Arenobufagin-loaded PEG-PLA nanoparticles for reducing toxicity and enhancing cancer therapy

Abstract

Arenobufagin (ArBu) is a natural anticancer drug with good anti-tumor effects, but its clinical applications and drug development potential are limited due to its toxicity. The purpose of this study is to reduce the toxic side effects of ArBu and improve the efficacy of tumor treatment by incorporating it into poly(ethylene glycol)-b-poly (lactide) co-polymer (PEG-PLA). ArBu@PEG-PLA micelles were prepared by a thin film hydration method. The optimized micelles were characterized by size, stability, drug loading, encapsulation rate, and drug release. The tumor-inhibition efficacy of the micelles was evaluated on A549 cells and tumor-bearing mice. The ArBu@PEG-PLA micelles have good drug-loading capacity, release performance, and stability. They can accumulate at the tumor site through the EPR effect. The micelles induce apoptosis through a mitochondrial apoptosis pathway. Compared with the free ArBu, the ArBu@PEG-PLA micelles had lower toxicity and higher safety in the acute toxicity evaluation experiment. The in vivo anti-tumor experiment with tumor-bearing mice showed that the tumor-inhibition rate of ArBu@PEG-PLA micelles was 72.9%, which was 1.28-fold higher than that of free ArBu (57.1%), thus showing a good tumor treatment effect. This study indicates that ArBu@PEG-PLA polymeric micelles can significantly improve the toxicity and therapeutic efficacy of ArBu. These can lead to a new therapeutic strategy to reduce the toxicity of ArBu and enhance tumor treatment.

Keywords:

• Arenobufagin
• polymeric micelles
• pharmacodynamics
• drug delivery
• cancer

Authors’ contributions

Jiaying Yang designed the experiments. Jiaying Yang, Bo Sun and Xiaolu Wei performed the experiments. Linna Wang, Yan Zhang, Wenya Gao and Keke Luo analyzed the data and prepared the figures. Shan Jiang, Yanyan Zhou, Hongjie Wang, Nan Si, Bo Gao and Chuan Luo contributed materials/analysis tools. Yu Zhao, Qinghe Zhao and Haiyu Zhao wrote and revised the paper.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethics committee

China Academy of Chinese Medical Sciences, Institute of Chinese Materia Medica, Beijing 100700, China.

Animal license: SCXK 2019-0004.

The experimental institutions meet the standards, and the experimental personnel have professional operation ability. During the experiment, the animals have well housing and husbandry, suffering was reduced and in accordance with humanitarianism.

Additional information

Funding

This work was financially supported by Science and Technology Innovation Project of China Academy of Chinese Medical Sciences (CI2021A04510); National Administration of Traditional Chinese Medicine Young Qihuang Scholar Project, China; Traditional Chinese Medicine Toxicology Innovation Team (Z2021180); National Natural Science Foundation of China (grant No. 22005344); The Open Research Project Programme of the State Key Laboratory of Quality Research in Chinese Medicine (University of Macau) (No. SKL-QRCM-OP21004)