ROS-responsive nano-drug delivery system combining mitochondria-targeting ceria nanoparticles with atorvastatin for acute kidney injury
ROS-responsive nano-drug delivery system combining mitochondria-targeting ceria nanoparticles with atorvastatin for acute kidney injury
复制标题
ROS响应纳米药物递送系统结合线粒体靶向二氧化铈纳米颗粒与阿托伐他汀治疗急性肾损伤
DOI：
10.7150/thno.40395
复制
发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Du, Yongzhong
中科院分区：
文献类型：
--
作者：
Yu, Hui;Jin, Feiyang;Du, Yongzhong
脓毒症引起的急性肾损伤（AKI）是线粒体氧化应激和炎症在其病理生理中起关键作用的严重疾病。二氧化铈纳米颗粒具有很强的可回收活性氧清除活性，已被应用于治疗活性氧相关疾病。然而，纳米二氧化铈不能选择性地靶向线粒体，而且超小的纳米二氧化铈容易团聚。为了克服这些缺点，提高治疗效率，我们设计了一种线粒体靶向氧化铈纳米颗粒与阿托伐他汀结合的ros反应纳米给药系统，用于治疗急性肾损伤。方法：以三苯基膦（TCeria NPs）修饰氧化铈纳米粒子，然后包覆ros -响应性有机聚合物（mPEG-TK-PLGA），并负载阿托伐他汀（Atv/PTP-TCeria NPs）。考察了Atv/PTP-TCeria NPs的理化性质、体外药物释放谱、线粒体靶向能力、体外抗氧化、抗凋亡活性和体内治疗效果。结果：Atv/PTP-TCeria NPs可在肾脏内蓄积，具有较强的ROS反应释放能力，TCeria NPs可靶向线粒体消除过量的ROS。体外实验表明，Atv/PTP-TCeria NPs具有较强的抗氧化和抗凋亡活性。体内实验表明，Atv/PTP-TCeria NPs在脓毒症诱导的AKI小鼠模型中可有效降低氧化应激和炎症，保护线粒体结构，减少小管细胞凋亡和小管坏死。结论：这种线粒体靶向氧化铈纳米颗粒与阿托伐他汀联合的ros反应纳米药物递送系统在败血症诱导的AKI治疗中具有良好的潜力。
Acute kidney injury (AKI) caused by sepsis is a serious disease which mitochondrial oxidative stress and inflammatory play a key role in its pathophysiology. Ceria nanoparticles hold strong and recyclable reactive oxygen species (ROS)-scavenging activity, have been applied to treat ROS-related diseases. However, ceria nanoparticles can't selectively target mitochondria and the ultra-small ceria nanoparticles are easily agglomerated. To overcome these shortcomings and improve therapeutic efficiency, we designed an ROS-responsive nano-drug delivery system combining mitochondria-targeting ceria nanoparticles with atorvastatin for acute kidney injury. Methods: Ceria nanoparticles were modified with triphenylphosphine (TCeria NPs), followed by coating with ROS-responsive organic polymer (mPEG-TK-PLGA) and loaded atorvastatin (Atv/PTP-TCeria NPs). The physicochemical properties, in vitro drug release profiles, mitochondria-targeting ability, in vitro antioxidant, anti-apoptotic activity and in vivo treatment efficacy of Atv/PTP-TCeria NPs were examined. Results: Atv/PTP-TCeria NPs could accumulate in kidneys and hold a great ability to ROS-responsively release drug and TCeria NPs could target mitochondria to eliminate excessive ROS. In vitro study suggested Atv/PTP-TCeria NPs exhibited superior antioxidant and anti-apoptotic activity. In vivo study showed that Atv/PTP-TCeria NPs effectively decreased oxidative stress and inflammatory, could protect the mitochondrial structure, reduced apoptosis of tubular cell and tubular necrosis in the sepsis-induced AKI mice model. Conclusions: This ROS-responsive nano-drug delivery system combining mitochondria-targeting ceria nanoparticles with atorvastatin has favorable potentials in the sepsis-induced AKI therapy.