Molecularly Engineered Theranostic Nanoparticles for Thrombosed Vessels: H₂O₂-Activatable Contrast-Enhanced Photoacoustic Imaging and Antithrombotic Therapy

Abstract

A thrombus (blood clot), composed mainly of activated platelets and fibrin, obstructs arteries or veins, leading to various life-threatening diseases. Inspired by the distinctive physicochemical characteristics of thrombi such as abundant fibrin and an elevated level of hydrogen peroxide (HO), we developed thrombus-specific theranostic (T-FBM) nanoparticles that could provide HO-triggered photoacoustic signal amplification and serve as an antithrombotic nanomedicine. T-FBM nanoparticles were designed to target fibrin-rich thrombi and be activated by HO to generate CO bubbles to amplify the photoacoustic signal. In the phantom studies, T-FBM nanoparticles showed significant amplification of ultrasound/photoacoustic signals in a HO-triggered manner. T-FBM nanoparticles also exerted HO-activatable antioxidant, anti-inflammatory, and antiplatelet activities on endothelial cells. In mouse models of carotid arterial injury, T-FBM nanoparticles significantly enhanced the photoacoustic contrast specifically in thrombosed vessels and significantly suppressed thrombus formation. We anticipate that T-FBM nanoparticles hold great translational potential as nanotheranostics for HO-associated cardiovascular diseases.

Photoacoustic Imaging: Contrast Agents and Their Biomedical Applications

“…PA imaging showed an irregular margin in the vessel surrounding the highlighted thrombus; however, when the thrombolytic agent was injected, the margin was gradually smoothed out and eventually regained the appearance of a normal vessel (Figure C). Lee and co‐workers reported a PA contrast agent and theranostic nanoagent (T‐FBM) offering an enhanced PA signal via H 2 O 2 ‐triggered CO 2 ‐bubble production that is suitable in the treatment of H 2 O 2 ‐associated vascular diseases through the release of anti‐inflammatory agents and antioxidants (Figure D) . In an in vivo mouse model of FeCl 3 ‐induced arterial thrombosis (Figure E), T‐FBM NPs showed a stronger ratiometric (thrombus/normal tissue) PA signal than that of the control nanoagent T‐FPLGA (Figure F,H), proving the good targeting ability of T‐FBM NPs to thrombus.…”

“…PA imaging has also been employed to evaluate the treatment efficacy of vasculature‐related diseases such as atherosclerosis and thrombus . For example, Fan and co‐workers prepared cRGD‐PDI NPs that bind glycoprotein IIb/IIIa (GPIIb/IIIa), which can specifically highlight early thrombus by PA imaging.…”

“…Copyright 2017, American Chemical Society. (D–G) Reproduced with permission . Copyright 2018, American Chemical Society.…”

Nano-Medicine for Thrombosis: A Precise Diagnosis and Treatment Strategy

“…Other than organic or inorganic nanostructures, a number of biomimetic nanoparticles have been applied in drug delivery systems for disease treatment [84,85]. Among them, cell [80]. Copyright 2018 American Chemical Society membrane nanoparticles obtained from natural cells have been widely studied due to their high biocompatibility, long circulation, and genetic engineering modification [86][87][88][89][90].…”

Technology Advancements in Blood Coagulation Measurements for Point-of-Care Diagnostic Testing

“…This hybrid has a significant and dose-dependent increase in photoacoustic signal in the presence of both heparin and low molecular weight heparin (LMWH) (Wang et al, 2016). Responsive thrombus-specific theranostic (T-FBM) nanoparticles that could provide H 2 O 2 -triggered photoacoustic signal amplification have been shown to be used as an antithrombotic nanomedicine (Jung et al, 2018).…”