Multi-Enzyme Cascade-Triggered Nitric Oxide Release Nanoplatform Combined with Chemo Starvation-like Therapy for
Ge Li1, Xinyue Lu1, Shixin Zhang1
1Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China.
Abstract:
Tumor drug resistance has long been a major challenge in medical oncology. Ferroptosis is a form of regulated cell death with promising clinical applications. However, the efficacy of ferroptosis-inducing agents is often limited by endogenous factors when used alone, and thus, synergistic therapy offers a promising strategy to address this issue. In this study, we developed an iron-doped metal-organic framework (MOF), Fe/ZIF-8, loaded with glucose oxidase (Gox), l-arginine (l-arg), and adriamycin hydrochloride (Dox). The folic acid (FA)-targeted ZIF-8 (GLDFe/Z-FA) prepared was shown to be a multifunctional nanoparticle based on endogenous hydrogen peroxide (H2O2) and glucose, which trigger adaptive cellular responses in cancer cells. The intracellular glucose level and adenosine-triphosphate (ATP) content decreased, indicating that GLDFe/Z-FA reduced the glucose metabolic rate and induced tumor starvation. And the generated •OH and H2O2 induced reactive oxygen species (ROS) overload to implement chemodynamic therapy (CDT). ROS catalyzed l-arg released from GLDFe/Z-FA to release nitric oxide (NO), which inhibited P-glycoprotein expression, prevented Dox efflux, and accumulated intracellular content of Dox to enhance cytotoxicity. GLDFe/Z-FA also catalyzed glutathione degradation, which further disrupted intracellular redox homeostasis, enhanced CDT, and induced cell death. It was shown to follow the ferroptosis pathway and strongly inhibited tumor proliferation both in vitro and in vivo. These findings demonstrate that GLDFe/Z-FA effectively inhibits tumor proliferation, highlighting its potential as a viable therapeutic approach to suppress cancer progression.
Insights
This study introduces GLDFe/Z-FA, a novel nanoparticle that combats tumor drug resistance by inducing ferroptosis and starvation. It enhances chemotherapy efficacy by preventing drug efflux and promoting cancer cell death both in vitro and in vivo.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Tumor drug resistance remains a significant challenge in cancer treatment.
- Ferroptosis, a regulated cell death pathway, shows therapeutic promise but faces limitations with single-agent efficacy.
- Synergistic therapeutic strategies are crucial for overcoming treatment resistance.
Purpose of the Study:
- To develop a multifunctional nanoparticle (GLDFe/Z-FA) for synergistic cancer therapy.
- To investigate the nanoparticle's ability to induce ferroptosis, tumor starvation, and enhance chemotherapy.
- To evaluate the therapeutic efficacy of GLDFe/Z-FA against tumors in vitro and in vivo.
Main Methods:
- Fabrication of folic acid-targeted, iron-doped ZIF-8 nanoparticles (GLDFe/Z-FA) loaded with glucose oxidase, l-arginine, and doxorubicin.
- Assessment of nanoparticle-induced changes in intracellular glucose, ATP, reactive oxygen species (ROS), and nitric oxide (NO) levels.
- Evaluation of ferroptosis pathway induction, P-glycoprotein inhibition, doxorubicin accumulation, and anti-tumor effects.
Main Results:
- GLDFe/Z-FA nanoparticles effectively reduced intracellular glucose and ATP, inducing tumor starvation.
- The nanoparticles generated ROS and NO, leading to chemodynamic therapy (CDT) and overcoming drug resistance.
- GLDFe/Z-FA induced ferroptosis, inhibited tumor proliferation significantly in vitro and in vivo, and enhanced doxorubicin's cytotoxicity.
Conclusions:
- GLDFe/Z-FA nanoparticles represent a promising multifunctional platform for synergistic cancer therapy.
- The nanoparticle effectively targets cancer cells, induces tumor starvation and ferroptosis, and overcomes drug resistance.
- GLDFe/Z-FA demonstrates significant potential for suppressing tumor progression and offers a viable therapeutic strategy.
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