Tissue plasminogen activator-based clot busting: Controlled delivery approaches

Abstract

Cardiovascular diseases are the leading cause of death worldwide. Thrombosis, the formation of blood clot (thrombus) in the circulatory system obstructing the blood flow, is one of the main causes behind various ischemic arterial syndromes such as ischemic stroke and myocardial infarction, as well as vein syndromes such as deep vein thrombosis, and consequently, pulmonary emboli. Several thrombolytic agents have been developed for treating thrombosis, the most common being tissue plasminogen activator (tPA), administrated systemically or locally via IV infusion directly proximal to the thrombus, with the aim of restoring and improving the blood flow. TPA triggers the dissolution of thrombi by inducing the conversion of plasminogen to protease plasmin followed by fibrin digestion that eventually leads to clot lysis. Although tPA provides powerful thrombolytic activity, it has many shortcomings, including poor pharmacokinetic profiles, impairment of the reestablishment of normal coronary flow, and impairment of hemostasis, leading to life-threatening bleeding consequences. The bleeding consequence is ascribed to the ability of tPA to circulate throughout the body and therefore can lysis all blood clots in the circulation system, even the good ones that prevent the bleeding and promote injury repair. This review provides an overview of the different delivery approaches for tPA including: liposomes, ultrasound-triggered thrombolysis, anti-fibrin antibody-targeted tPA, camouflaged-tPA, tpA-loaded microcarriers, and nano-modulated delivery approaches.

Tissue plasminogen activator-based nanothrombolysis for ischemic stroke

“…Standard dosage used in CLOTBUST was: standard intravenous tPA (0.9 mg/kg body weight, 10 % as bolus, the remainder over 1 hour) in combination with 2-hours continuous 2-MHz diagnostic transcranial Doppler (TCD) ultrasound. Moreover, it has been found that lower ultrasound frequencies (e.g., 300 kHz, in kilohertz) can cause higher rates of intracerebral hemorrhage 59 , whereas the diagnostic frequencies (e.g.,2-MHz, in megahertz) show no such side effect and are safe enough to be used in humans 57, 58, 60 .…”

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

“…[9][10][11] TPA is a serine protease which catalyzes the conversion of plasminogen to plasmin, the primary enzyme which degrades fibrin, causing the fibrinolysis which results in clot dissolution. 12,13 TPA may be used intravenously or locally (i.e., through a catheter) in the treatment of conditions resulting from thrombus formation, such as myocardial infarction, pulmonary embolism, and peripheral arterial disease. 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.…”

“…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 limitations have prompted researchers to improve thrombolysis by developing artificial PAs that are more enzymatically active, using adjuvants that assist PA, or inhibiting PAI‐1 or factor XIIIa . Another approach is to modify PAs with macromolecules to protect them from clearance and degradation in blood, thereby improving circulation half‐life . Further modifications of PA facilitate thrombus targeting via functionalization with moieties that bind to activated platelets or fibrin .…”

“…26 Another approach is to modify PAs with macromolecules to protect them from clearance and degradation in blood, thereby improving circulation half-life. 27,28 Further modifications of PA facilitate thrombus targeting via functionalization with moieties that bind to activated platelets or fibrin. 29 However, these approaches offer only marginal improvements over tPA, rely on blood flow for delivery, and still exhibit high risk of bleeding.…”