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Theranostics 2020; 10(5):2342-2357. doi:10.7150/thno.40395 This issue Cite

Research Paper

ROS-responsive nano-drug delivery system combining mitochondria-targeting ceria nanoparticles with atorvastatin for acute kidney injury

Hui Yu¹, Feiyang Jin¹, Di Liu¹, Gaofeng Shu¹, Xiaojuan Wang², Jing Qi¹, Mingchen Sun¹, Ping Yang², Saiping Jiang^2✉, Xiaoying Ying¹, Yongzhong Du^1✉

1. Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, 866 Yu-Hang-Tang Road, Hangzhou, 310058, China.
2. Department of Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, China.

✉ Corresponding authors: duyongzhongedu.cn, j5145edu.cn

Abstract

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.

Keywords: acute kidney injury, oxidative stress, ROS-responsive, ceria, mitochondria-targeting.

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