Currently, cancer has turned into the main reason of death in China and some developed countries. In 2022, there had been approximately 4,820,000 and 2,370,000 new cancer cases, and 3,210,000 and 640,000 cancer deaths in China and the USA, respectively. The most common cancers are lung cancer in China and breast cancer in USA, and lung cancer is the leading cause of cancer death in both [1,2]. Cancer treatment mainly includes chemotherapy, radiotherapy, surgical excision and biological immunotherapy, among which chemotherapy is the most universal treatment way [3,4]. Among the anticancer chemotherapy regiments in Chinese hospitals, the regiments dominated by cisplatin or with the participation of cisplatin account for 70 % ∼ 80 % of all chemotherapy regiments, however, which damaged normal cells extensively and had a high rate of resistance [5,6]. Therefore, it is of great significance to develop a class of drugs with high anticancer activity and little damage to normal cells.
Compared to the less stable iridiumI (IrI) complexes, IrIII complexes have received wide attention because of their good anti-proliferative activity and a different mechanism of action from cisplatin [7,8], although the similar to platinum-based drugs for IrI-based ones and may interact with DNA, potentially causing crosslinks or strand breaks that induce cancer cell apoptosis. IrIII anticancer complexes can be divided into two categories according to their structural characteristics, which are cyclic IrIII structures with excellent luminescence properties and half-sandwich IrIII structures with high antitumor activity. IrIII complex has been widely used in the fields of biological probes, photosensitizers to reveal anticancer mechanisms and drug transportation/ targeting. Meanwhile, the anticancer activity of IrIII complexes can be effectively regulated by screening and regulating the peripheral ligands [[9], [10], [11]].
Ferrocene (Fc) derivatives have shown potential effects on a range of cancer cell lines in vitro or in vivo [[12], [13], [14]]. However, the anticancer activity of Fc derivatives is relatively weak compared with that of noble metallic anticancer compounds [14]. Therefore, it is a good design method to try to combine Fc with IrIII anticancer complex to improve the overall biological activity, which have shown excellent thermal stability, redox property, cell permeability and low toxicity, then contributing to the unique design idea [16]. In our previous study, structure-modified Fc-IrIII pyridine/bipyridine/phenylpyridine complexes were prepared, and their synergistic anticancer activity was also ascertained [[17], [18], [19], [20]]. Considering that acylhydrazone group has good strong complexation ability to metal ions and multiple coordination modes in comparison to the common Schiff base functional groups, including the combined metallic complexes showing high selectivity and anti-proliferative activity toward cancer cells [21], two ferrocene‑iridium(III) heteronuclear metallic complexes (Fe-Ir1 and Fe-Ir2) linked by acylhydrazone group were designed and characterized in this study (Fig. 1). Fe-Ir1, a complex with good in-vitro anti-proliferative activity, selectivity and anti-migration activity against A549 cells and cisplatin-resistant A549/DDP cells, was screened and investigated its anticancer mechanism at the cellular level, such as uptake mechanism, intracellular targeting, apoptosis, cycle, glycolytic pressure, scar healing rate, and apoptosis pathway detection. Finally, the in vivo anticancer activity and safety of Fe-Ir1 were also investigated using a nude mouse model.
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