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Nanomedicine Assembled by Coordinated Selenium-Platinum Complexes Can Selectively Induce Cytotoxicity in Cancer Cells by Targeting the Glutathione Antioxidant Defense System Feng Li, Tianyu Li, Xuexiang Han, Hao Zhuang, Guangjun Nie, and Huaping Xu ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/ acsbiomaterials.7b00362 • Publication Date (Web): 27 Jul 2017 Downloaded from http://pubs.acs.org on July 28, 2017
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ACS Biomaterials Science & Engineering
Nanomedicine Assembled by Coordinated Selenium-Platinum Complexes Can Selectively Induce Cytotoxicity in Cancer Cells by Targeting the Glutathione Antioxidant Defense System Feng Li,a‖ Tianyu Li,a‖ Xuexiang Han,b,c Hao Zhuanga, Guangjun Nie,b,c and Huaping Xua,*
a
Key Lab of Organic Optoelectronics & Molecular Engineering, Department of
Chemistry, Tsinghua University, Beijing, 100084, People’s Republic of China; b
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety,
National Center for Nanoscience and Technology, Beijing 100190, China; c
‖
University of Chinese Academy of Sciences, Beijing 100049, China.
These two authors contributed equally to this manuscript.
*Address correspondence to: Huaping Xu Key Lab of Organic Optoelectronics & Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing, 100084, People’s Republic of China E-mail:
[email protected] ACS Paragon Plus Environment
ACS Biomaterials Science & Engineering
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Abstract： Selenium is a unique, essential trace element that plays an important role in the antioxidant defense and redox regulation of biological processes. We have reported that novel selenium-containing platinum-based anticancer molecules (EG-Se/Pt) had selective cytotoxicity toward cancer cells. Herein, we found the underlying mechanism of selective cytotoxicity to be closely related to the glutathione antioxidant defense system. Elevated reactive oxygen species (ROS) make cancer cells more vulnerable to further elevation of ROS. EG-Se/Pt can induce abnormal increases in ROS by depletion of glutathione. Consequently, the mitochondrial membrane potential collapses and cytochrome c is released, resulting in cell apoptosis. However, EG-Se/Pt analogues, such as EG-Se/Cu and EG-Se/Ni, did not exhibit glutathione depletion capacity or selective killing activity in our investigation, although they can effectively kill cancer cells. These results suggest that the glutathione antioxidant system is an effective target to enable therapeutic selectivity. The amphiphilic property of the selenium-platinum coordination molecules facilitates their assembly into nanoparticles and prolongs the circulation time of the drug in the bloodstream, which is important for in vivo drug delivery. Our in vivo anticancer study demonstrated that the tumor growth inhibition rate of EG-Se/Pt can reach 69% (p
