PUBLICATION
Direct delivery of plasmin using clot-anchoring thrombin-responsive nanoparticles for targeted fibrinolytic therapy
- Authors
- Sun, M., Hao Pontius, M.H., Yang, S., Pendekanti, T., Raghunathan, S., Shavit, J.A., Sen Gupta, A.
- ID
- ZDB-PUB-230126-2
- Date
- 2022
- Source
- Journal of thrombosis and haemostasis : JTH 21(4): 983-994 (Journal)
- Registered Authors
- Shavit, Jordan
- Keywords
- Fibrin, Fibrinolysis, Nanomedicine, Plasmin, Targeted Delivery, Thrombin
- MeSH Terms
-
- Animals
- Fibrin/chemistry
- Fibrinolysin/metabolism
- Fibrinolysis
- Nanoparticles*
- Plasminogen
- Thrombin/chemistry
- Thrombolytic Therapy
- Thrombosis*/drug therapy
- Tissue Plasminogen Activator
- Zebrafish/metabolism
- PubMed
- 36696210 Full text @ J. Thromb. Haemost.
Citation
Sun, M., Hao Pontius, M.H., Yang, S., Pendekanti, T., Raghunathan, S., Shavit, J.A., Sen Gupta, A. (2022) Direct delivery of plasmin using clot-anchoring thrombin-responsive nanoparticles for targeted fibrinolytic therapy. Journal of thrombosis and haemostasis : JTH. 21(4):983-994.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping