Photo-Activated Oxidative Stress Amplifier: A Strategy for Targeting Glutathione Metabolism and Enhancing
Li Zhao1, Yao Tong2, Jiawei Yin2
1Liquid-Solid Structural Evolution & Processing of Materials (Ministry of Education), School of Materials Science and Engineering, Shandong University, Jinan, Shandong, 250061, China.
Abstract:
Amplifying oxidative stress within tumor cells can effectively inhibit the growth and metastasis of triple-negative breast cancer (TNBC). Therefore, the development of innovative nanomedicines that can effectively disrupt the redox balance represents a promising yet challenging therapeutic strategy for TNBC. In this study, an oxidative stress amplifier, denoted as PBCH, comprising PdAg mesoporous nanozyme and a CaP mineralized layer, loaded with GSH inhibitor L-buthionine sulfoximine (BSO), and further surface-modified with hyaluronic acid that can target CD44, is introduced. In the acidic tumor microenvironment, Ca2+ is initially released, thereby leading to mitochondrial dysfunction and eventually triggering apoptosis. Additionally, BSO suppresses the synthesis of intracellular reduced GSH and further amplifies the level of oxidative stress in cancer cells. Furthermore, PdAg nanozyme can be activated by near-infrared light to induce photothermal and photodynamic effects, causing a burst of ROS and simultaneously promoting cell apoptosis via provoking immunogenic cell death. The high-performance therapeutic effects of PBCH, based on the synergistic effect of aforementioned multiple oxidative damage and photothermal ablation, are validated in TNBC cells and animal models, declaring its potential as a safe and effective anti-tumor agent. The proposed approach offers new perspectives for precise and efficient treatment of TNBC.
Insights
This study introduces PBCH, a novel nanomedicine that amplifies oxidative stress to treat triple-negative breast cancer (TNBC). PBCH effectively inhibits tumor growth and metastasis by disrupting cellular redox balance.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Triple-negative breast cancer (TNBC) is aggressive, necessitating novel therapeutic strategies.
- Disrupting the redox balance via oxidative stress amplification shows promise for TNBC treatment.
- Developing targeted nanomedicines is crucial for effective TNBC therapy.
Purpose of the Study:
- To develop and evaluate PBCH, a novel nanomedicine designed to amplify oxidative stress for TNBC treatment.
- To investigate the synergistic therapeutic effects of PBCH's components, including a PdAg nanozyme, CaP layer, GSH inhibitor, and CD44 targeting.
- To assess the potential of PBCH as a safe and effective anti-tumor agent for TNBC.
Main Methods:
- PBCH nanomedicine synthesized with PdAg nanozyme, CaP mineralized layer, L-buthionine sulfoximine (BSO), and hyaluronic acid.
- Evaluation of PBCH's mechanism in acidic tumor microenvironment, including Ca2+ release, mitochondrial dysfunction, and apoptosis induction.
- Assessment of BSO's role in inhibiting reduced glutathione (GSH) synthesis and amplifying oxidative stress.
- Activation of PdAg nanozyme by near-infrared light for photothermal and photodynamic effects, inducing reactive oxygen species (ROS) and immunogenic cell death.
- In vitro and in vivo validation of PBCH's therapeutic efficacy in TNBC cells and animal models.
Main Results:
- PBCH effectively triggers apoptosis in TNBC cells through Ca2+ release and mitochondrial dysfunction.
- BSO significantly suppresses GSH synthesis, amplifying oxidative stress within cancer cells.
- Near-infrared light activation of PdAg nanozyme induces potent photothermal and photodynamic effects, generating ROS and promoting immunogenic cell death.
- PBCH demonstrates high-performance therapeutic effects due to the synergistic action of oxidative damage and photothermal ablation.
- Validated efficacy in TNBC cells and animal models, indicating significant anti-tumor activity.
Conclusions:
- PBCH is a potent nanomedicine that synergistically combines multiple oxidative damage mechanisms and photothermal ablation for effective TNBC treatment.
- The developed nanomedicine offers a promising strategy for precise and efficient treatment of triple-negative breast cancer.
- PBCH exhibits potential as a safe and effective anti-tumor agent, warranting further clinical investigation.
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