Astaxanthin-loaded polymer-lipid hybrid nanoparticles (ATX-LPN): assessment of potential otoprotective effects
Astaxanthin-loaded polymer-lipid hybrid nanoparticles (ATX-LPN): assessment of potential otoprotective effects
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DOI：
10.1186/s12951-020-00600-x
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发表时间：
2020-03-19
影响因子：
10.2
通讯作者：
Wu, Hao
中科院分区：
文献类型：
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作者：
Gu, Jiayi;Chen, Yuming;Wu, Hao
背景：耳毒性是铂类药物化疗的主要副作用之一，尤其是顺铂。迄今为止，没有FDA批准的药物可以缓解或预防这种耳毒性。然而，耳毒性通常被认为是由内耳中活性氧（ROS）的过度产生的，从而导致各种抗氧化剂的产生，这些抗氧化剂起耳保护剂的作用。由于其独特的抗氧化能力，虾青素（ATX）在开发用于预防和治疗氧化应激相关病理的新疗法中是一个有趣的候选者。方法和结果在这项研究中，我们的目的是评估潜在的抗氧化特性的ATX在内耳使用HEI-OC 1细胞系，斑马鱼，和豚鼠。由于ATX的溶解性差，不能通过圆窗膜（RWM），我们建立了脂质-聚合物杂化纳米粒子（LPN）负载ATX。LPN使ATX能够穿透RWM，并在单次注射后保持内耳外淋巴液中的浓度24小时。在HEI-OC 1细胞中的DCFHDA染色的基础上，发现ATX-LPN具有良好的生物相容性，并且强烈地影响顺铂诱导的ROS的产生。JC-1和MitoTracker绿色染色表明，ATX-LPN在体外成功逆转了顺铂诱导的线粒体膜电位降低，并从凋亡的早期阶段拯救了细胞，如Annexin V-FITC/PI染色的FACS所示。此外，ATX-LPN在体内成功地减弱了培养的Corti器官和动物模型（斑马鱼和豚鼠）中的OHC损失。在研究ATX-LPN的保护机制时，我们发现ATX-LPN降低了促凋亡蛋白（caspase 3/9和细胞色素-c）的表达，并增加了抗凋亡蛋白Bcl-2的表达。另外，ATX-LPN可上调CDDP诱导的JNK活化，但对P38无明显影响。结论ATX-LPN是预防顺铂耳毒性的新药物。
Background Ototoxicity is one of the major side effects of platinum-based chemotherapy, especially cisplatin therapy. To date, no FDA approved agents to alleviate or prevent this ototoxicity are available. However, ototoxicity is generally believed to be produced by excessive generation of reactive oxygen species (ROS) in the inner ear, thus leading to the development of various antioxidants, which act as otoprotective agents. Astaxanthin (ATX) is an interesting candidate in the development of new therapies for preventing and treating oxidative stress-related pathologies, owing to its unique antioxidant capacity. Methods and results In this study, we aimed to evaluate the potential antioxidant properties of ATX in the inner ear by using the HEI-OC1 cell line, zebrafish, and guinea pigs. Because ATX has poor solubility and cannot pass through round window membranes (RWM), we established lipid-polymer hybrid nanoparticles (LPN) for loading ATX. The LPN enabled ATX to penetrate RWM and maintain concentrations in the perilymph in the inner ear for 24 h after a single injection. ATX-LPN were found to have favorable biocompatibility and to strongly affect cisplatin-induced generation of ROS, on the basis of DCFHDA staining in HEI-OC1 cells. JC-1 and MitoTracker Green staining suggested that ATX-LPN successfully reversed the decrease in mitochondrial membrane potential induced by cisplatin in vitro and rescued cells from early stages of apoptosis, as demonstrated by FACS stained with Annexin V-FITC/PI. Moreover, ATX-LPN successfully attenuated OHC losses in cultured organ of Corti and animal models (zebrafish and guinea pigs) in vivo. In investigating the protective mechanism of ATX-LPN, we found that ATX-LPN decreased the expression of pro-apoptotic proteins (caspase 3/9 and cytochrome-c) and increased expression of the anti-apoptotic protein Bcl-2. In addition, the activation of JNK induced by CDDP was up-regulated and then decreased after the administration of ATX-LPN, while P38 stayed unchanged. Conclusions To best of our knowledge, this is first study concluded that ATX-LPN as a new therapeutic agent for the prevention of cisplatin-induced ototoxicity.