Redox Dyshomeostasis Strategy for Hypoxic Tumor Therapy Based on DNAzyme‐Loaded Electrophilic ZIFs

Abstract

Redox homeostasis is one of the main reasons for reactive oxygen species (ROS) tolerance in hypoxic tumors, limiting ROS‐mediated tumor therapy. Proposed herein is a redox dyshomeostasis (RDH) strategy based on a nanoplatform, FeCysPW@ZIF‐82@CAT Dz, to disrupt redox homeostasis, and its application to improve ROS‐mediated hypoxic tumor therapy. Once endocytosed by tumor cells, the catalase DNAzyme (CAT Dz) loaded zeolitic imidazole framework‐82 (ZIF‐82@CAT Dz) shell can be degraded into Zn2+ as cofactors for CAT Dz mediated CAT silencing and electrophilic ligands for glutathione (GSH) depletion under hypoxia, both of which lead to intracellular RDH and H2O2 accumulation. These “disordered” cells show reduced resistance to ROS and are effectively killed by ferrous cysteine‐phosphotungstate (FeCysPW) induced chemodynamic therapy (CDT). In vitro and in vivo data demonstrate that the pH/hypoxia/H2O2 triple stimuli responsive nanocomposite can efficiently kill hypoxic tumors. Overall, the RDH strategy provides a new way of thinking about ROS‐mediated treatment of hypoxic tumors.

Recent Advances in Nanomaterial‐Based Nanoplatforms for Chemodynamic Cancer Therapy

“…As a new type of immobilization nanoplatform for biomacromolecule (such as enzyme, nucleic acid, and antibody), biomolecules-MOFs composites have also been developed to catalyze Fenton reaction. [58] For instance, Bu et al designed a nanoplatform FeCysPW@ ZIF-82@CAT Dz (Figure 4b), [59] which can be used to disrupt the redox homeostasis for improving the treatment of ROSmediated hypoxic tumors. Once endocytosed by tumor cells, the nanoplatform, zeolitic imidazole framework-82 (ZIF-82) can be degraded into Zn 2+ and electrophilic ligands (2-nitroimidazole and 1H-imidazole-4-carbonitrile).…”

“…Reproduced with permission. [ 59 ] Copyright 2019, Wiley‐VCH. c) Illustration of preparation of CFAP.…”

“…b) Schematic illustration of the design of FeCysPW@ZIF-82@CAT Dz. Reproduced with permission [59]. Copyright 2019, Wiley-VCH.…”

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

“…Excessive H 2 O 2 is specifically catalyzed to generate H 2 O and O 2 . [ 10 ] ii) In powerful ROS scavenging system, abnormal proliferation behaviors and the exuberant cellular respiration of cancer cells result in the increase of ROS level. [ 11 ] To balance such oxidative stress, glutathione (GSH), a typical intracellular biochemical reducing agent, [ 12 ] is upregulated (≈10 × 10 −3 m ) to prevent cellular redox disorder, resulting in the stronger tolerance of cancer cells to various ROS treatments.…”

“…[ 11 ] To balance such oxidative stress, glutathione (GSH), a typical intracellular biochemical reducing agent, [ 12 ] is upregulated (≈10 × 10 −3 m ) to prevent cellular redox disorder, resulting in the stronger tolerance of cancer cells to various ROS treatments. [ 10 ] Therefore, we envision that maintaining intracellular catalysts (free iron) and reactants (H 2 O 2 ) at high levels while decreasing the content of ROS scavengers (GSH) can bring more enduring and effective CDT.…”