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

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Pharmacology

Background:

• Ischemic stroke treatment relies on recombinant tissue plasminogen activator (rtPA), which has limitations including a short half-life and hemorrhagic risks.
• Sonosensitive sub-micrometric capsules (SCs) loaded with rtPA were developed using layer-by-layer (LbL) technique and gelatine coating for targeted clot delivery.

Purpose of the Study:

• To evaluate ultrasound-triggered rtPA release from SCs in healthy mice.
• To assess the therapeutic efficacy and safety of rtPA-loaded SCs in a thromboembolic stroke model.

Main Methods:

• Synthesis of ~600 nm SCs via LbL technique, loaded with rtPA, and coated with gelatine.
• In vivo studies in healthy mice to assess drug half-life and ultrasound responsiveness.
• Evaluation in a thromboembolic stroke model to determine therapeutic effects and aggregation potential.

Main Results:

• SCs extended rtPA's half-life in healthy mice compared to free rtPA, with gelatine enhancing stability and US response.
• In the stroke model, SCs aggregated in the ischemic region, potentially causing secondary embolisms and limiting thrombolysis.
• The study identified aggregation as a risk factor for these capsules in stroke treatment.

Conclusions:

• This study highlights the aggregation risk of drug carriers in neurological conditions like stroke.
• In-depth biocompatibility analysis of nano- and microparticles is essential for safe clinical translation.
• Future nanoparticle design must consider and mitigate potential limitations for human therapies.