Synergistic photoinduction of ferroptosis and apoptosis by a mitochondria-targeted iridium complex for bladder cancer therapy

Herein, we designed two iridium(III)-based photosensitizers, Ir-Mito1 and Ir-Mito2, for photodynamic anticancer therapy. Ir-Mito2 could not only disrupt mitochondrial function but also elevate intracellular lipid peroxide levels, ultimately leading to the induction of apoptosis-ferroptosis cell deat...

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Veröffentlicht in:Journal of colloid and interface science 2025-04, Vol.683 (Pt 1), p.420-431
Hauptverfasser: Zheng, Jianguo, Zhang, Aijing, Du, Qinglong, Li, Chi, Zhao, Zhongwei, Li, Luchao, Zhang, Zhao, Qin, Xin, Li, Yi, Wang, Kang-Nan, Yu, Nengwang
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Sprache:eng
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Zusammenfassung:Herein, we designed two iridium(III)-based photosensitizers, Ir-Mito1 and Ir-Mito2, for photodynamic anticancer therapy. Ir-Mito2 could not only disrupt mitochondrial function but also elevate intracellular lipid peroxide levels, ultimately leading to the induction of apoptosis-ferroptosis cell death in bladder cancer. [Display omitted] •Mitochondrial metabolism influences the therapeutic effect of bladder cancer.•Two mitochondria-targeted Ir(III) complexes utilizing type I and II PDT were synthesized.•Ir-Mito2 targeted mitochondria to accumulate ROS and LPO and decrease ΔΨm.•The first Ir-based PS induced hybrid ferroptosis-apoptosis to treat bladder cancer. Bladder cancer (BC) is one of the most common malignant tumors of the urinary system, and has a high recurrence rate and treatment resistance. Recent results indicate that mitochondrial metabolism influences the therapeutic outcomes of BC. Mitochondria-targeted photosensitizer (PS) is a promising anticancer therapeutic approach that may overcome the limitations of conventional BC treatments. Herein, two mitochondria-targeted iridium(III) PSs, Ir-Mito1 and Ir-Mito2, have been designed for BC treatment. Mechanically, Ir-Mito2 induced a decrease in mitochondrial membrane potential via white light activation, further triggering a reduction of the B-cell lymphoma 2 protein (Bcl-2)/Bcl-associated X protein (Bax) ratio and increment of cleaved caspase3. Meanwhile, the reduction of glutathione, deactivation of glutathione peroxidase 4 (GPX4), increase of acyl-CoA synthetase long chain family member 4 (ACSL4), and accumulation of lipid peroxide resulted in synergistically activating of ferroptosis and apoptosis. The results demonstrated that Ir-Mito2 exhibited excellent antitumor efficacy with superior biosafety in vivo. This work on light-activated and mitochondrial-targeted PS provides an innovative therapeutic platform for BC.
ISSN:0021-9797
1095-7103
1095-7103
DOI:10.1016/j.jcis.2024.12.073