Artesunate-Nanoliposome-TPP, a Novel Drug Delivery System That Targets the Mitochondria, Attenuates Cisplatin-Induced Acute Kidney Injury by Suppressing Oxidative Stress and Inflammatory Effects

Abstract

Background

Acute kidney injury (AKI) is a syndrome, posing a substantial healthcare burden. The pathological basis of AKI is associated with inflammation and oxidative stress which cause additional damage to mitochondria. Artesunate (ATS) is a derivative of artemisinin isolated from Artemisia annua L. that is an effective treatment for malaria and favored for the prevention and treatment of kidney diseases. However, there are still challenges related to its efficacy, including poor water solubility, limited oral bioavailability and short half-life. Liposome-based nanoparticles are used for drug delivery due to their ideal biocompatibility and their ability to improve the bioavailability of specific drugs and enhance drug efficacy.

Methods

In this study, a novel TPP-based natural ATS-nanoliposome, namely T-A-Ls, was applied for the treatment of AKI. ATS was encapsulated with or without triphenylphosphonium (TPP)-modified nanoliposomes. AKI was induced by cisplatin in C57BL/6J mice and a cisplatin-induced injury model was generated in HK-2 cells in vitro. Blood urea nitrogen (BUN), serum creatinine (Scr) measurements and section staining were utilized to assess renal protective effect of T-A-Ls. Inflammatory-related factors and proteins were quantified via Elisa, Immunofluorescence and Western Blot (WB). The anti-mitochondrial oxidative stress effect of T-A-Ls was determined by ROS, JC-1 and oxygen consumption rate (OCR) kits. Immunohistochemistry and WB were conducted to measure associated protein expressions. In vivo biodistribution and the concentration of T-A-Ls in kidney were also explored.

Results

T-A-Ls exhibited good oxidative resistance, preferential renal uptake, mitochondrial targeting, and it ameliorated kidney injury in cisplatin-induced AKI mice. Mitochondrial dysfunction, ATP production and respiratory capacity were improved in damaged HK-2 cells; ROS content decreased while mitochondrial membrane potential recovered. T-A-Ls exerted renal protection by inhibiting inflammation and reducing oxidative stress; these effects were mediated by a downregulation in the expression of RAGE and iNOS and an upregulation in both Nrf2 and HO-1.

Conclusion

T-A-Ls could improve the delivery of ATS to the kidney, offering a promising avenue to treat AKI.

Graphical Abstract

Keywords:

• artesunate
• liposomes
• AKI
• cisplatin
• oxidative stress
• inflammation

Ethics Approval and Informed Consent

All animal experiments received ethical approval from the Laboratory Animal Ethics Committee of Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences (2022B030). The experiments were conducted in strict accordance with the Guidelines for Ethical Review of Laboratory Animal Welfare in China (GB/ T35892-2018).

Acknowledgments

The authors thank Ms. Guihua Yu in the Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences for her technical support. The work was supported by National Natural Science Foundation of China (Grant No. 81873332); Guang Dong Basic and Applied Basic Research Foundation (Grant No. 2021A1515110381); Fundamental Research Funds for the Central public welfare research institutes (Grant No. ZZ13-YQ-103; ZZ16-ND-10-11).

Author Contributions

All authors made significant contributions to the design and conception of the study, as well as the acquisition, execution, analysis, and interpretation of the data. Additionally, they participated in drafting, revising, or critically reviewing the manuscript and gave final approval for the version to be published. They also have agreed on the journal to which the article has been submitted, and agreed on all versions of the article before submission, during revision, the final version accepted for publication. All authors reached an agreement to take responsibility for all aspects of the article, ensuring that any questions regarding the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Disclosure

None of the authors have any conflicts of interest to disclose.