Sialic Acid-Targeted Ru(II)/Ir(III)/Re(I) Complexes\nfor Ferroptosis Induction in Triple-Negative Breast Cancer

Ferroptosis\nhas been recognized as an iron-based nonapoptotic-regulated\ncell death process. In the quest of resisting the unyielding vehemence\nof triple-negative breast cancer (TNBC), herein we have showcased\nthe ferroptosis-inducing heteroleptic [<b>LIr</b><sub><b>c</b></sub><b>Ru</b>], [<b>LIr</b><sub><b>c</b></sub><b>Ir</b><sub><b>h</b></sub>], and [<b>LIr</b><sub><b>c</b></sub><b>Re</b>] complexes, enabling them\nto selectively target “sialic acid”, an overexpressed\ncancer cell-surface marker. The open-circuit potential (OCP) measurements\nin live cancer cells revealed the specific interaction between TNBC\nand the complexes, whereas control experiments with normal cells did\nnot exhibit such interactions. GSH depletion, GPx4 inhibition, NADH/NADPH\noxidation, lipid peroxidation, COX-2 activation, and Nrf2 inactivation\nwere meticulously investigated upon treatment with these complexes\nto establish a strong basis for ferroptosis. Among all complexes,\nthe complex [<b>LIr</b><sub><b>c</b></sub><b>Ir</b><sub><b>h</b></sub>] (IC<sub>50</sub> = 25 ± 2.17 μM)\nhas been well-documented as a potent ferroptosis inducer, which unveils\nthe sturdy interaction with sialic acid possessing the highest binding\nconstant (<i>K</i><sub>b</sub> = 0.71 × 10<sup>5</sup> M<sup>–1</sup>, Δ<i>G</i> = −279345.8026\nkcal/mol) along with the highest serum albumin binding affinity (<i>K</i><sub>HSA</sub> = 0.67 × 10<sup>6</sup> M<sup>–1</sup>) and significant DNA intercalation (<i>K</i><sub>b</sub> = 0.56 × 10<sup>5</sup> M<sup>–1</sup>, <i>K</i><sub>app</sub> = 1.06 × 10<sup>6</sup> M<sup>–1</sup>, and <i>C</i><sub>50</sub> of intercalation is 76.56 μM),\ndisplaying the decreased current intensity in differential pulse voltammetry\n(DPV). Moreover, the complex [<b>LIr</b><sub><b>c</b></sub><b>Ir</b><sub><b>h</b></sub>] exhibited mitochondrial\ndysfunction and membrane damage (diminished MMP, ΔΨ<sub>m</sub>) through the production of copious reactive oxygen species\n(ROS) in MDA-MB-231 cells upon considerable accumulation in mitochondria\n(Pearson’s coefficient = 0.842). The analysis of the field\nemission scanning electron microscopy (FE-SEM) image has marked the\nvivid membrane damage induced by the complex [<b>LIr</b><sub><b>c</b></sub><b>Ir</b><sub><b>h</b></sub>], exhibiting\nablaze evidence for the destruction of TNBC cells through ferroptosis.