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Clot-Targeted Magnetic Hyperthermia Permeabilizes Blood Clots to Make Them More Susceptible to Thrombolysis

Cabrera, David; Sharifabad, Maneea Eizadi; Ranjbar, Jacob A.; Telling, Neil D.; Harper, Alan G.S.

Authors

Maneea Eizadi Sharifabad

Jacob A. Ranjbar



Abstract

BACKGROUND: Thrombolysis is a frontline treatment for stroke, which involves the application of tissue plasminogen activator (tPA) to trigger endogenous clot-degradation pathways.However, it is only effective within 4.5 hours of symptom onset due to clot contraction preventing tPA permeation into the clot. Magnetic hyperthermia (MH) mediated by tumor-targeted magnetic nanoparticles are used to treat cancer by using local heat generation to trigger apoptosis of cancer cells. OBJECTIVES: To develop clot-targeting magnetic nanoparticles to deliver MH to the surface of human blood clots, and to assess whether this can improve the efficacy of thrombolysis of contracted blood clots. METHODS: Clot-targeting magnetic nanoparticles were developed by functionalizing iron oxide nanoparticles with an antibody recognizing activated integrin aIIbß3 (PAC-1). The magnetic properties of the PAC-1-tagged magnetic nanoparticles were characterized and optimized to deliver clot-targeted MH. RESULTS: Clot-targeted MH increases the efficacy of tPA-mediated thrombolysis in contracted human blood clots, leading to a reduction in clot weight. MH increases the permeability of the clots to tPA, facilitating their breakdown. Scanning electron microscopy reveals that this effect is elicited through enhanced fibrin breakdown and triggering the disruption of red blood cells on the surface of the clot. Importantly, endothelial cells viability in a 3D blood vessel model is unaffected by exposure to MH. CONCLUSIONS: This study demonstrates that clot-targeted MH can enhance the thrombolysis of contracted human blood clots and can be safely applied to enhance the timeframe in which thrombolysis is effective.

Journal Article Type Article
Acceptance Date Aug 3, 2022
Online Publication Date Aug 11, 2022
Publication Date 2022-11
Journal Journal of Thrombosis and Haemostasis
Print ISSN 1538-7933
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 20
Issue 11
DOI https://doi.org/10.1111/jth.15846
Publisher URL https://onlinelibrary.wiley.com/doi/10.1111/jth.15846

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