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 |
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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.
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•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. |
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ISSN: | 0021-9797 1095-7103 1095-7103 |
DOI: | 10.1016/j.jcis.2024.12.073 |