Thrombolytic Agents: Nanocarriers in Controlled Release

Abstract

Thrombosis is a life-threatening pathological condition in which blood clots form in blood vessels, obstructing or interfering with blood flow. Thrombolytic agents (TAs) are enzymes that can catalyze the conversion of plasminogen to plasmin to dissolve blood clots. The plasmin formed by TAs breaks down fibrin clots into soluble fibrin that finally dissolves thrombi. Several TAs have been developed to treat various thromboembolic diseases, such as pulmonary embolisms, acute myocardial infarction, deep vein thrombosis, and extensive coronary emboli. However, systemic TA administration can trigger non-specific activation that can increase the incidence of bleeding. Moreover, protein-based TAs are rapidly inactivated upon injection resulting in the need for large doses. To overcome these limitations, various types of nanocarriers have been introduced that enhance the pharmacokinetic effects by protecting the TA from the biological environment and targeting the release into coagulation. The nanocarriers show increasing half-life, reducing side effects, and improving overall TA efficacy. In this work, the recent advances in various types of TAs and nanocarriers are thoroughly reviewed. Various types of nanocarriers, including lipid-based, polymer-based, and metal-based nanoparticles are described, for the targeted delivery of TAs. This work also provides insights into issues related to the future of TA development and successful clinical translation.

Thrombus-Targeting Polymeric Nanocarriers and Their Biomedical Applications in Thrombolytic Therapy

“…Therefore, Huang et al reported an activated-platelet-sensitive nanocarrier capable of inducing selective thrombolysis through targeted delivery and controlled release of tPA to blood clot (Huang et al, 2019). The nanothrombolytic system loaded with tPA was based on FIGURE 2 | Illustration of the principles of thrombolysis in a fibrin surface and circulating blood environment (Hassanpour et al, 2020). This figure describes the catalytic principle of the conversion of plasminogen to plasmin according to the binding method of the plasminogen activator [e.g., tissue-type plasminogen activator (tPA), urokinase (UK), and streptokinase (SK)]) Plasminogen specifically binds to the surface of the fibrin blood clot.…”

“…Taking into account the cost of surgical treatment and the damage it causes to the body, the application of thrombolytic drugs has increasingly become an important strategy. Thrombolytic agents include tissue plasminogen activators (tPA), recombinant tissue plasminogen activators (rtPA), urokinase (UK), streptokinase (SK), and other plasminogen activators (PAs; Marder, 2013 ; Cheng et al, 2018 ; Zamanlu et al, 2018 ; Ma et al, 2019 ; Hassanpour et al, 2020 ). The diverse antigenicity, half-life, lytic potential, fibrin specificity, and hemorrhagic risks associated with these agents lead to their differing effectiveness ( Marshall, 2015 ).…”

“…With the rapid development of nanotechnology and biotechnology ( Jiang et al, 2020 ; Cornel et al, 2021 ), the combination of thrombolytic therapy and nanocarriers may provide a novel solution to key issues, such as the short half-life, low targeting ability, and unexpected bleeding complications of the existing therapeutic drugs ( Zamanlu et al, 2018 ; Ma et al, 2019 ; Hassanpour et al, 2020 ). Polymeric nanocarriers based on macromolecules can provide the protection and targeted delivery of thrombolytic drugs through the unique physicochemical property brought by the nanoscale and the facile design of polymer chains.…”

pH‐Sensitive, Cerebral Vasculature‐Targeting Hydroxyethyl Starch Functionalized Nanoparticles for Improved Angiogenesis and Neurological Function Recovery in Ischemic Stroke

“…In recent years, nanotechnology approaches have demonstrated a promising possibility to improve the pharmacokinetics and biodistribution profile of many drugs. [21,23,24] Some studies have shown that the pH gradients between ischemic and normal tissues are used to achieve targeted release. [25] However, the instability of the local environment and the physiological state of other parts of the body limits the release of drugs.…”

Targeted delivery of thrombolytic enzymes

“…Yet, the list of examples mentioned above is only partial; for a more detailed introduction of thrombolytic agents and nanocarrier approaches for thrombolytics, readers are directed to recent, comprehensive reviews by Hassanpour and coworkers 17 and Zenych and coworkers. 18 There certainly is a growing and/or renewed interest in this area.…”