Glycyrrhetinic acid-modified chitosan nanoparticles enhanced the effect of 5-fluorouracil in murine liver cancer model via regulatory T-cells

This paper has been retracted.

Mingrong Cheng,^1,2,* Hongzhi Xu,^3,* Yong Wang,^4,* Houxiang Chen,⁵ Bing He,³ Xiaoyan Gao,⁶ Yingchun Li,² Jiang Han,¹ Zhiping Zhang<sup>1

1</sup>Department of General Surgery, ²Department of Endoscopy, Pudong New Area District Zhoupu Hospital, Shanghai, People’s Republic of China; ³Department of General Surgery, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, People’s Republic of China; ⁴School of Materials Science and Engineering, Wuhan University of Technology, Wuhan, People’s Republic of China; ⁵Zhejiang Huafon Fiber Research Institute, Zhejiang Huafon Spandex Co, Ltd, Wenzhou, People’s Republic of China; ⁶Department of Plastic Surgery, Pudong New Area District Zhoupu Hospital, Shanghai, People’s Republic of China

*These authors contributed equally to this work

Abstract: Modified chitosan nanoparticles are a promising platform for drug, such as 5-fluorouracil (5-FU), gene, and vaccine delivery. Here, we used chitosan and hepatoma cell-specific binding molecule glycyrrhetinic acid (GA) to synthesize glycyrrhetinic acid-modified chitosan (GA-CTS). The synthetic product was confirmed by infrared spectroscopy and hydrogen nuclear magnetic resonance. By combining GA-CTS and 5-FU, we obtained a GA-CTS/5-FU nanoparticle, with a particle size of 193.7 nm, drug loading of 1.56%, and a polydispersity index of 0.003. The GA-CTS/5-FU nanoparticle provided a sustained-release system comprising three distinct phases of quick, steady, and slow release. In vitro data indicated that it had a dose- and time-dependent anticancer effect. The effective drug exposure time against hepatic cancer cells was increased in comparison with that observed with 5-FU. In vivo studies on an orthotropic liver cancer mouse model demonstrated that GA-CTS/5-FU significantly inhibited cancer cell proliferation, resulting in increased survival time. The antitumor mechanisms for GA-CTS/5-FU nanoparticle were possibly associated with an increased expression of regulatory T-cells, decreased expression of cytotoxic T-cell and natural killer cells, and reduced levels of interleukin-2 and interferon gamma.

Keywords: hepatic carcinoma, regulatory T cells, glycyrrhetinic acid, targeted therapy, 5-fluorouracil