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Fibrin-targeted ROS-scavenging micelles with photothermal and NO delivery for thrombolysis and post-thrombotic
Yueming Xue1, Cheng Li2, Jiale Si1
1School of Chemistry, State Key Laboratory of Fluorine & Nitrogen Chemicals, Institute of New Concept Sensors and Molecular Materials (INCSMM), Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi'an Key Laboratory of Sustainable Polymer Materials, Xi'an Jiaotong University, Xi'an 710049, China.
Insights
This study introduces novel micelles that target blood clots, scavenge harmful reactive oxygen species (ROS), and use light to break down clots and release nitric oxide (NO) for vascular repair, offering a safe and effective thrombosis treatment.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cardiovascular Research
Background:
- Cardiovascular diseases (CVDs) are a leading cause of death, often caused by thrombosis (blood clots).
- Current antithrombotic therapies have limitations, including bleeding risks and suboptimal outcomes.
- Integrating clot targeting, reactive oxygen species (ROS) scavenging, thrombolysis, and vascular repair into a single nanocarrier remains a challenge.
Purpose of the Study:
- To develop a multifunctional nanocarrier for comprehensive thrombosis treatment.
- To combine thrombus targeting, ROS scavenging, photothermal thrombolysis, and nitric oxide (NO) release in one system.
- To evaluate the therapeutic efficacy and safety of the developed nanocarrier in a thrombosis model.
Main Methods:
- Synthesized CREKA peptide-functionalized micelles (CREKA-PEG-b-PPS) encapsulating indocyanine green (ICG) and a nitric oxide donor (BNN6).
- Utilized the CREKA peptide for specific targeting of fibrin in thrombi.
- Employed 808 nm light irradiation for photothermal effects, ROS scavenging by PPS, and NO release for thrombolysis and vascular repair.
Main Results:
- The developed micelles effectively targeted thrombus sites.
- The thioether moieties in PPS efficiently scavenged ROS, reducing oxidative stress.
- Photothermal effects from ICG and NO release promoted rapid thrombolysis, restored blood flow in a murine carotid artery model, and facilitated vascular repair.
Conclusions:
- The multifunctional micelles offer a promising strategy for effective and safe thrombosis treatment.
- This integrated approach addresses the limitations of conventional therapies by combining multiple therapeutic actions.
- The nanocarrier promotes clot dissolution, vascular homeostasis, and prevents recurrence, representing a significant advancement in antithrombotic therapy.
Abstract:
Cardiovascular diseases (CVDs), a major contributor to global mortality, are often precipitated by thrombosis. Conventional antithrombotic therapies based on thrombolytic medicine often yield suboptimal therapeutic outcomes and are often accompanied with the risk of tissue bleeding. Despite of advances in nanocarrier-mediated drug delivery with improved hemostatic safety and thrombolytic efficiency, the integration of thrombus targeting, reactive oxygen species (ROS) scavenging, thrombolysis, and post-treatment vascular repair to achieve comprehensive thrombus eradication while preventing recurrence remains a challenge. Herein, we develop pentapeptide CREKA-terminated poly(ethylene glycol)-block-poly(propylene sulfide) (CREKA-PEG-b-PPS) micelles with ROS-scavenging properties to load indocyanine green (ICG) and the NO donor, N,N'-di-sec-butyl-N,N'-dinitroso-1,4-phenylenediamine (BNN6). Fibrin-targeting peptide CREKA enables precise targeting thrombotic sites after intravenous injection. The thioether moieties in the PPS block scavenge ROS, thereby effectively alleviating the oxidative stress microenvironment at thrombus sites. Upon exposure to light irradiation at 808 nm, photothermal effects from ICG can facilitate the deep thrombus penetration and thrombolysis effect, further triggering the localized release of NO from BNN6. Moreover, NO contributes to the restoration of endothelial cell function, thereby maintaining vascular homeostasis post-thrombolysis. Integration of ROS-scavenging, localized photothermal effects, and NO release achieves rapid clot ablation, restoring complete blood flow in a murine carotid artery thrombosis model while promoting vascular repair and homeostasis. Thus, the developed micelles represent a safe and efficient therapeutic strategy for the treatment of thrombosis.
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