Theranostics 2019; 9(24):7200-7209. doi:10.7150/thno.39831

Research Paper

Cooperation of endogenous and exogenous reactive oxygen species induced by zinc peroxide nanoparticles to enhance oxidative stress-based cancer therapy

Li-Sen Lin1,2*, Jun-Feng Wang3*, Jibin Song4*, Yijing Liu2, Guizhi Zhu2, Yunlu Dai2, Zheyu Shen2, Rui Tian2, Justin Song2, Zhantong Wang2, Wei Tang2, Guocan Yu2, Zijian Zhou2, Zhen Yang2, Tao Huang5, Gang Niu2, Huang-Hao Yang4, Zhi-Yi Chen1✉, Xiaoyuan Chen2✉

1. Department of Ultrasound Medicine, Laboratory of Ultrasound Molecular Imaging, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
2. Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, Maryland 20892, United States
3. Department of Ultrasound, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150076, China
4. MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou 350108, China
5. Department of Radiology, the Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang 150076, China
*These authors contributed equally to this work.

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Citation:
Lin LS, Wang JF, Song J, Liu Y, Zhu G, Dai Y, Shen Z, Tian R, Song J, Wang Z, Tang W, Yu G, Zhou Z, Yang Z, Huang T, Niu G, Yang HH, Chen ZY, Chen X. Cooperation of endogenous and exogenous reactive oxygen species induced by zinc peroxide nanoparticles to enhance oxidative stress-based cancer therapy. Theranostics 2019; 9(24):7200-7209. doi:10.7150/thno.39831. Available from http://www.thno.org/v09p7200.htm

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Abstract

Reactive oxygen species (ROS)-generating anticancer agents can act through two different mechanisms: (i) elevation of endogenous ROS production in mitochondria, or (ii) formation/delivery of exogenous ROS within cells. However, there is a lack of research on the development of ROS-generating nanosystems that combine endogenous and exogenous ROS to enhance oxidative stress-mediated cancer cell death.

Methods: A ROS-generating agent based on polymer-modified zinc peroxide nanoparticles (ZnO2 NPs) was presented, which simultaneously delivered exogenous H2O2 and Zn2+ capable of amplifying endogenous ROS production for synergistic cancer therapy.

Results: After internalization into tumor cells, ZnO2 NPs underwent decomposition in response to mild acidic pH, resulting in controlled release of H2O2 and Zn2+. Intriguingly, Zn2+ could increase the production of mitochondrial O2·- and H2O2 by inhibiting the electron transport chain, and thus exerted anticancer effect in a synergistic manner with the exogenously released H2O2 to promote cancer cell killing. Furthermore, ZnO2 NPs were doped with manganese via cation exchange, making them an activatable magnetic resonance imaging contrast agent.

Conclusion: This study establishes a ZnO2-based theranostic nanoplatform which achieves enhanced oxidative damage to cancer cells by a two-pronged approach of combining endogenous and exogenous ROS.

Keywords: reactive oxygen species, zinc peroxide nanoparticles, pH-responsiveness, magnetic resonance imaging, cancer therapy