Sonosensitive capsules for brain thrombolysis increase ischemic damage in a stroke model

Journal of Nanobiotechnology

Pablo del Pino¹  Ester Polo¹  Beatriz Pelaz¹  María F. Navarro Poupard¹  Manuel Rodríguez-Pérez¹  Martina Migliavacca¹  Clara Correa-Paz²  José Castillo²  Ramón Iglesias-Rey²  Elena Maqueda²  Francisco Campos²  Alberto Ouro²  Pablo Hervella²  Tomás Sobrino² 

[1] Center for Research in Biological Chemistry and Molecular Materials (CiQUS), University of Santiago de Compostela;Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS);

关键词: Capsules;    Ischemic stroke;    Layer-by-layer;    Magnetic resonance imaging;    Tissue plasminogen activator;    Ultrasound;   

DOI  :  10.1186/s12951-022-01252-9

来源: DOAJ

【 摘 要 】

Abstract Background Ischemic stroke is the most common cerebrovascular disease and is caused by interruption of blood supply to the brain. To date, recombinant tissue plasminogen activator (rtPA) has been the main pharmacological treatment in the acute phase. However, this treatment has some drawbacks, such as a short half-life, low reperfusion rate, risk of hemorrhagic transformations, and neurotoxic effects. To overcome the limitations of rtPA and improve its effectiveness, we recently designed sonosensitive sub-micrometric capsules (SCs) loaded with rtPA with a size of approximately 600 nm, synthesized using the layer-by-layer (LbL) technique, and coated with gelatine for clot targeting. In this study, we evaluated the rtPA release of ultrasound (US)-responsive SCs in healthy mice and the therapeutic effect in a thromboembolic stroke model. Results In healthy mice, SCs loaded with rtPA 1 mg/kg responded properly to external US exposure, extending the half-life of the drug in the blood stream more than the group treated with free rtPA solution. The gelatine coating also contributed to stabilizing the encapsulation and maintaining the response to US. When the same particles were administered in the stroke model, these SCs appeared to aggregate in the ischemic brain region, probably generating secondary embolisms and limiting the thrombolytic effect of rtPA. Despite the promising results of these thrombolytic particles, at least under the dose and size conditions used in this study, the administration of these capsules represents a risk factor for stroke. Conclusions This is the first study to report the aggregation risk of a drug carrier in neurological pathologies such as stroke. Biocompatibility analysis related to the use of nano-and microparticles should be deeply studied to anticipate the limitations and orientate the design of new nanoparticles for translation to humans. Graphical Abstract

【 授权许可】

Unknown