Size-dependent cytotoxicity of Fe₃O₄ nanoparticles induced by biphasic regulation of oxidative stress in different human hepatoma cells

Abstract

The application of Fe₃O₄ nanoparticles (NPs) has made great progress in the diagnosis of disease and in the drug delivery system for cancer therapy, but the relative mechanisms of potential toxicity induced by Fe₃O₄ have not kept pace with its development in the application, which has hampered its further clinical application. In this article, we used two kinds of human hepatoma cell lines, SK-Hep-1 and Hep3B, to investigate the cytotoxic effects and the involved mechanisms of small Fe₃O₄ NPs with different diameters (6 nm, 9 nm, and 14 nm). Results showed that the size of NPs effectively influences the cytotoxicity of hepatoma cells: 6 nm Fe₃O₄ NPs exhibited negligible cytotoxicity and 9 nm Fe₃O₄ NPs affected cytotoxicity via cellular mitochondrial dysfunction and by inducing necrosis mediated through the mitochondria-dependent intracellular reactive oxygen species generation. Meanwhile, 14 nm Fe₃O₄ NPs induced cytotoxicity by impairing the integrity of plasma membrane and promoting massive lactate dehydrogenase leakage. These results explain the detailed mechanism of different diameters of small Fe₃O₄ NPs-induced cytotoxicity. We anticipate that this study will provide different insights into the cytotoxicity mechanism of Fe₃O₄ NPs, so as to make them safer to use in clinical application.

Keywords:

• hepatoma cells
• nanoparticles
• cytotoxicity
• mechanism
• oxidative stress

Acknowledgments

We gratefully acknowledge the financial support by the National Natural Science Foundation of China (Nos 31400719, 81472842, 81402548, and 81560495), the Experimental Animal Project from Science and Technology Commission of Shanghai (No 15140902700), the Scientific Research Innovation Program from the Shanghai Municipal Education Commission (14YZ029), Shanghai Municipal Commission of Health and Family Planning (No 20144Y0203), the Medical-Engineering Joint Funds from the Shanghai Jiao Tong University (No YG2011MS53), and the Fund of Shanghai Jiao Tong University School of Medicine (No 12XJ10079).

Disclosure

The authors report no conflicts of interest in this work.