PEG-nanolized ultrasmall selenium nanoparticles overcome drug resistance in hepatocellular carcinoma HepG2 cells through induction of mitochondria dysfunction

Shanyuan Zheng,^1,2 Xiaoling Li,¹ Yibo Zhang,¹ Qiang Xie,³ Yum-Shing Wong,² Wenjie Zheng,¹ Tianfeng Chen,<sup>1,3,4

1</sup>Department of Chemistry, Jinan University, Guangzhou, China; ²School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China; ³Wu Jing Zong Dui Hospital of Guangdong Province, Guangzhou, China; ⁴State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China

Abstract: Gray selenium (Se) is one of the most widely used Se sources with very limited biocompatibility and bioactivity. In the present study, a simple method for the preparation of ultrasmall selenium nanoparticles (SeNPs) through direct nanolization of gray selenium by polyethylene glycol (PEG) was demonstrated. Monodisperse and homogeneous PEG-SeNPs with ultrasmall diameters were successfully prepared under optimized conditions. The products were characterized using various microscopic and spectroscopic methods, and the results suggest that the amphoteric properties of PEG and the coordination between oxygen and selenium atoms contributed to the formation of ultrasmall nanoparticles. PEG-SeNPs exhibited stronger growth inhibition on drug-resistant hepatocellular carcinoma (R-HepG2) cells than on normal HepG2 cells. Dose-dependent apoptosis was induced by PEG-SeNPs in R-HepG2 cells, as evidenced by an increase in the sub-G1 cell population. Further investigation on the underlying molecular mechanisms revealed that depletion of mitochondrial membrane potential and generation of superoxide anions contributed to PEG-SeNPs-induced apoptotic cell death in R-HepG2 cells. Our results suggest that PEG-SeNPs may be a candidate for further evaluation as a chemotherapeutic agent for drug-resistant liver cancer, and the strategy to use PEG200 as a surface decorator could be a highly efficient way to enhance the anticancer efficacy of nanomaterials.

Keywords: selenium, PEG, nanolization, drug resistance, apoptosis