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Redox Dyshomeostasis Strategy for Hypoxic Tumor Therapy Based on DNAzyme-Loaded Electrophilic ZIFs
Yanli Li1, Peiran Zhao1, Teng Gong1,2
1Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, P. R. China.
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 H2 O2 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/H2 O2 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.
Insights
This study introduces a redox dyshomeostasis (RDH) strategy using a nanoplatform to disrupt tumor cell redox balance. This approach enhances reactive oxygen species (ROS) therapy effectiveness in hypoxic tumors.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Tumor cells exhibit tolerance to reactive oxygen species (ROS) due to maintained redox homeostasis, hindering ROS-mediated therapies.
- Hypoxic microenvironments within tumors exacerbate ROS tolerance, presenting a significant challenge for effective cancer treatment.
Purpose of the Study:
- To develop a novel nanoplatform-based strategy for inducing redox dyshomeostasis (RDH) in hypoxic tumor cells.
- To enhance the efficacy of ROS-mediated tumor therapy by disrupting the tumor's redox balance.
Main Methods:
- A nanoplatform, FeCysPW@ZIF-82@CAT Dz, was designed to deliver catalase DNAzyme (CAT Dz) into tumor cells.
- The nanoplatform triggers intracellular RDH via Zn2+-mediated CAT silencing and glutathione (GSH) depletion under hypoxia.
- Ferrous cysteine-phosphotungstate (FeCysPW) was utilized for chemodynamic therapy (CDT) on the compromised tumor cells.
Main Results:
- The nanoplatform effectively induced RDH and H2O2 accumulation within tumor cells under hypoxic conditions.
- The compromised tumor cells exhibited reduced resistance to ROS, leading to enhanced cell death.
- In vitro and in vivo studies confirmed the triple stimuli-responsive nanocomposite's efficacy in killing hypoxic tumors.
Conclusions:
- The proposed RDH strategy effectively disrupts tumor redox homeostasis, making hypoxic tumors more susceptible to ROS-mediated therapies.
- This approach offers a promising new paradigm for improving the treatment outcomes of ROS-mediated therapies in hypoxic tumors.
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