Ferrocene conjugated glutathione consumption for enhanced ferroptosis therapy and chemotherapy
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)Graphical Abstract
Abstract
As the backbone of tumor therapy, chemotherapy is prone to tumor resistance due to its apoptotic pathway. Ferroptosis, as an effective form of non-apoptotic cell death, can overcome chemotherapy apoptosis-induced resistance. Therefore, the combination of chemotherapy and ferroptosis is a highly promising tumor treatment strategy. However, high glutathione (GSH) and insufficient intracellular iron content in the tumor environment limit the efficiency of ferroptosis-mediated anticancer. Not only that, simultaneous intracellular delivery of iron sources, ferroptosis inducers, and chemotherapeutic agents remains a major challenge. Here, we constructed a self-assembled nano prodrug system to co-deliver iron sources, ferroptosis inducers, and anti-cancer drugs for combined ferroptosis and chemotherapy. In the tumor microenvironment, high levels of GSH triggered redox-responsive disulfide bonding, which induced the disassembly of this nano prodrug system (PFSH@HCPT), releasing hydroxycamptothecin (HCPT), honokiol (HNK) and ferrocene (Fc). HCPT induced cell death via apoptosis and Fc triggered the Fenton reaction, which induced ferroptosis. HNK inhibited the activity of glutathione peroxidase 4 (GPX4) to enhance ferroptosis, and on the other hand, it further induced cell death via apoptosis. Meanwhile, the combined strategy of HNK-mediated resistance and ferroptosis-induced resistance mechanism further overcame the resistance of HCPT and significantly improved the therapeutic efficacy. This nano prodrug system realized the “multi-machine integrated” therapeutic efficacy and showed great therapeutic potential, which may open up a new way for effective cancer treatment.
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References
Tan, H. X.; Shen, Z. Q.; Wang, X. H.; Shu, S. C.; Deng, J.; Lu, L.; Fan, Z. Y.; Hu, D. N.; Cheng, P.; Cao, X. et al. Endoplasmic reticulum-targeted biomimetic nanoparticles induce apoptosis and ferroptosis by regulating endoplasmic reticulum function in colon cancer. J. Control. Release 2024, 375, 422–437.
Wang, X.; Shao, G.; Hong, X. Y.; Shi, Y.; Zheng, Y. T.; Yu, Y. C.; Fu, C. Y. Targeting annexin A1 as a druggable player to enhance the anti-tumor role of honokiol in colon cancer through autophagic pathway. Pharmaceuticals 2023, 16, 70.
Zhang, Z. T.; Ji, Y.; Hu, N.; Yu, Q. Q.; Zhang, X. R.; Li, J.; Wu, F. L.; Xu, H. E.; Tang, Q. Y.; Li, X. L. Ferroptosis-induced anticancer effect of resveratrol with a biomimetic Nano-delivery system in colorectal cancer treatment. Asian J. Pharm. Sci. 2022, 17, 751–766.
Akakuru, O. U.; Zhang, Z. J.; Iqbal, M. Z.; Zhu, C. J.; Zhang, Y. W.; Wu, A. G. Chemotherapeutic nanomaterials in tumor boundary delineation: Prospects for effective tumor treatment. Acta Pharm. Sin. B 2022, 12, 2640–2657.
Jin, H. J.; Wang, L. Q.; Bernards, R. Rational combinations of targeted cancer therapies: Background, advances and challenges. Nat. Rev. Drug Discov. 2023, 22, 213–234.
Davodabadi, F.; Sajjadi, S. F.; Sarhadi, M.; Mirghasemi, S.; Nadali Hezaveh, M.; Khosravi, S.; Kamali Andani, M.; Cordani, M.; Basiri, M.; Ghavami, S. Cancer chemotherapy resistance: Mechanisms and recent breakthrough in targeted drug delivery. Eur. J. Pharmacol. 2023, 958, 176013.
Pang, L.; Feng, H. H.; Zhong, W.; Dong, H. N.; Shen, Y. Q.; Yu, B.; Cong, H. L. Design of crown ether based micelles and their anti-tumor properties by perturbing potassium ion homeostasis. Mater. Des. 2021, 211, 110159.
Zhang, C.; Liu, X. Y.; Jin, S. D.; Chen, Y.; Guo, R. H. Ferroptosis in cancer therapy: A novel approach to reversing drug resistance. Mol. Cancer 2022, 21, 47.
Hangauer, M. J.; Viswanathan, V. S.; Ryan, M. J.; Bole, D.; Eaton, J. K.; Matov, A.; Galeas, J.; Dhruv, H. D.; Berens, M. E.; Schreiber, S. L. et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 2017, 551, 247–250.
Chen, Y.; Yao, Z.; Liu, P. L.; Hu, Q. D.; Huang, Y.; Ping, L.; Zhang, F.; Tang, H. L.; Wan, T.; Ping, Y. et al. A self-assembly nano-prodrug for triple-negative breast cancer combined treatment by ferroptosis therapy and chemotherapy. Acta Biomater. 2023, 159, 275–288.
Viswanathan, V. S.; Ryan, M. J.; Dhruv, H. D.; Gill, S.; Eichhoff, O. M.; Seashore-Ludlow, B.; Kaffenberger, S. D.; Eaton, J. K.; Shimada, K.; Aguirre, A. J. et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 2017, 547, 453–457.
Yang, J.; Ma, S. Y.; Xu, R.; Wei, Y. W.; Zhang, J.; Zuo, T. T.; Wang, Z. H.; Deng, H. Z.; Yang, N.; Shen, Q. Smart biomimetic metal organic frameworks based on ROS-ferroptosis-glycolysis regulation for enhanced tumor chemo-immunotherapy. J. Control. Release 2021, 334, 21–33.
Xu, R.; Yang, J.; Qian, Y.; Deng, H. Z.; Wang, Z. H.; Ma, S. Y.; Wei, Y. W.; Yang, N.; Shen, Q. Ferroptosis/pyroptosis dual-inductive combinational anti-cancer therapy achieved by transferrin decorated nanoMOF. Nanoscale Horiz. 2021, 6, 348–356.
Li, J. S.; Zong, Q. Y.; Liu, Y.; Xiao, X.; Zhou, J. L.; Zhao, Z. Y.; Yuan, Y. Y. Self-catalyzed tumor ferroptosis based on ferrocene conjugated reactive oxygen species generation and a responsive polymer. Chem. Commun. 2022, 58, 3294–3297.
Gao, M.; Deng, J.; Liu, F.; Fan, A. P.; Wang, Y. J.; Wu, H. Y.; Ding, D.; Kong, D. L.; Wang, Z.; Peer, D. et al. Triggered ferroptotic polymer micelles for reversing multidrug resistance to chemotherapy. Biomaterials 2019, 223, 119486.
Ren, Y. Q.; Mao, X. R.; Xu, H.; Dang, Q.; Weng, S. Y.; Zhang, Y. Y.; Chen, S.; Liu, S. T.; Ba, Y. H.; Zhou, Z. K. et al. Ferroptosis and EMT: Key targets for combating cancer progression and therapy resistance. Cell. Mol. Life Sci. 2023, 80, 263.
Luo, J. J.; Li, Y.; Li, Y. R.; Chen, X. F.; Du, P. Y.; Wang, Z.; Tian, A. X.; Zhao, Y. J. Reversing ferroptosis resistance in breast cancer via tailored lipid and iron presentation. ACS Nano 2023, 17, 25257–25268.
Hou, C. Y.; Yang, Y. M.; Wang, P. W.; Xie, H. M.; Jin, S. L.; Zhao, L. B.; Wu, G. H.; Xing, H.; Chen, H.; Liu, B. Y. et al. CCDC113 promotes colorectal cancer tumorigenesis and metastasis via TGF-β signaling pathway. Cell Death Dis. 2024, 15, 666.
Gong, J.; Lin, Y. Y.; Zhang, H. Q.; Liu, C. Q.; Cheng, Z.; Yang, X. W.; Zhang, J. M.; Xiao, Y. Y.; Sang, N.; Qian, X. Y. et al. Reprogramming of lipid metabolism in cancer-associated fibroblasts potentiates migration of colorectal cancer cells. Cell Death Dis. 2020, 11, 267.
Cai, M. R.; Fu, T. T.; Zhu, R. Y.; Hu, P. X.; Kong, J. H.; Liao, S. L.; Du, Y. J.; Zhang, Y. Q.; Qu, C. H.; Dong, X. et al. An iron-based metal-organic framework nanoplatform for enhanced ferroptosis and oridonin delivery as a comprehensive antitumor strategy. Acta Pharm. Sin. B 2024, 14, 4073–4086.
Luo, S. W.; Ma, D.; Wei, R. L.; Yao, W.; Pang, X. R.; Wang, Y.; Xu, X. D; Wei, X. H.; Guo, Y.; Jiang, X. Q. et al. A tumor microenvironment responsive nanoplatform with oxidative stress amplification for effective MRI-based visual tumor ferroptosis. Acta Biomater 2022, 138, 518–527.
Yang, Y. X.; Zuo, S. Y.; Li, L. X.; Kuang, X.; Li, J. B.; Sun, B. J.; Wang, S. J.; He, Z. G.; Sun, J. Iron-doxorubicin prodrug loaded liposome nanogenerator programs multimodal ferroptosis for efficient cancer therapy. Asian J. Pharm. Sci. 2021, 16, 784–793.
Liu, J. P.; Zhan, J. Z.; Zhang, Y.; Huang, L.; Yang, J.; Feng, J.; Ding, L. W.; Shen, Z. Y.; Chen, X. Y. Ultrathin clay nanoparticles-mediated mutual reinforcement of ferroptosis and cancer immunotherapy. Adv. Mater. 2024, 36, e2309562.
Han, Y. K.; Dong, Z. L.; Wang, C. J.; Li, Q. G.; Hao, Y.; Yang, Z. J.; Zhu, W. J.; Zhang, Y. Y.; Liu, Z.; Feng, L. Z. Ferrous ions doped calcium carbonate nanoparticles potentiate chemotherapy by inducing ferroptosis. J. Control. Release 2022, 348, 346–356.
Zhang, Y. R.; Song, Q. C.; Zhang, Y. Y.; Xiao, J. H.; Deng, X. T.; Xing, X.; Hu, H. Z.; Zhang, Y. Z. Iron-based nanovehicle delivering fin56 for hyperthermia-boosted ferroptosis therapy against osteosarcoma. Int. J. Nanomedicine 2024, 19, 91–107.
Xin, H.; Yuan, P. J.; Wang, Y. J.; Xiao, J. M.; Tian, G.; Fan, Y.; Zhang, G. L.; Liu, L. Highly selective and effective ferroptosis liposomal nanodrugs for synergistic antitumor therapy. Chem. Eng. J. 2024, 493, 152480.
Huang, Y.; Lin, Y.; Li, B. W.; Zhang, F.; Zhan, C. Y.; Xie, X.; Yao, Z.; Wu, C. Z.; Ping, Y.; Shen, J. L. Combination therapy to overcome ferroptosis resistance by biomimetic self-assembly Nano-prodrug. Asian J. Pharm. Sci. 2023, 18, 100844.
Wang, W. J.; Ling, Y. Y.; Zhong, Y. M.; Li, Z. Y.; Tan, C. P.; Mao, Z. W. Ferroptosis-enhanced cancer immunity by a ferrocene-appended iridium(III) diphosphine complex. Angew. Chem., Int. Ed. 2022, 61, e202115247.
Gao, Y. C.; Zhang, H. C.; Tang, L.; Li, F. F.; Yang, L.; Xiao, H. H.; Karges, J.; Huang, W. H.; Zhang, W.; Liu, C. Y. Cancer nanobombs delivering artoxplatin with a polyigniter bearing hydrophobic ferrocene units upregulate PD-L1 expression and stimulate stronger anticancer immunity. Adv. Sci. 2024, 11, e2300806.
Guo, C.; Liu, P.; Deng, G. L.; Han, Y.; Chen, Y. H.; Cai, C. J.; Shen, H.; Deng, G. P.; Zeng, S. Honokiol induces ferroptosis in colon cancer cells by regulating GPX4 activity. Am. J. Cancer Res. 2021, 11, 3039–3054.
Wang, Z. Q.; Li, X. R.; Wang, D. S.; Zou, Y.; Qu, X. Y.; He, C. Y.; Deng, Y. Q.; Jin, Y.; Zhou, Y. H.; Zhou, Y. X. et al. Concurrently suppressing multidrug resistance and metastasis of breast cancer by co-delivery of paclitaxel and honokiol with pH-sensitive polymeric micelles. Acta Biomater. 2017, 62, 144–156.
Xu, D.; Lu, Q. H.; Hu, X. Down-regulation of P-glycoprotein expression in MDR breast cancer cell MCF-7/ADR by honokiol. Cancer Lett. 2006, 243, 274–280.
Dai, S. Y.; Qin, W. X.; Yu, S.; Li, C.; Yang, Y. H.; Pei, Y. H. Honokiol and magnolol: A review of structure-activity relationships of their derivatives. Phytochemistry 2024, 223, 114132.
Le, D. T. T.; Nguyen, N. H.; Do, H. T. M.; Vu, C. M.; Nguyen, P. T. M.; Chu, H. H. Honokiol-loaded PLGA-PEG nanoparticles with solubility in water for infusion treatment of solid cancer. J. Drug Deliv. Sci. Technol. 2025, 103, 106436.
Yang, B.; Gao, J.; Pei, Q.; Xu, H. X.; Yu, H. J. Engineering prodrug nanomedicine for cancer immunotherapy. Adv. Sci. 2020, 7, 2002365.
Zhou, S.; Zhong, Q.; Wang, Y.; Hu, P.; Zhong, W.; Huang, C. B.; Yu, Z. Q.; Ding, C. D.; Liu, H. X.; Fu, J. J. Chemically engineered mesoporous silica nanoparticles-based intelligent delivery systems for theranostic applications in multiple cancerous/non-cancerous diseases. Coord. Chem. Rev. 2022, 452, 214309.
Li, Y. R.; Feng, S. M.; Dai, P. P.; Liu, F.; Shang, Y. Q.; Yang, Q.; Qin, J.; Yuchi, Z.; Wang, Z.; Zhao, Y. J. Tailored Trojan horse nanocarriers for enhanced redox-responsive drug delivery. J. Control. Release 2022, 342, 201–209.
Yao, W. H.; Liu, C. Y.; Wang, N.; Zhou, H. J.; Chen, H. L.; Qiao, W. H. An MRI-guided targeting dual-responsive drug delivery system for liver cancer therapy. J. Colloid Interface Sci. 2021, 603, 783–798.
Cheng, R.; Meng, F. H.; Deng, C.; Zhong, Z. Y. Bioresponsive polymeric nanotherapeutics for targeted cancer chemotherapy. Nano Today 2015, 10, 656–670.
Chen, J. J.; Song, Y. R.; Yang, W. Q.; Guo, J. H.; Zhang, S. H.; Wan, D.; Liu, Y. H.; Pan, J. Enzyme and reduction dual-responsive peptide micelles as nanocarriers for smart drug delivery. ACS Appl. Nano Mater. 2023, 6, 16179–16188.
Li, B. L.; Teng, J. K.; Chen, S.; Yang, J. M.; Liu, X. Q.; Zhang, J.; Zhao, Y. A dual‐stimuli responsive supramolecular nanovector anchoring folic acid ligands for targeted delivery of anti‐colorectal drug hydroxycamptothecin. J. Appl. Polym. Sci. 2023, 140, e53525.
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