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Published on: June 11, 2020
ROS-responsive death receptor 5 fusion protein nano-delivery system enhances myocardial ischemia-reperfusion injury
Xiaoyu Liang1,2,3, Yang Zhang1, Changduo Wang2
1Center for Coronary Artery Disease, Division of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China.
Abstract:
The microenvironment characterized by inflammation and oxidative stress plays a crucial role in the pathogenesis of myocardial ischemia-reperfusion (I/R) injury. The death receptor 5 fusion protein (sDR5-Fc) specifically targets and blocks the key protein-tumor necrosis factor related apoptosis inducing ligand (TRAIL), which is involved in cell apoptosis. This study focuses on the development of reactive oxygen species (ROS) intelligent responsive sDR5-Fc nanoparticles, aimed at improving the pathological microenvironment associated with oxidative stress and inflammatory damage, inhibiting myocardial cell apoptosis while worsening, and enhancing the bioavailability and selectivity of sDR5-Fc. The successful synthesis of 6S-PLGE-PO-PEG was verified through infrared nuclear magnetic resonance and other analytical experiments. The ROS intelligent responsive sDR5-Fc nanoparticles (DPP) were successfully constructed in vitro, exhibiting a particle size of approximately 200 nm, as well as a certain stability and H2O2 responsive release ability. DPP demonstrated good biocompatibility. The cell viability and apoptosis assays indicated that DPP significantly reduced myocardial cell damage caused by hypoxia reoxygenation and decreased cell apoptosis. In myocardial I/R rat model, the administration of DPP nanoparticle displayed superior therapeutic effects compared to the sDR5-Fc group, evidenced by the reduction in myocardial infarction area, improvement in fibrosis, decreased myocardial cell apoptosis, increased cell proliferation, enhanced angiogenesis, and inhibition of myocardial hypertrophy. The synergistic effect of ROS responsive sDR5-Fc nanoparticles in mitigating I/R injury is expected to provide a new interdisciplinary treatment approach.
Insights
New nanoparticles targeting reactive oxygen species (ROS) effectively treat myocardial ischemia-reperfusion (I/R) injury. These ROS-intelligent responsive sDR5-Fc nanoparticles reduce heart damage and apoptosis, offering a promising new therapy.
Area of Science:
- Biomedical Engineering
- Cardiovascular Research
- Nanomedicine
Background:
- Myocardial ischemia-reperfusion (I/R) injury is exacerbated by inflammation and oxidative stress.
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway contributes to myocardial cell apoptosis.
- Current treatments for I/R injury have limitations in addressing the complex microenvironment.
Purpose of the Study:
- To develop ROS-intelligent responsive sDR5-Fc nanoparticles (DPP) for targeted I/R injury treatment.
- To enhance the bioavailability and selectivity of sDR5-Fc by encapsulating it in nanoparticles.
- To investigate the therapeutic efficacy of DPP in mitigating oxidative stress, inflammation, and apoptosis in myocardial I/R injury.
Main Methods:
- Synthesis and characterization of 6S-PLGE-PO-PEG polymer.
- Construction and in vitro evaluation of ROS-intelligent responsive sDR5-Fc nanoparticles (DPP).
- Assessment of DPP's biocompatibility, stability, and drug release profile.
- In vitro studies on hypoxia-reoxygenation-induced myocardial cell damage and apoptosis.
- In vivo evaluation of DPP's therapeutic effects in a rat model of myocardial I/R injury.
Main Results:
- Successfully synthesized and characterized the polymer and constructed DPP nanoparticles (~200 nm) with H2O2-responsive release.
- DPP demonstrated good biocompatibility and significantly reduced myocardial cell damage and apoptosis in vitro.
- In vivo, DPP administration markedly reduced myocardial infarction area, fibrosis, and apoptosis.
- DPP treatment improved cell proliferation, enhanced angiogenesis, and inhibited myocardial hypertrophy in the I/R rat model.
- DPP showed superior therapeutic effects compared to free sDR5-Fc.
Conclusions:
- ROS-intelligent responsive sDR5-Fc nanoparticles (DPP) represent a novel and effective therapeutic strategy for myocardial I/R injury.
- DPP's ability to target the oxidative stress microenvironment and inhibit apoptosis offers significant advantages over conventional treatments.
- This interdisciplinary approach holds promise for advancing cardiovascular regenerative medicine and treatment strategies.
