Thrombin-Responsive and Sequential Targeted Nanoplatform for Synergistic Thrombolysis Therapy

Area of Science:

• Biomaterials Science
• Nanotechnology
• Pharmacology

Background:

• Traditional thrombolytic therapies face challenges including low specificity, bleeding complications, and secondary re-embolism.
• Developing targeted drug delivery systems is crucial for improving treatment efficacy and safety.

Purpose of the Study:

• To develop a thrombin-responsive, sequentially targeted nanoplatform (MMSN-UK/TI@pep-Fuco) for efficient thrombolysis.
• To integrate an attack-defense-protection strategy for enhanced therapeutic outcomes in arterial thrombosis.

Main Methods:

• Synthesis of multilevel mesoporous silica nanoparticles (MMSN) modified with fucoidan (Fuco) via peptide (pep) linkage.
• Sequential loading of urokinase (UK) and tirofiban (TI) into MMSN@pep-Fuco to create nano drug delivery systems (NDDS).
• In vitro and in vivo evaluation of NDDS stability, targeting, drug release kinetics, and thrombolytic efficacy.

Main Results:

• MMSN-UK/TI@pep-Fuco demonstrated stability in circulation, reducing bleeding risk.
• Fuco facilitated active targeting to thrombus via P-selectin interaction.
• Thrombin-triggered Fuco shedding enabled rapid UK release for thrombolysis, followed by sustained TI release to prevent re-embolism.
• Achieved a low thrombus blockage rate of 4.87% with minimal bleeding.

Conclusions:

• The developed nanoplatform provides an effective strategy for arterial thrombosis treatment.
• The integrated attack-defense-protection approach enhances thrombolysis and minimizes adverse effects.
• This nanoplatform holds promise for future therapeutic applications in vascular diseases.