Thrombolytic therapy based on lyophilized platelet-derived nanocarriers for ischemic stroke
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...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-01-01
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| Series: | Journal of Nanobiotechnology |
| Online Access: | https://doi.org/10.1186/s12951-023-02206-5 |
| _version_ | 1797362905030590464 |
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| author | Martina Migliavacca Clara Correa-Paz María Pérez-Mato Patrick-Brian Bielawski Issan Zhang Pauline Marie Pablo Hervella Marina Rubio Dusica Maysinger Denis Vivien Pablo del Pino Beatriz Pelaz Ester Polo Francisco Campos |
| author_facet | Martina Migliavacca Clara Correa-Paz María Pérez-Mato Patrick-Brian Bielawski Issan Zhang Pauline Marie Pablo Hervella Marina Rubio Dusica Maysinger Denis Vivien Pablo del Pino Beatriz Pelaz Ester Polo Francisco Campos |
| author_sort | Martina Migliavacca |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T16:14:08Z |
| format | Article |
| id | doaj.art-3c16e2c2faf04e7d93125ff009c30c71 |
| institution | Directory Open Access Journal |
| issn | 1477-3155 |
| language | English |
| last_indexed | 2024-03-08T16:14:08Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj.art-3c16e2c2faf04e7d93125ff009c30c712024-01-07T12:43:03ZengBMCJournal of Nanobiotechnology1477-31552024-01-0122111610.1186/s12951-023-02206-5Thrombolytic therapy based on lyophilized platelet-derived nanocarriers for ischemic strokeMartina Migliavacca0Clara Correa-Paz1María Pérez-Mato2Patrick-Brian Bielawski3Issan Zhang4Pauline Marie5Pablo Hervella6Marina Rubio7Dusica Maysinger8Denis Vivien9Pablo del Pino10Beatriz Pelaz11Ester Polo12Francisco Campos13Center for Research in Biological Chemistry and Molecular Materials (CiQUS), University of Santiago de CompostelaTranslational Stroke Laboratory Group (TREAT), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS)Translational Stroke Laboratory Group (TREAT), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS)Department of Pharmacology and Therapeutics, McGill UniversityDepartment of Pharmacology and Therapeutics, McGill UniversityUMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Normandie University, UNICAEN, INSERM, GIP Cyceron, Institute Blood and Brain @ Caen-Normandie (BB@C)Neuroimaging and Biotechnology Laboratory (NOBEL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS)UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Normandie University, UNICAEN, INSERM, GIP Cyceron, Institute Blood and Brain @ Caen-Normandie (BB@C)Department of Pharmacology and Therapeutics, McGill UniversityUMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Normandie University, UNICAEN, INSERM, GIP Cyceron, Institute Blood and Brain @ Caen-Normandie (BB@C)Center for Research in Biological Chemistry and Molecular Materials (CiQUS), University of Santiago de CompostelaCenter for Research in Biological Chemistry and Molecular Materials (CiQUS), University of Santiago de CompostelaCenter for Research in Biological Chemistry and Molecular Materials (CiQUS), University of Santiago de CompostelaTranslational Stroke Laboratory Group (TREAT), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS)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.https://doi.org/10.1186/s12951-023-02206-5 |
| spellingShingle | Martina Migliavacca Clara Correa-Paz María Pérez-Mato Patrick-Brian Bielawski Issan Zhang Pauline Marie Pablo Hervella Marina Rubio Dusica Maysinger Denis Vivien Pablo del Pino Beatriz Pelaz Ester Polo Francisco Campos Thrombolytic therapy based on lyophilized platelet-derived nanocarriers for ischemic stroke Journal of Nanobiotechnology |
| title | Thrombolytic therapy based on lyophilized platelet-derived nanocarriers for ischemic stroke |
| title_full | Thrombolytic therapy based on lyophilized platelet-derived nanocarriers for ischemic stroke |
| title_fullStr | Thrombolytic therapy based on lyophilized platelet-derived nanocarriers for ischemic stroke |
| title_full_unstemmed | Thrombolytic therapy based on lyophilized platelet-derived nanocarriers for ischemic stroke |
| title_short | Thrombolytic therapy based on lyophilized platelet-derived nanocarriers for ischemic stroke |
| title_sort | thrombolytic therapy based on lyophilized platelet derived nanocarriers for ischemic stroke |
| url | https://doi.org/10.1186/s12951-023-02206-5 |
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