Dataset Information

Direct delivery of plasmin using clot-anchoring thrombin-responsive nanoparticles for targeted fibrinolytic therapy.

ABSTRACT:

Background

Fibrin-rich clot formation in thrombo-occlusive pathologies is currently treated by systemic administration of plasminogen activators (e.g. tPA), to convert fibrin-associated plasminogen to plasmin for fibrinolytic action. However, this conversion is not restricted to clot site only but also occurs on circulating plasminogen, causing systemic fibrinogenolysis and bleeding risks. To address this, past research has explored tPA delivery using clot-targeted nanoparticles.

Objectives

We designed a nanomedicine system that can (1) target clots via binding to activated platelets and fibrin, (2) package plasmin instead of tPA as a direct fibrinolytic agent, and (3) release this plasmin triggered by thrombin for clot-localized action.

Methods

Clot-targeted thrombin-cleavable nanoparticles (CTNPs) were manufactured using self-assembly of peptide-lipid conjugates. Plasmin loading and its thrombin-triggered release from CTNPs were characterized by UV-visible spectroscopy. CTNP-targeting to clots under flow was studied using microfluidics. Fibrinolytic effect of CTNP-delivered plasmin was studied in vitro using BioFlux imaging and D-dimer analysis and in vivo in a zebrafish thrombosis model.

Results

Plasmin-loaded CTNPs significantly bound to clots under shear flow and showed thrombin-triggered enhanced release of plasmin. BioFlux studies confirmed that thrombin-triggered plasmin released from CTNPs rendered fibrinolysis similar to free plasmin, further corroborated by D-dimer analysis. In the zebrafish model, CTNP-delivered plasmin accelerated time-to-recanalization, or completely prevented occlusion when infused before thrombus formation.

Conclusion

Considering that the very short circulation half-life (<1 second) of plasmin prevents its systemic use but also makes it safer without off-target drug effects, clot-targeted delivery of plasmin using CTNPs can enable safer and more efficacious fibrinolytic therapy.

SUBMITTER: Sun M

PROVIDER: S-EPMC10148984 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

Direct delivery of plasmin using clot-anchoring thrombin-responsive nanoparticles for targeted fibrinolytic therapy.

Sun Michael M Hao Pontius M Hao MH Yang Stephanie S Pendekanti Tejal T Raghunathan Shruti S Shavit Jordan A JA Sen Gupta Anirban A

Journal of thrombosis and haemostasis : JTH 20221222 4

<h4>Background</h4>Fibrin-rich clot formation in thrombo-occlusive pathologies is currently treated by systemic administration of plasminogen activators (e.g. tPA), to convert fibrin-associated plasminogen to plasmin for fibrinolytic action. However, this conversion is not restricted to clot site only but also occurs on circulating plasminogen, causing systemic fibrinogenolysis and bleeding risks. To address this, past research has explored tPA delivery using clot-targeted nanoparticles.<h4>Obje ...[more]

PMID: 36696210

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Dataset Information

Direct delivery of plasmin using clot-anchoring thrombin-responsive nanoparticles for targeted fibrinolytic therapy.

Background

Objectives

Methods

Results

Conclusion

Publications

Direct delivery of plasmin using clot-anchoring thrombin-responsive nanoparticles for targeted fibrinolytic therapy.

Similar Datasets

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