Ferroptosis Photoinduced by New Cyclometalated Iridium(III) Complexes and Its Synergism with Apoptosis in Tumor Cell Inhibition

Yuan, Hao; Han, Zhong; Chen, Yuncong; Qi, Fen; Fang, Hongbao; Guo, Zijian; Zhang, Shuren; He, Weijiang

doi:10.1002/anie.202014959

Cited by 171 publications

(143 citation statements)

References 56 publications

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“…S5), indicating that this homologous targeting-based theranostic nanoplatform had superior advantages in inducing ferroptosis under NIR irradiation, and the inadequate ability of PLGA-IR780 NPs combined with NIR irradiation to induce ferroptosis may be due to the lack of mitochondrial dysfunction and PUFAs. Mitochondrial shrinkage is another important characteristic of the death phenotype in ferroptosis [ 42 , 43 ]. The TEM results also demonstrated that the morphology of mitochondria treated with targeted PDT became rounded, decreased in size, exhibited reduced or absent mitochondrial cristae, and exhibited structural damage, while mitochondria in the other five groups showed a normal physiological morphology (Fig.…”

Section: Resultsmentioning

confidence: 99%

Homologous targeting nanoparticles for enhanced PDT against osteosarcoma HOS cells and the related molecular mechanisms

et al. 2022

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Background No prominent advancements in osteosarcoma (OS) treatment have been made in the past 20 years. Although photodynamic therapy (PDT) is an emerging technique for cancer therapy, the lack of targeted photosensitizers for OS treatment severely limits its applications. Results In this study, we constructed a potential theranostic nanoplatform by using (poly (lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) encapsulating IR780 into the shell (PLGA-IR780 NPs), which were further camouflaged with human OS cell membranes from the HOS cell line (MH-PLGA-IR780 NPs). These constructed NPs showed the capacity for homologous targeting with excellent photoacoustic (PA)/fluorescence (FL) imaging ability. Benefitting from their homologous targeting capacity, MH-PLGA-IR780 NPs obviously promoted cell endocytosis in vitro and tumor accumulation in vivo, which could further improve PDT performance under near-infrared (NIR) irradiation. In addition, to their homologous targeting and PA/FL dual-mode imaging ability, MH-PLGA-IR780 NPs had advantages in penetrating deeper into tumor tissues and in real-time dynamic distribution monitoring in vivo, which laid a foundation for further clinical applications in OS. Moreover, we demonstrated that PDT guided by the constructed NPs could significantly induce HOS cells apoptosis and ferroptosis via excessive accumulation of reactive oxygen species (ROS), and further determined that the potential anticancer molecular mechanism of apoptosis was triggered by the release of cytochrome c-activated mitochondrial apoptosis (endogenous apoptosis), and that ferroptosis caused the activation of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and the inactivation of glutathione peroxidase 4 (GPX4), synergistically leading to excessive accumulation of Lipid-ROS and Lipid peroxides (LPOs). Concurrently, MH-PLGA-IR780 NPs-guided PDT also showed an obvious inhibitory effect on tumor growth in vivo. Conclusion These results suggest that this homologous targeting-based theranostic nanoplatform provides an effective method to improve PDT performance in OS and contributes a new and promising approach for OS therapy. Graphical Abstract

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Section: Resultsmentioning

confidence: 99%

Homologous targeting nanoparticles for enhanced PDT against osteosarcoma HOS cells and the related molecular mechanisms

et al. 2022

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“…Moreover, quantitative analysis via FC illustrated the same phenomenon (Figure 7O-R), indicating that this dual-targeting-based theranostic nanoplatform had superior advantages on inducing ferroptosis under NIR irradiation, and the inadequate ability of PEG-PLGA-IR780 NPs combined with NIR irradiation to induce ferroptosis may be due to the lack of mitochondrial targeting and PUFAs. Mitochondria shrinkage is another important character of death phenotype in ferroptosis [42,43]. The results of TEM also demonstrated that the morphology of mitochondria treated with targeted PDT became round, dwindled in size, reduced or disappeared mitochondrial cristae, and exhibited structural damage, while mitochondria in the other ve groups showed a normal physiological morphology (Figure 7S).…”

Section: Homologous and Mitochondrial Targeting Synergistically Induced Apoptosis And Ferroptosismentioning

confidence: 85%

Homologous and Mitochondrial Targeting Synergistic Induction of Apoptosis and Ferroptosis Enhanced PDT Performance Against Osteosarcoma HOS

Wang

Zhang

Zhao

et al. 2021

Preprint

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Background: There have been no prominent advancements in osteosarcoma (OS) treatment in the past 20 years. Although photodynamic therapy (PDT) is an emerging technique for cancer therapy, its lack of targeting in OS treatment severely limits its applications.Methods: In this study, we constructed a potential theranostic nanoplatform by using (poly (ethylene glycol) polylactic-co-Glycolic acid (PEG-PLGA) nanoparticles (NPs) wrapping IR780 into the core (PEG-PLGA-IR780 NPs), which was further camouflaged with human OS cell membranes from the HOS cell line (MH-PEG-PLGA-IR780 NPs) to show homologous and mitochondrial targeting capacities. In addition, the potential underlying anticancer mechanisms of MH-PEG-PLGA-IR780 NPs-mediated PDT was investigated.Results: We demonstrated that the MH-PEG-PLGA-IR780 NPs had excellent tumor/mitochondrial targeting with the help of homologous targeting to HOS cell line. Moreover, the excellent photoacoustic (PA)/fluorescence (FL) imaging ability of MH-PEG-PLGA-IR780 NPs laid a foundation for further applications. Under near-infrared (NIR) irradiation, we demonstrated that dual-targeting NPs-mediated PDT could significantly induce HOS cell apoptosis and ferroptosis, and further explored apoptosis was triggered by cytochrome c-activated mitochondrial apoptosis (endogenous apoptosis), and the specific molecular mechanisms of ferroptosis is the activation of NCOA4-mediated ferritinophagy and the passivation of GPX4 in vitro, synergistically leading to the excessive accumulation of ROS. In addition, MH-PEG-PLGA-IR780 NPs-induced PDT also showed an obvious inhibitory effect on tumor growth in vivo. Conclusion: These results suggest the dual-targeting-based theranostic nanoplatform provides an effective method to improve PDT performance in OS and paves a new and promising way for OS therapy.

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“…As mitochondrial changes are a characteristic manifestation of ferroptosis, we also investigated the membrane potential and morphological changes in the mitochondria of 4T1 tumor cells after various treatments. [50][51][52] Results of the JC-1 staining assay showed that the most severe mitochondrial depolarization occurred in the siMCT4-PAMAM-PEG-TK-Fc@DEM group, in which the mitochondrial membrane potential has become highly negative due to the enhanced proferroptosis capability of ferrocene under siMCT4-mediated acidification and DEM-mediated GSH depletion (Figure 2e). [53][54][55] According to the quantitative fluorescence analysis, the relative ratio of tumor cells undergone mitochondrial depolarization after different treatment increased from 24.2% in the control group to 76.4% in the siMCT4-PAMAM-PEG-TK-Fc-DEM group.…”

Section: Investigation On the Nanoassembly-enhanced Ferroptosis Therapy In Vitromentioning

confidence: 99%

An ROS‐Activatable Nanoassembly Remodulates Tumor Cell Metabolism for Enhanced Ferroptosis Therapy

Zhang

et al. 2021

Adv Healthcare Materials

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Ferroptosis is an emerging antitumor option and has demonstrated unique advantages against many tumor indications. However, its efficacy is potentially hindered by the endogenous lipid peroxide-scavenging mechanisms and the reliance on acidic pH. Herein, a nanointegrated strategy based on clinically-safe components to synergistically remodel glutathione and lactate metabolism in tumor cells for enhanced ferroptosis therapy is developed. First ferrocene is conjugated on PEGylated polyamidoamine dendrimers via reactive oxygen species (ROS)-cleavable thioketal linkage, which would further self-assemble with the glutathione (GSH)-depleting agent diethyl maleate (DEM) and monocarboxylate transporter 4-inhibiting siRNA (siMCT4) to afford biostable nanoassemblies (siMCT4-PAMAM-PEG-TK-Fc@DEM). The nanoassemblies can be activated by the elevated ROS levels in tumor intracellular environment and readily release the incorporated therapeutic contents, afterward DEM can directly conjugate to GSH to disrupt the glutathione peroxidase 4 (GPX4)-mediated antioxidant defense, while siMCT4 can block the MCT4-mediated efflux of lactic acid and acidify the intracellular milieu, both of which can improve the ferrocene-catalyzed lipid peroxidation and induce pronounced ferroptotic damage. The siMCT4-PAMAM-PEG-TK-Fc@DEM nanoplatform demonstrates high ferroptosis-based antitumor potency and good biocompatibility in vitro and in vivo, which may offer new avenues for the development of more advanced antitumor therapeutics with improved translatability.

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Ferroptosis Photoinduced by New Cyclometalated Iridium(III) Complexes and Its Synergism with Apoptosis in Tumor Cell Inhibition

Cited by 171 publications

References 56 publications

Homologous targeting nanoparticles for enhanced PDT against osteosarcoma HOS cells and the related molecular mechanisms

Homologous targeting nanoparticles for enhanced PDT against osteosarcoma HOS cells and the related molecular mechanisms

Homologous and Mitochondrial Targeting Synergistic Induction of Apoptosis and Ferroptosis Enhanced PDT Performance Against Osteosarcoma HOS

An ROS‐Activatable Nanoassembly Remodulates Tumor Cell Metabolism for Enhanced Ferroptosis Therapy

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