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

Clara Correa-Paz,Pablo Del Pino,Alberto Ouro,Martina Migliavacca,Pablo Hervella,Francisco Campos,Ramón Iglesias-Rey,María F Navarro Poupard,José Castillo,Elena Maqueda,Manuel Rodríguez-Pérez,Ester Polo,Tomás Sobrino,Beatriz Pelaz

doi:10.1186/s12951-022-01252-9

Abstract

BackgroundIschemic 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.ResultsIn 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.ConclusionsThis 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

Highlights

Ischemic stroke is the most common cerebrovascular disease and is caused by interruption of blood supply to the brain
Synthesis and characterization of capsules Different batches of sub-micrometric capsules (SCs) loaded with recombinant tissue plasminogen activator (rtPA), with or without gelatine, were synthesized following the same synthesis protocol described in our previous study [19]
The colloidal stability of all synthesized SCs was confirmed after the layer-by-layer process, core removal, and gelatine coating, as indicated by dynamic light scattering (DLS) analysis (Fig. 1G; Additional file 1: Fig. S3, Table S1)

Summary

Introduction

Ischemic stroke is the most common cerebrovascular disease and is caused by interruption of blood supply to the brain. Recombinant tissue plasminogen activator (rtPA) has been the main pharmacological treatment in the acute phase This treatment has some drawbacks, such as a short half-life, low reperfusion rate, risk of hemorrhagic transformations, and neurotoxic effects. Its use has some limitations, such as a low reperfusion rate, which occurs in—40–50% of treated patients, the risk of hemorrhagic transformation in 7–15% of cases, and neurotoxic effects [4,5,6]. These drawbacks limit the rtPA therapeutic window to 4.5 h after symptom onset [3]. The short half-life of rtPA (~ 5 min) requires that it be administered as an initial loading bolus (10% of the dose) followed by a continuous infusion for 1 h (90% of the dose) [7, 8]

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Discussion

Conclusion