Anticancer Ir^III–Aspirin Conjugates for Enhanced Metabolic Immuno‐Modulation and Mitochondrial Lifetime Imaging

Abstract

The chemo‐anti‐inflammatory strategy is attracting ever more attention for the treatment of cancer. Here, two cyclometalated IrIII complexes Ir2 and Ir3 formed by conjugation of Ir1 with two antiphlogistics (aspirin and salicylic acid) have been designed. Ir2 and Ir3 exhibit higher antitumor and anti‐inflammatory potencies than a mixture of Ir1 and aspirin/salicylic acid. We show that they can be hydrolyzed, accumulate in mitochondria, and induce mitochondrial dysfunction. Due to their intense long‐lived phosphorescence, Ir2 and Ir3 can track mitochondrial morphological changes. Phosphorescence lifetime imaging shows that Ir2 and Ir3 can aggregate during mitochondrial dysfunction. As expected, Ir2 and Ir3 exhibit immunomodulatory properties by regulating the activity of immune factors. Both Ir2 and Ir3 can induce caspase‐dependent apoptosis and caspase‐independent paraptosis and inhibit several events related to metastasis. Moreover, Ir2 and Ir3 show potent tumor growth inhibition in vivo. Our study demonstrates that the combination of mitochondrial‐targeting and immunomodulatory activities is feasible to develop multifunctional metal‐based anticancer agents.

Metal Complexes or Chelators with ROS Regulation Capacity: Promising Candidates for Cancer Treatment

“…In addition, cyclometalated iridium complexes are another type of anti-cancer agent acting on functional mitochondria ( Figure 4 ). Mao et al reported several representative cyclometalated iridium complexes with anti-cancer activity through loss of mitochondrial membrane potential and elevation of intracellular ROS, such as iridium complexes 17 and 18 [ 103 , 104 ]. For 17 , the ubiquitin-proteasome system (UPS) was also induced and resulted in the collapse of mitochondria and subsequent cytoplasmic vacuolation because of the rapid loss of mitochondrial functions [ 103 ].…”

Advances in the Study of Structural Modification of Aspirin and Their Biological Activities

“…[90] . 阿司 匹林与 Ir 配合物反应制得金属衍生物 102, 其在 PC3、 CT26、HT29 癌细胞中的 IC 50 值分别为(4.5±0.5)、 (4.4±0.7)和(2.8±0.3) μmol•L -1 , 具有抗癌活性 [91] . [93] .…”

Ru(II) Complexes Bearing O, O-Chelated Ligands Induced Apoptosis in A549 Cells through the Mitochondrial Apoptotic Pathway

“…As multifunctional ligands, SA and AS are attracting ever more attention for the treatment of cancer. For instance, the research of Wu et al demonstrated that conjugation of SA or AS to the Ir(III) moiety could improve the cellular uptake efficacies of the Ir(III) complexes and achieve a high synergistic effect [ 19 ]. Liu and Dhar et al reported that a novel Pt(IV) prodrug of cisplatin, asplatin, with the ligation of aspirin ( c , c , t -[PtCl 2 (NH 3 ) 2 (OH) (aspirin)]), demonstrated significantly higher cytotoxicity than cisplatin towards tumor cells and nearly completely overcame the drug resistance of cisplatin-resistant cells [ 20 – 22 ].…”