Fibrin-Targeted and H₂O₂-Responsive Nanoparticles as a Theranostics for Thrombosed Vessels

Abstract

A thrombus (blood clot) is formed in injured vessels to maintain the integrity of vasculature. However, obstruction of blood vessels by thrombosis slows blood flow, leading to death of tissues fed by the artery and is the main culprit of various life-threatening cardiovascular diseases. Herein, we report a rationally designed nanomedicine that could specifically image obstructed vessels and inhibit thrombus formation. On the basis of the physicochemical and biological characteristics of thrombi such as an abundance of fibrin and an elevated level of hydrogen peroxide (HO), we developed a fibrin-targeted imaging and antithrombotic nanomedicine, termed FTIAN, as a theranostic system for obstructive thrombosis. FTIAN inhibited the generation of HO and suppressed the expression of tumor necrosis factor-alpha (TNF-α) and soluble CD40 ligand (sCD40L) in activated platelets, demonstrating its intrinsic antioxidant, anti-inflammatory, and antiplatelet activity. In a mouse model of ferric chloride (FeCl)-induced carotid thrombosis, FTIAN specifically targeted the obstructive thrombus and significantly enhanced the fluorescence/photoacoustic signal. When loaded with the antiplatelet drug tirofiban, FTIAN remarkably suppressed thrombus formation. Given its thrombus-specific imaging along with excellent therapeutic activities, FTIAN offers tremendous translational potential as a nanotheranostic agent for obstructive thrombosis.

Bioresponsive drug delivery systems for the treatment of inflammatory diseases

“…In other studies, ROS-responsive as well as pH- and/or thrombin-responsive nanotherapies were examined for targeted treatment of thrombus formation [ 330 ], peripheral arterial disease [ 226 ], and ischemic stroke [ [331] , [332] , [333] , [334] ], offering promising therapeutic effects in different animal models. Collectively, studies by others and our group demonstrated that bioresponsive nanotherapies possess great potential for precision therapy of different inflammatory vascular diseases.…”

COVID-19: Nanomedicine Uncovers Blood-Clot Mystery

“…Using H 2 O 2 -responsive boronate antioxidant polymer (BAP) linked to fibrin-targeting lipopeptides, Kang et al showed that the nanoparticles could deliver tirofiban to the thrombus site in rat models inhibiting the generation of H 2 O 2 , therefore suppressing TNF-α and soluble CD40. 47 Similarly, by the use of iron oxide nanoparticle micelles functionalized with a fibrin-specific binding peptide as well as bare nanoparticles, thrombus sites have been detected using magnetic particle imaging. 48 Ultrasmall superparamagnetic iron oxide nanoparticles coated with fucoidan, a polysaccharide with high affinity for activated platelets, have been shown to attach to P-selectin and assist with in vivo diagnosis of thrombus formation.…”

Targeting Oxidative Stress Using Nanoparticles as a Theranostic Strategy for Cardiovascular Diseases

“…The conversion of fibrinogen to fibrin by thrombin is a critical step in thrombus formation (113,121). Various investigators have used nanoparticles targeting fibrin to image clots in different animal and human models of thrombus formation (51,75,110). EP-2104R, an MRI contrast agent designed to detect thrombus by binding to the fibrin, has been showed to effectively detect thrombi with high sensitivity (4,104).…”

“…Nanomaterial-based imaging agents that target other components of the blood clotting factors, such as thrombin and factor XIIIA, have been also studied (59,110). The pentapeptide Cys-Arg-Glu-Lys-Ala has been shown to be specific for the fibrinogen/fibrin complex in a newly formed clot and has been used for bioimaging of active thrombus formation (51).…”