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Oxygen/Nitric Oxide Dual-Releasing Nanozyme for Augmenting TMZ-Mediated Apoptosis and Necrosis
Jun Ma1, Jingjing Qiu2, Gus A Wright3
1Department of Biomedical Engineering, Texas A&M University, College Station, Texas 77843, United States.
Abstract:
Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor, with a poor prognosis. Temozolomide (TMZ) represents the standard chemotherapy for GBM but has limited efficacy due to poor targeting and a hypoxic tumor microenvironment (TME). To address these challenges, we developed a dual-gas-releasing, cancer-cell-membrane-camouflaged nanoparticle to deliver TMZ. This nanoceria, camouflaged with a cancer cell membrane (CCM-CeO2), targets explicitly GBM cells and accumulates in lysosomes, triggering the rapid release of TMZ. Additionally, CCM-CeO2 could release oxygen (O2) and nitric oxide (NO) in response to the TME. Synthesized using d-arginine, catalytic nanoceria could decompose excessive hydrogen peroxide (H2O2) in the TME to produce O2, while d-arginine could nonenzymatically react with H2O2 to generate NO. CCM-CeO2 could penetrate GBM spheroids to a depth of 148.3 ± 31 μm, with the O2 and NO produced, reducing HIF-1α protein expression. When loaded with TMZ, CCM-CeO2 could increase the intracellular ROS produced by TMZ, leading to lysosome membrane permeabilization and notably augmented apoptosis and necrosis in GBM cells. An in vitro antitumor assay using spheroids showed that CCM-CeO2 reduced the IC50 value of TMZ from 174.5 to 42.6 μg/mL, likely due to the catalase-like activity of nanoceria. These results suggest that alleviating hypoxia and increasing ROS produced by chemotherapeutics could be an effective therapeutic strategy for treating GBM.
Insights
This study introduces a novel nanoparticle that delivers chemotherapy for glioblastoma. The nanoparticle releases oxygen and nitric oxide, enhancing treatment efficacy by targeting cancer cells and overcoming tumor hypoxia.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor outcomes.
- Standard chemotherapy (Temozolomide - TMZ) has limited efficacy due to poor targeting and tumor hypoxia.
- Hypoxia in the tumor microenvironment (TME) hinders chemotherapy effectiveness.
Purpose of the Study:
- To develop a dual-gas-releasing, cancer-cell-membrane-camouflaged nanoparticle for targeted TMZ delivery.
- To investigate the nanoparticle's ability to release oxygen (O2) and nitric oxide (NO) in the TME.
- To evaluate the combined therapeutic effect of TMZ delivery and gas release on GBM.
Main Methods:
- Developed cancer-cell-membrane-camouflaged nanoceria (CCM-CeO2) loaded with TMZ.
- Investigated O2 and NO release mechanisms in response to TME conditions (H2O2).
- Assessed nanoparticle penetration in GBM spheroids and effects on HIF-1α expression.
- Evaluated in vitro antitumor activity and IC50 values.
Main Results:
- CCM-CeO2 demonstrated targeted GBM cell delivery and lysosomal accumulation.
- Nanoparticles released O2 and NO, reducing HIF-1α protein expression in GBM spheroids.
- TMZ-loaded CCM-CeO2 enhanced intracellular reactive oxygen species (ROS), leading to increased apoptosis and necrosis.
- In vitro assays showed a significant reduction in TMZ's IC50 value.
Conclusions:
- Alleviating tumor hypoxia and increasing ROS are effective strategies for GBM treatment.
- The developed CCM-CeO2 nanoparticle system shows promise for enhancing TMZ chemotherapy in GBM.
- This approach offers a potential new therapeutic avenue for aggressive brain tumors.
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