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A Facile and Efficient Approach for the Production of Reversible Disulfide Cross-linked Micelles
Published on: December 23, 2016
Poly(sodium lipoate) Particles with Nitroimidazole Modification for Disulfide Stress-Mediated Antitumor Metastasis
1College of Biomedical Engineering and National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
Abstract:
Disulfidptosis, a form of programmed cell death triggered by disulfide stress, holds promise for antimetastatic strategies by promoting cytoskeletal collapse, while no relevant applied study was reported. Herein, we develop a disulfide stress inducer for antitumor metastasis by nitroimidazole-grafted poly(sodium lipoate) nanoparticles (NI@PSL). Upon thiol-mediated cellular uptake, NI@PSL degraded into dihydrolipoic acid (DHLA) and exposed grafted nitroimidazole (NI) in response to glutathione (GSH). DHLA formed aberrant disulfide bonds with cytoskeletal cysteine thiols. NI moieties were reduced to aminoimidazole by hypoxia-activated nitroreductase, resulting in nicotinamide adenine dinucleotide phosphate (NADPH) depletion. This redox imbalance prevented the reduction of intercytoskeletal disulfide bonds, leading to irreversible cytoskeletal collapse and subsequent metastasis inhibition. In vitro assays demonstrated that NI@PSL decreased the migration and invasion rates of highly metastatic B16F10 cells to 12.8 and 7.0%, respectively. In the B16F10 tumor-bearing mice model, NI@PSL nearly eliminated lung and liver metastatic foci. These results provide a strong basis for using disulfide stress to combat tumor metastasis.
Insights
We developed novel nanoparticles that induce disulfide stress, leading to programmed cell death and inhibiting cancer metastasis. This approach shows significant promise for developing new antimetastatic therapies.
Area of Science:
- Biochemistry
- Nanotechnology
- Oncology
Background:
- Disulfidptosis is a programmed cell death pathway induced by disulfide stress.
- Disulfidptosis offers potential for antimetastatic strategies by causing cytoskeletal collapse.
- No applied studies have explored disulfidptosis for antimetastasis.
Purpose of the Study:
- To develop a novel disulfide stress inducer for combating tumor metastasis.
- To investigate the efficacy of nitroimidazole-grafted poly(sodium lipoate) nanoparticles (NI@PSL) in inhibiting cancer spread.
Main Methods:
- Synthesized NI@PSL nanoparticles for targeted drug delivery.
- Investigated nanoparticle uptake, degradation, and intracellular mechanisms involving glutathione (GSH) and hypoxia-activated nitroreductase.
- Assessed the impact of NI@PSL on cell migration and invasion in vitro.
- Evaluated antimetastatic efficacy in a B16F10 tumor-bearing mice model.
Main Results:
- NI@PSL nanoparticles were effectively taken up by cells and degraded, releasing dihydrolipoic acid (DHLA) and nitroimidazole (NI).
- DHLA formed aberrant disulfide bonds with cytoskeletal cysteine thiols, while NI depletion of nicotinamide adenine dinucleotide phosphate (NADPH) caused redox imbalance.
- This led to irreversible cytoskeletal collapse, significantly reducing B16F10 cell migration (12.8%) and invasion (7.0%) in vitro.
- NI@PSL treatment nearly eliminated lung and liver metastatic foci in a mouse model.
Conclusions:
- NI@PSL nanoparticles effectively induce disulfidptosis and inhibit tumor metastasis.
- This study provides a strong foundation for utilizing disulfide stress as a therapeutic strategy against cancer metastasis.
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