Fe3O4‐Incorporated Metal‐Organic Framework for Chemo/Ferroptosis Synergistic Anti‐Tumor via the Enhanced Chemodynamic Therapy

• Published in: Advanced healthcare materials 2024-06, Vol.13 (14), p.e2303839-n/a
• Main Authors: Xu, Yuliang, Wang, Sihan, Xiong, Jincheng, Zheng, Pimiao, Zhang, Huixia, Chen, Shiqi, Ma, Qiang, Shen, Jianzhong, Velkov, Tony, Dai, Chongshan, Jiang, Haiyang
• Format: Article
• Language: English
• Subjects: Biocompatibility; Cancer; Cancer therapies; Carboxymethyl cellulose; Carboxymethylcellulose; Cellulose; chemodynamic therapy; Doxorubicin; Drug delivery; Electrostatic properties; Ferroptosis; Free radicals; Glutathione; Glutathione peroxidase; Hydroxyl radicals; In vivo methods and tests; Iron oxides; JNK protein; Kinases; Lysosomes; Metal-organic frameworks; metal‐organic framework; Nanomaterials; Nanoparticles; Nanotechnology; Peroxidase; Signal transduction; Therapy; Toxicity; Tumors; Zeolites
• ISSN: 2192-2640; 2192-2659; 2192-2659
• DOI: 10.1002/adhm.202303839

Metal‐organic framework (MOF)‐based drug delivery nanomaterials for cancer therapy have attracted increasing attention in recent years. Here, an enhanced chemodynamic anti‐tumor therapy strategy by promoting the Fenton reaction by using core‐shell zeolitic imidazolate framework‐8 (ZIF‐8)@Fe3O4 as a therapeutic platform is proposed. Carboxymethyl cellulose (CMC) is used as a stabilizer of Fe3O4, which is then decorated on the surface of ZIF‐8 via the electrostatic interaction and serves as an efficient Fenton reaction trigger. Meanwhile, the pH‐responsive ZIF‐8 scaffold acts as a container to encapsulate the chemotherapeutic drug doxorubicin (DOX). The obtained DOX‐ZIF‐8@Fe3O4/CMC (DZFC) nanoparticles concomitantly accelerate DOX release and generate more hydroxyl radicals by targeting the lysosomes in cancer cells. In vitro and in vivo studies verify that the DZFC nanoparticles trigger glutathione peroxidase 4 (GPX4)‐dependent ferroptosis via the activation of the c‐Jun N‐terminal kinases (JNK) signaling pathway, following to achieve the chemo/ferroptosis synergistic anti‐tumor efficacy. No marked toxic effects are detected during DZFC treatment in a tumor‐bearing mouse model. This composite nanoparticle remarkably suppresses the tumor growth with minimized systemic toxicity, opening new horizons for the next generation of theragnostic nanomedicines. Schematic illustration of doxorubicin (DOX)‐ZIF‐8@Fe3O4/carboxymethyl cellulose (DZFC) nanoparticles for enhanced cancer therapy. DZFC nanoparticles entered lysosomes via the clathrin‐mediated endocytosis pathway, which promoted the Fenton reaction and accelerated the release of DOX. Subsequently, DZFC nanoparticles induced lysosomal membrane permeability (LMP), mitochondrial membrane potential (MMP) decline and lipid peroxidation (LPO), finally triggering glutathione peroxidase 4 (GPX4)‐dependent ferroptosis.