Tissue plasminogen activator-based nanothrombolysis for ischemic stroke

ABSTRACT

Introduction: Thrombolysis with intravenous tissue plasminogen activator (tPA) is the only FDA approved treatment for patients with acute ischemic stroke, but its use is limited by narrow therapeutic window, selective efficacy, and hemorrhagic complication. In the past two decades, extensive efforts have been undertaken to extend its therapeutic time window and explore alternative thrombolytic agents, but both show little progress. Nanotechnology has emerged as a promising strategy to improve the efficacy and safety of tPA.

Areas covered: We reviewed the biology, thrombolytic mechanism, and pleiotropic functions of tPA in the brain and discussed current applications of various nanocarriers intended for the delivery of tPA for treatment of ischemic stroke. Current challenges and potential further directions of t-PA-based nanothrombolysis in stroke therapy are also discussed.

Expert opinion: Using nanocarriers to deliver tPA offers many advantages to enhance the efficacy and safety of tPA therapy. Further research is needed to characterize the physicochemical characteristics and in vivo behavior of tPA-loaded nanocarriers. Combination of tPA based nanothrombolysis and neuroprotection represents a promising treatment strategy for acute ischemic stroke. Theranostic nanocarriers co-delivered with tPA and imaging agents are also promising for future stroke management.

KEYWORDS:

• Drug delivery
• ischemic stroke
• nanocarriers
• nanoparticles
• nanothrombolysis
• thrombolytic therapy
• tissue plasminogen activator

Article Highlights

• To date, intravenous tPA remains the only FDA approved thrombolytic drug treatment for acute ischemic stroke, despite its limitations in both efficacy and safety. Tectophase is a potential alternative for tPA.

• Incorporating tPA into nanocarriers can 1) prolong the circulation time of tPA, thus achieve effective thrombolysis at a lower-than-standard dose; 2) temporally camouflage the thrombolytic activity of tPA during circulation thus reduce risk of intracerebral hemorrhage; 3) achieve targeted thrombolysis by modifying nanocarriers with targeting moieties or by ultrasound/magnetic force irradiation.

• Using nanocarriers to co-deliver tPA and neuroprotective agents shows great promise in extending treatment time window of tPA and improving therapeutic efficacy through synergistic actions.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by National Institutes of Health grants NS088719 and NS089991 (Dr. Li).