文献：An enhanced antioxidant strategy of astaxanthin encapsulated in ROS-responsive nanoparticles for combating cisplatin-induced ototoxicity

文献链接：https://link.springer.com/article/10.1186/s12951-022-01485-8

作者：Shuaishuai Bian , Xiuli Zheng , Weimin Liu , Zekun Gao , Yingpeng Wan , Jihao Li , Haohui Ren , Wenjun Zhang , Chun-Sing Lee , Pengfei Wang

相关产品：PPS-PEG（聚苯硫醚聚乙二醇）

FITC-PPS-PEG（异硫氰酸荧光素-聚苯硫醚-聚乙二醇）

原文摘要：

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.

PPS-PEG：聚苯硫醚（Polyphenylene sulfide，PPS）与聚乙二醇（Polyethylene glycol，PEG）的结合物。聚苯硫醚是一种高性能的热塑性树脂，具有规整的苯环和硫原子交替排列的线性结构。其化学结构赋予它良好的热稳定性、化学稳定性和机械性能。聚乙二醇是一种具有良好水溶性和生物相容性的聚合物，由环氧乙烷聚合而成，分子链中含有大量的醚键。PPS - PEG 将两者的特性结合在一起，其中 PPS 部分提供了材料的强度和稳定性，PEG 部分提供了亲水性和一些生物相关的特性。

FITC-PPS-PEG：一种复合结构的化合物。它是在 PPS - PEG（聚苯硫醚 - 聚乙二醇）的基础上，连接了异硫氰酸荧光素（FITC）。从结构上来看，PPS 部分依旧保持其苯环和硫原子交替排列的线性结构，提供了材料的稳定性和一定的机械性能。PEG 部分由环氧乙烷聚合而成，分子链中有大量醚键，负责提供亲水性和生物相容性。FITC 部分含有异硫氰酸酯基团（- N = C = S），这个基团可以与 PPS - PEG 中的活泼基团（如氨基等）发生反应，从而连接到 PPS - PEG 上。FITC 的分子式为，它的存在使得整个化合物具有荧光特性。基于PPS-PEG、FITC-PPS-PEG的相关性能，ATX-PPS-NP的合成介绍如下：

图：机制示意

ATX-PPS-NP的制备：

将PPS-PEG和ATX溶解于二氯甲烷溶液中，然后将胆酸钠溶液倒入有机溶剂中。混合物超声处理。将得到的油/水乳液用胆酸钠溶液进一步稀释，搅拌过夜以去除有机溶剂。通过离心收集ATX- pps - np，洗涤以去除多余的乳化剂并卸载ATX。FITC-PPS-NP的制备方法相同，只是将PPS-PEG替换为FITC-PPS-PEG。nre - pps - np负载荧光探针尼罗红。NP保存在4°C。

图：合成示意

结论：

该文献成功制备出基于PPS-PEG、FITC-PPS-PEG合成的抗氧化虾青素 (ATX) 和 ROS 响应/消耗纳米粒子 (PPS-NP)的组合ATX-PPS-NP。ATX-PPS-NP 能有效抑制顺铂诱导的 HEI-OC1 细胞poison性和细胞Apoptosis ，表明天然活性化合物 ATX 和消耗 ROS 的 PPS-NP 组合的效果增强。数据显示，这种封装 ATX 的 ROS 响应纳米颗粒在预防顺铂引起的听力损失方面具有良好的潜力。