Thrombolytic therapy based on lyophilized platelet-derived nanocarriers for ischemic stroke
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Published:2024-01-03
Issue:1
Volume:22
Page:
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ISSN:1477-3155
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Container-title:Journal of Nanobiotechnology
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language:en
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Short-container-title:J Nanobiotechnol
Author:
Migliavacca Martina,Correa-Paz Clara,Pérez-Mato María,Bielawski Patrick-Brian,Zhang Issan,Marie Pauline,Hervella Pablo,Rubio Marina,Maysinger Dusica,Vivien Denis,del Pino Pablo,Pelaz Beatriz,Polo Ester,Campos Francisco
Abstract
Abstract
Background
Intravenous administration of fibrinolytic drugs, such as recombinant tissue plasminogen activator (rtPA) is the standard treatment of acute thrombotic diseases. However, current fibrinolytics exhibit limited clinical efficacy because of their short plasma half-lives and risk of hemorrhagic transformations. Platelet membrane-based nanocarriers have received increasing attention for ischemic stroke therapies, as they have natural thrombus-targeting activity, can prolong half-life of the fibrinolytic therapy, and reduce side effects. In this study we have gone further in developing platelet-derived nanocarriers (defined as cellsomes) to encapsulate and protect rtPA from degradation. Following lyophilization and characterization, their formulation properties, biocompatibility, therapeutic effect, and risk of hemorrhages were later investigated in a thromboembolic model of stroke in mice.
Results
Cellsomes of 200 nm size and loaded with rtPA were generated from membrane fragments of human platelets. The lyophilization process did not influence the nanocarrier size distribution, morphology, and colloidal stability conferring particle preservation and long-term storage. Encapsulated rtPA in cellsomes and administered as a single bolus showed to be as effective as a continuous clinical perfusion of free rtPA at equal concentration, without increasing the risk of hemorrhagic transformations or provoking an inflammatory response.
Conclusions
This study provides evidence for the safe and effective use of lyophilized biomimetic platelet-derived nanomedicine for precise thrombolytic treatment of acute ischemic stroke. In addition, this new nanoformulation could simplify the clinical use of rtPA as a single bolus, being easier and less time-consuming in an emergency setting than a treatment perfusion, particularly in stroke patients. We have successfully addressed one of the main barriers to drug application and commercialization, the long-term storage of nanomedicines, overcoming the potential chemical and physical instabilities of nanomedicines when stored in an aqueous buffer.
Funder
Instituto de Salud Carlos III Agence Nationale de la Recherche Ministerio de Ciencia e Innovación European Research Council Xunta de Galicia
Publisher
Springer Science and Business Media LLC
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