Thrombus-Targeted Theranostic Microbubbles: A New Technology towards Concurrent Rapid Ultrasound Diagnosis and Bleeding-free Fibrinolytic Treatment of Thrombosis

Abstract

Rationale: Myocardial infarction and stroke are leading causes of morbidity/mortality. The typical underlying pathology is the formation of thrombi/emboli and subsequent vessel occlusion. Systemically administered fibrinolytic drugs are the most effective pharmacological therapy. However, bleeding complications are relatively common and this risk as such limits their broader use. Furthermore, a rapid non-invasive imaging technology is not available. Thereby, many thrombotic events are missed or only diagnosed when ischemic damage has already occurred.Objective: Design and preclinical testing of a novel 'theranostic' technology for the rapid non-invasive diagnosis and effective, bleeding-free treatment of thrombosis.Methods and Results: A newly created, innovative theranostic microbubble combines a recombinant fibrinolytic drug, an echo-enhancing microbubble and a recombinant thrombus-targeting device in form of an activated-platelet-specific single-chain antibody. After initial in vitro proof of functionality, we tested this theranostic microbubble both in ultrasound imaging and thrombolytic therapy using a mouse model of ferric-chloride-induced thrombosis in the carotid artery. We demonstrate the reliable highly sensitive detection of in vivo thrombi and the ability to monitor their size changes in real time. Furthermore, these theranostic microbubbles proofed to be as effective in thrombolysis as commercial urokinase but without the prolongation of bleeding time as seen with urokinase.Conclusions: We describe a novel theranostic technology enabling simultaneous diagnosis and treatment of thrombosis, as well as monitoring of success or failure of thrombolysis. This technology holds promise for major progress in rapid diagnosis and bleeding-free thrombolysis thereby potentially preventing the often devastating consequences of thrombotic disease in many patients.

Thrombolytic therapy based on fucoidan-functionalized polymer nanoparticles targeting P-selectin

“…The in vitro binding assays performed on recombinant P-selectin confirmed that fucoidan could efficiently recognize and bind P-selectin, even when incorporated in the polysaccharide shell (Figure 3). Interestingly, this experiment showed that the affinity of Fuco-NPs for P-selectin was observed both at low shear stress (6.75 dyne/cm 2 ) and at high shear stress (67.5 dyne/cm 2 ), whereas most in vitro affinity assays described in the literature are performed in static conditions [21,24] or at very low (<6.75 dyne/cm 2 ) or uncontrolled shear stress [50,51].…”

An unmet clinical need: The history of thrombus imaging

“…98,99 In addition to imaging, microbubbles offer a theranostic component to the treatment of thrombus through mechanical disruption by particle cavitation and local release of fibrinolytic agents. 100,101 …”

Click‐Chemistry‐Mediated Rapid Microbubble Capture for Acute Thrombus Ultrasound Molecular Imaging

“…Thrombosis is developed through blood vessel wall damage or through a pathological process that induces activation of coagulation factor to cause accumulation of platelets and fibrin . Although many imaging strategies—including magnetic resonance imaging (MRI), ultrasound, computed tomography (CT), etc.—for visualization of the thrombus formation process have been developed, the specific detection and rapid evaluation of thrombotic events, especially at the molecular level, still presents a major clinical challenge. Ultrasound is a clinical diagnostic imaging modality that is widely available, portable, and non‐invasive for visualizing anatomy and physiology .…”