Intracellular Mutual Promotion of Redox Homeostasis Regulation and Iron Metabolism Disruption for Enduring Chemodynamic Therapy

Abstract

Intracellular redox homeostasis and the iron metabolism system in tumor cells are closely associated with the limited efficacy of chemodynamic therapy (CDT). Despite extensive attempts, maintaining high levels of intracellular catalysts (free iron) and reactants (H2O2) while decreasing the content of reactive oxygen species (ROS) scavengers (especially glutathione (GSH)) for enduring CDT still remains great challenges. Herein, SS bond‐rich dendritic mesoporous organic silica nanoparticles (DMON) are utilized as GSH‐depleting agents. After co‐loading Fe0 and a catalase inhibitor (3‐amino‐1,2,4‐triazole (AT)), a novel biodegradable nanocarrier is constructed as DMON@Fe0/AT. In the mildly acidic tumor microenvironment, on‐demand ferrous ions and AT are intelligently released. AT suppresses the activity of catalase for H2O2 hoarding, and the exposed DMON weakens ROS scavenging systems by persistently depleting intracellular GSH. The highly efficient •OH production by DMON@Fe0/AT can effectively attack mitochondria and downregulate the expression of ferroportin 1, which can disrupt the cellular iron metabolism system, leading to the desired retention of iron in the cytoplasm. More importantly, DMON@Fe0/AT exhibits a much more efficient CDT killing effect on 4T1 tumor cells than plain Fe0 nanoparticles, benefiting from their synergistic redox regulation and iron metabolism disruption. Overall, the as‐prepared intelligent, degradable DMON@Fe0/AT provides an innovative strategy for enduring CDT.

Chemodynamic Therapy via Fenton and Fenton‐Like Nanomaterials: Strategies and Recent Advances

“…designed disulfide bond (SS)‐rich dendritic mesoporous organic silica NPs (DMON) loaded with 3‐amino‐1,2,4‐triazole (AT) and iron (Fe 0 ) dots (termed DMON@Fe 0 /AT). [ 47 ] These NPs entered cancer cells by endocytosis, and the mildly acidic environment triggered the release of Fe 2+ and AT. Fe 2+ reacted with intracellular H 2 O 2 to produce •OH for CDT.…”

Nanocatalyst‐Mediated Chemodynamic Tumor Therapy

“…[1][2][3] Owing to the rapid development of biology, chemistry, physics, and materials science, various therapeutic agents and strategies are proposed for the treatment of tumor. [4][5][6][7] In particular, nanomaterials have shown great potentials for tumor treatment due to the great potentials in improving therapeutic efficiencies and minimizing side effects, [8,9] which are widely applied in various antitumor modalities, including chemotherapy, [10,11] radiotherapy, [12,13] thermal ablation therapy, [14,15] reactive oxygen species (ROS)-based therapy, [16][17][18][19] and immunotherapy. [20,21] Among these, ROS-based treatments have attracted extensive attention because of the reduced drug resistance and strong oxidative lethality of ROS to cells and even to DOI: 10.1002/adhm.202101971 specific subcellular organelles.…”

“…[18,43,44] For in vivo application, the limited efficiency of Fenton or Fenton-like reaction is a major challenge restricting the in vivo application of CDT. [19,45] Elements in CDT like H 2 O 2 , catalysts and TME are all determining factors in terms of reaction efficiency for •OH generation. Any defects in this reaction related to these elements can cause a severe reduction of efficiency.…”

Enhanced porphyrin-based fluorescence imaging-guided photodynamic/photothermal synergistic cancer therapy by mitochondrial targeting

“…However, the challenge is to enhance the efficacy of phototherapy [9][10][11][12], considering that the produced ROS exhibits a short half-life (<40 ns) and diffusion range (0.1 µm) in the phototherapy procedure [13][14][15]. It could be a great and promising choice for the comprehensive utilization of the generated cytotoxic substances (e.g., substantial ROS and hyperthermia) to antitumor.…”