Source: School of Chemistry
Written by: School of Chemistry
Edited by: Xu Jia, Wang Dongmei

Recently Prof. Hui Chao’s group from the School of Chemistry at Sun Yat-sen University presented a cyclometalated iridium(III) complex (FerriIridium) that can be selectively activated by the lysosomal labile iron pool (LIP). The complex’s diagnostic and therapeutic properties are demonstrated in gastric cancer cells both in vitro and in vivo. To the best of our knowledge, this Ir(III) complex is the very first example of an iron(III)-activated smart prodrug that can used for gastric cancer theranostics.

Although iron is not normally considered carcinogenic, recent work has shown that excess iron can contribute to tumor initiation and tumor growth. Since iron is closely associated with redox cycling and free radical formation, iron homeostasis dysregulation is observed in many diseases including neurodegenerative disease, cardiovascular disease, inflammation and cancer. It is therefore important to develop a platform that can integrate iron-specific cancer diagnosis with iron-activated therapeutics. However, to date, reports on the combination of iron-responsive cancer diagnosis and therapy remain scarce. Indeed, the majority of current research is confined to either diagnosis or therapy. Little effort has yet been made to devise an iron-activated theranostic prodrug.

FerriIridium exhibits selectivity for tumor cells over normal cells. This selective cytotoxicity is achieved as Ferrilridium is taken up through lysosomes and activated by lysosomal Fe³⁺ ions, which activates Ferrilridium prodrug into its cytotoxic components. Subsequently, these components exert cytotoxicity through causing (1) intense ROS generation (2) respiratory chain interference (3) mitochondria membrane depolarization within the cell. The in vivo experiments also verify FerriIridium can selectively target a gastric tumor leading to efficient tumor growth inhibition with negligible side effects. FerriIridium is a promising candidate for gastric cancer theranostics.

Recently this research data was published as a Very Important Paper in Angewandte Chemie International Edition. Prof. Hui Chao and Dr. Yu Chen are the corresponding authors, and Ph.D. candidate Shi Kuang is the first author (Shi Kuang, Xinxing Liao, Xianrui Zhang, Thomas W. Rees, Ruilin Guan, Kai Xiong, Yu Chen*, Liangnian Ji, Hui Chao*, FerriIridium: A Lysosome-Targeting Iridium(III) Prodrug for Iron(III)-Activated Chemotherapy in Gastric Cancer Cells, Angew. Chem. Int. Ed., 2020, 59, 3315-3321). This work was supported by the National Science Foundation of China (Nos. 21525105, 21778079), the 973 Program of China (No. 2015CB856301), the Ministry of Education of China (No. IRT-17R111), and the Pearl River S&T Nova Program of Guangzhou (No. 201806010136).

Link to the paper: https://doi.org/10.1002/anie.201915828