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.

Fibrinolysis: strategies to enhance the treatment of acute ischemic stroke

“…Other experimental methods to enhance t‐PA delivery or activity include the use of nanocarriers and microbubbles combined with ultrasound . Examples of nanocarriers include liposomes and polymer‐based or magnetic nanoparticles.…”

“…These encapsulate t‐PA or allow t‐PA binding to its outer layer of the liposome lipid bilayer or the inorganic shell of nanoparticles. In stroke models in animals, encapsulating t‐PA within nanocarriers or binding of it to their surfaces enhances fibrinolysis by protecting t‐PA from inhibition by circulating PAI‐1, and by increasing the capacity of t‐PA to permeate into the clot .…”

“…Although, in one study, t‐PA in combination with microbubbles resulted in more rapid recanalization in patients with acute ischemic stroke than t‐PA alone , additional trials are needed to confirm these results. By coating of microbubbles with lipid or albumin and binding t‐PA to the surface coating, microbubbles can be used as nanocarriers . The efficacy of microbubble nanocarriers relative to other nanocarriers of t‐PA, however, requires further investigation.…”

<p>An in vitro Model System for Evaluating Remote Magnetic Nanoparticle Movement and Fibrinolysis</p>

“…14,15 Current clinical use of IV tPA is limited by its narrow therapeutic time window, hemorrhagic complications, and suboptimal delivery to the precise location of the thrombus. 7,8,13,16,17 In computational studies, IV administration of a thrombolytic such as tPA to a thrombus situated within an occluded blood vessel occurs primarily as a function of the length of the occluded vessel and may take 2-3 hrs for peak delivery. 18 It has been estimated that less than 1/100,000% of drug administered intravenously actually reaches the offending blood clot.…”

Engineered microparticles and nanoparticles for fibrinolysis

“…These can contain immobilized or encapsulated PA, preventing systemic interaction with the blood‐brain barrier, and can be actuated to improve at‐site drug delivery. Nanoparticle and microparticle carriers for PA have been developed to improve circulation time, reduce inhibition and degradation, and target occlusive thrombi . Many of these are polymeric or liposomal spheres that encapsulate or embed PA.…”