A nanoreactor boosts chemodynamic therapy and ferroptosis for synergistic cancer therapy using molecular amplifier dihydroartemisinin

Abstract

Background Chemodynamic therapy (CDT) relying on intracellular iron ions and H2O2 is a promising therapeutic strategy due to its tumor selectivity, which is limited by the not enough metal ions or H2O2 supply of tumor microenvironment. Herein, we presented an efficient CDT strategy based on Chinese herbal monomer-dihydroartemisinin (DHA) as a substitute for the H2O2 and recruiter of iron ions to amplify greatly the reactive oxygen species (ROS) generation for synergetic CDT-ferroptosis therapy. Results The DHA@MIL-101 nanoreactor was prepared and characterized firstly. This nanoreactor degraded under the acid tumor microenvironment, thereby releasing DHA and iron ions. Subsequent experiments demonstrated DHA@MIL-101 significantly increased intracellular iron ions through collapsed nanoreactor and recruitment effect of DHA, further generating ROS thereupon. Meanwhile, ROS production introduced ferroptosis by depleting glutathione (GSH), inactivating glutathione peroxidase 4 (GPX4), leading to lipid peroxide (LPO) accumulation. Furthermore, DHA also acted as an efficient ferroptosis molecular amplifier by direct inhibiting GPX4. The resulting ROS and LPO caused DNA and mitochondria damage to induce apoptosis of malignant cells. Finally, in vivo outcomes evidenced that DHA@MIL-101 nanoreactor exhibited prominent anti-cancer efficacy with minimal systemic toxicity. Conclusion In summary, DHA@MIL-101 nanoreactor boosts CDT and ferroptosis for synergistic cancer therapy by molecular amplifier DHA. This work provides a novel and effective approach for synergistic CDT-ferroptosis with Chinese herbal monomer-DHA and Nanomedicine. Graphical Abstract

Biotin-Functionalized Iridium-Based Nanoparticles as Tumor Targeted Photosensitizers for Enhanced Oxidative Damage in Tumor Photodynamic Therapy

“…The aforementioned findings suggested that Ir-PB NPs could effectively lead to the photoinduced depletion of NADPH and GSH and photoinduced production of a single oxygen ( 1 O 2 ). GSH depletion is known to result in the inactivation of GPX4 and the accumulation of intracellular LPO, thereby causing ferroptosis . The accumulation of LPO in A549 cells was evaluated by CLSM and flow cytometry using C11-BODIPY 581/591 as the fluorescent probe.…”

“…GSH depletion is known to result in the inactivation of GPX4 and the accumulation of intracellular LPO, thereby causing ferroptosis. 14 The accumulation of LPO in A549 cells was evaluated by CLSM and flow cytometry using C11-BODIPY 581/591 as the fluorescent probe. As depicted in Figure 4A, A549 cells treated with Ir-PB NPs exhibited significant green fluorescence under light irradiation, indicating extensive LPO accumulation in the cells.…”

Ignored role of polyphenol in boosting reactive oxygen species generation for polyphenol/chemodynamic combination therapy

“…Apparently, treatments of AVC and DMSN-AVC significantly down-regulated the protein expression of DDX3, ND2, ND5, CYTB, COX2, indicating the inhibition of mitochondrial translation and the damage to electron transport pathways that leaded to a high intra-mitochondrial ROS level [ 29 ]; in terms of the CDT strategy, DMSNAF showed slight impact on DDX3 and ETC complexes, and consequent minor effects on the intra-mitochondrial ROS production, whereas it significantly promoted the upregulation of Bax/Bcl-2, Cytochrome C, and Caspase-3. This indicated the production of extra-mitochondrial ROS (in cytoplasm) by CDT also damaged the mitochondrial membrane permeability, and activated the cellular apoptosis via Caspase-3 pathway [ 48 ]. Taken AVC and DMSNAF together, DMSNAF-AVC-FA group exhibited the lowest protein level of DDX3, the subunits of ETC complexes (ND2, ND5, CYTB, COX2), and the highest level of Bax/Bcl-2, Cytochrome C, and Caspase-3.…”

Multifunctional metal-organic framework (MOF)-based nanoplatforms for cancer therapy: from single to combination therapy

“…(D) The synthesis of DHA@MIL-101 and its mechanism in CDT against tumor. Adapted with permission from 53 . Copyright 2022, Springer Nature.…”

“…Recently, Li, Wen, and coworkers proposed a peroxidase-like nanoreactor based on MIL-101, i.e., DHA@MIL-101, for Lewis lung cancer therapy by an efficient CDT method ( Figure 3 D ) 53 . Chinese herbal monomer-dihydroartemisinin (DHA), a sesquiterpene lactone compound extracted from Artemisia annua, was embedded in the pores of MIL-101 constructed from Fe 3+ and NH 2 -BDC ligands to form DHA@MIL-101 equipped with improved water solubility and biocompatibility, reaching the loading capacity efficiency of 20 wt% for DHA.…”