An enhanced antioxidant strategy of astaxanthin encapsulated in ROS-responsive nanoparticles for combating cisplatin-induced ototoxicity.
An enhanced antioxidant strategy of astaxanthin encapsulated in ROS-responsive nanoparticles for combating cisplatin-induced ototoxicity.
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DOI：
10.1186/s12951-022-01485-8
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发表时间：
2022-06-10
影响因子：
10.2
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Gu J;Wang X;Chen Y;Xu K;Yu D;Wu H
活性氧（ROS）的过度积累已被证明是顺铂诱导耳毒性的关键细胞机制。然而，许多抗氧化剂在临床研究中失败，部分原因是药物输送到耳蜗的效率低下。药物递送系统是克服该缺点的有吸引力的策略。在本研究中，我们提出了抗氧化剂虾青素（ATX）和ROS响应/消耗纳米颗粒（PPS-NP）的组合，以对抗顺铂诱导的耳毒性。ATX-PPS-NP是由两亲性超支化聚磷酸酯（含硫代缩酮单元）自组装而成，其清除ROS并分解以释放封装的ATX。ROS敏感性通过1H核磁共振光谱、透射电子显微镜和H2 O2 ON/OFF刺激模型证实。在人工外淋巴液、HEI-OC 1细胞系和豚鼠中验证了H2 O2刺激的增强释放曲线。此外，与单独的ATX或PPS-NP相比，ATX-PPS-NP有效地抑制顺铂诱导的HEI-OC 1细胞毒性和凋亡，表明天然活性化合物ATX和ROS消耗性PPS-NP的组合的增强效果。此外，ATX-PPS-NP减轻了培养的Corti器官中外毛细胞的损失。在豚鼠中，NiRe-PPS-NP证实了快速穿透圆窗膜，并且ATX-PPS-NP显示出对螺旋神经节神经元的保护作用，这进一步减轻了顺铂诱导的中度听力损失。进一步的研究表明，保护机制涉及减少过量的ROS产生，减少炎性趋化因子（白细胞介素-6）的释放，增加抗氧化剂谷胱甘肽的表达和抑制线粒体凋亡途径。因此，这种封装ATX的ROS响应性纳米颗粒在预防顺铂诱导的听力损失中具有有利的潜力。在线版本包含补充材料，可通过10.1186/s12951-022-01485-8获得。
Excessive accumulation of reactive oxygen species (ROS) has been documented as the crucial cellular mechanism of cisplatin-induced ototoxicity. However, numerous antioxidants have failed in clinical studies partly due to inefficient drug delivery to the cochlea. A drug delivery system is an attractive strategy to overcome this drawback. In the present study, we proposed the combination of antioxidant astaxanthin (ATX) and ROS-responsive/consuming nanoparticles (PPS-NP) to combat cisplatin-induced ototoxicity. ATX-PPS-NP were constructed by the self-assembly of an amphiphilic hyperbranched polyphosphoester containing thioketal units, which scavenged ROS and disintegrate to release the encapsulated ATX. The ROS-sensitivity was confirmed by 1H nuclear magnetic resonance spectroscopy, transmission electron microscopy and an H2O2 ON/OFF stimulated model. Enhanced release profiles stimulated by H2O2 were verified in artificial perilymph, the HEI-OC1 cell line and guinea pigs. In addition, ATX-PPS-NP efficiently inhibited cisplatin-induced HEI-OC1 cell cytotoxicity and apoptosis compared with ATX or PPS-NP alone, suggesting an enhanced effect of the combination of the natural active compound ATX and ROS-consuming PPS-NP. Moreover, ATX-PPS-NP attenuated outer hair cell losses in cultured organ of Corti. In guinea pigs, NiRe-PPS-NP verified a quick penetration across the round window membrane and ATX-PPS-NP showed protective effect on spiral ganglion neurons, which further attenuated cisplatin-induced moderate hearing loss. Further studies revealed that the protective mechanisms involved decreasing excessive ROS generation, reducing inflammatory chemokine (interleukin-6) release, increasing antioxidant glutathione expression and inhibiting the mitochondrial apoptotic pathway. Thus, this ROS-responsive nanoparticle encapsulating ATX has favorable potential in the prevention of cisplatin-induced hearing loss. The online version contains supplementary material available at 10.1186/s12951-022-01485-8.
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