisplatin treatment. In cisplatin-treated guinea pigs, pretreatment with A666-DEX-NP effectively preserved OHCs and showed significant hearing protection at 4, 8, and 16 kHz as compared to pretreatment with saline, DEX, or DEX-NP formulation.Conclusion: This OHC-targeting DDS provides a novel strategy for DEX application that can be potentially used to combat cisplatin ototoxicity.