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

Abstract

Due to the high morbidity and mortality of cardiovascular diseases, there is an urgent need for research on antithrombotic strategies. In view of the short half-life, insufficient drug penetration, poor targeting capabilities, and hemorrhagic side-effects of traditional thrombus treatment methods, the combination of thrombolytic therapy and nanocarriers brought by the development of nanotechnology in recent years may provide effective solutions for these undesirable side-effects caused by insufficient targeting. Polymeric nanocarriers, based on macromolecules and various functional groups, can connect specific targeting molecules together through chemical modification to achieve the protection and targeted delivery of thrombolytic drugs. However, simple chemical molecular modifications may be easily affected by the physiological environment encountered in the circulatory system. Therefore, the modification of nanocarriers with cell membranes can provide camouflage to these platforms and help to extend their circulation time while also imparting them with the biological functions of cell membranes, thus providing them with precise targeting capabilities, among which the most important is the biological modification of platelet membranes. In addition, some nanoparticles with their own therapeutic functions have also been developed, such as polypyrrole, which can exhibit a photothermal effect to induce thrombolysis. Herein, combined with the mechanism of thrombosis and thrombolysis, we outline the recent advances achieved with thrombus-targeting nanocarriers with regard to thrombosis treatment. On this basis, the design considerations, advantages, and challenges of these thrombolytic therapies in clinical transformation are discussed.

Clot-Targeted Antithrombotic Liposomal Nanomedicine Containing High Content of H2O2-Activatable Hybrid Prodrugs

“…A thrombus is heterogeneous in composition but mainly composed of fibrin, platelets, red blood cells, and leukocytes. , Thrombosis is reported to be one of the leading causes of death worldwide, accounting for one in four deaths. , A thrombus can be dissolved by tissue plasminogen activator (tPA) and urokinase plasminogen activator, and the rate of thrombus formation can be reduced with the help of various antiplatelet agents and anticoagulant agents. , However, these agents suffer from several drawbacks such as a short half-life, narrow therapeutic window, and unwanted hemorrhage in tissues. In this regard, there has been increasing interest in the development of nanomaterial-based drug delivery systems that effectively and specifically deliver sufficient antithrombotic agents to the thrombosed vessel, while minimizing their side effects. ,, …”

“…In this regard, there has been increasing interest in the development of nanomaterial-based drug delivery systems that effectively and specifically deliver sufficient antithrombotic agents to the thrombosed vessel, while minimizing their side effects. 6,8,9 atRA is an active derivative of retinol, a fat-soluble vitamin in the vitamin A family that is critical for normal cellular growth, differentiation, and death. 10,11 atRA is known to have potent antioxidant activity owing to its ability to scavenge reactive oxygen species (ROS) such as hydroxyl radical, superoxide, and nitric oxide.…”

A Fibrinogen‐Mimicking, Activated‐Platelet‐Sensitive Nanocoacervate Enhances Thrombus Targeting and Penetration of Tissue Plasminogen Activator for Effective Thrombolytic Therapy

“…[13][14][15][16] To date, a variety of fibrinolytic enzyme delivery systems have attempted to solve the above challenges. [17][18][19][20][21][22][23] For example, Jin et al [24] and Berger et al [25] reported a PEGylated delivery system by direct conjugation of lumbrokinase (LK) and tPA enzymes, respectively, with polyethylene glycol (PEG) to prolong the circulation half-life. Absar et al demonstrated a camouflaged tPA delivery system by conjugating tPA with human serum albumin followed by surface decoration with a thrombus-homing peptide (CQQHHLGGAKQAGDV) for thrombus-targeted delivery of tPA.…”

“…To date, a variety of fibrinolytic enzyme delivery systems have attempted to solve the above challenges. [ 17–23 ] For example, Jin et al. [ 24 ] and Berger et al.…”

Nanoassemblies of Self-Immolative Boronate-Bridged Retinoic Acid Dimeric Prodrug as a Clot-Targeted Self-Deliverable Antithrombotic Nanomedicine

“…In particular, despite their potent antithrombotic actions, the clinical use of antithrombotic drugs such as tissue plasminogen activator is limited by their shortcomings such as high risk of undesirable bleeding complications, short-half-life in circulation, and lack of thrombus targeting ability. 4 In this regard, the concept of targeted delivery systems and stimulus-responsive nanoprodrugs have been exploited to develop strategies to maximize the therapeutic efficacy of antithrombotic agents and minimize their adverse side effects. 5 atRA is a physiologically active metabolite of retinol, a family of vitamin A.…”