Targeting Contrast Agents With Peak Near-Infrared-II (NIR-II) Fluorescence Emission for Non-invasive Real-Time Direct Visualization of Thrombosis.

Kenneth S Hettie

doi:10.3389/fmolb.2021.670251

Abstract

Thrombosis within the vasculature arises when pathological factors compromise normal hemostasis. On doing so, arterial thrombosis (AT) and venous thrombosis (VT) can lead to life-threatening cardio-cerebrovascular complications. Unfortunately, the therapeutic window following the onset of AT and VT is insufficient for effective treatment. As such, acute AT is the leading cause of heart attacks and constitutes ∼80% of stroke incidences, while acute VT can lead to fatal therapy complications. Early lesion detection, their accurate identification, and the subsequent appropriate treatment of thrombi can reduce the risk of thrombosis as well as its sequelae. As the success rate of therapy of fresh thrombi is higher than that of old thrombi, detection of the former and accurate identification of lesions as thrombi are of paramount importance. Magnetic resonance imaging, x-ray computed tomography (CT), and ultrasound (US) are the conventional non-invasive imaging modalities used for the detection and identification of AT and VT, but these modalities have the drawback of providing only image-delayed indirect visualization of only late stages of thrombi development. To overcome such limitations, near-infrared (NIR, ca. 700–1,700 nm) fluorescence (NIRF) imaging has been implemented due to its capability of providing non-invasive real-time direct visualization of biological structures and processes. Contrast agents designed for providing real-time direct or indirect visualization of thrombi using NIRF imaging primarily provide peak NIR-I fluorescence emission (ca. 700–1,000 nm), which affords limited tissue penetration depth and suboptimal spatiotemporal resolution. To facilitate the enhancement of the visualization of thrombosis via providing detection of smaller, fresh, and/or deep-seated thrombi in real time, the development of contrast agents with peak NIR-II fluorescence emission (ca. 1000–1,700 nm) has been recently underway. Currently, however, most contrast agents that provide peak NIR-II fluorescence emissions that are purportedly capable of providing direct visualization of thrombi or their resultant occlusions actually afford only the indirect visualization of such because they only provide for the (i) measuring of the surrounding vascular blood flow and/or (ii) simple tracing of the vasculature. These contrast agents do not target thrombi or occlusions. As such, this mini review summarizes the extremely limited number of targeting contrast agents with peak NIR-II fluorescence emission developed for non-invasive real-time direct visualization of thrombosis that have been recently reported.

Highlights

Thrombosis (i.e., localized formation of a clot) in the vasculature can occur within the arterial or venous system when pathological factors compromise normal hemostasis, which is the complex process that maintains vascular integrity (e.g., in response to stasis, injury, or hypercoagulability) by regulating blood flow via platelet recruitment, fibrin formation, and blood coagulation (Rasche, 2001; Arnout et al, 2006; Tynngård et al, 2015; Stone et al, 2017; Yusof et al, 2019; Zhao Z. et al, 2020)
The use of targeting contrast agents that afford peak NIR-II fluorescence emission to directly interrogate Arterial thrombosis (AT) and venous thrombosis (VT) in real time via NIRF imaging holds tremendous promise, due to providing higher sensitivity, lower limits of detection, and superior resolution, as well as direct visualization, when compared to the standard non-invasive clinical imaging modalities such as MRI, X-ray CT, and US. These targeting contrast agents that demonstrate peak NIR-II fluorescence emission for directly imaging thrombosis maintain characteristics that are more favorable than those that display peak fluorescence emission in the visible and NIR-I spectral regions that are designed for similar purposes
The recent advent of targeting contrast agents with peak NIR-II fluorescence emission to selectively and/or identify biomarkers for direct visualization of thrombosis is a very new frontier that is ripe for significant advancements and acquisition of informative details in thrombosis, especially given the fact that an exhaustive review of the literature revealed that all of the contrast agents that provide peak NIR-II fluorescence emission purportedly for thrombosis imaging only allow for the indirect visualization of thrombi, non-occlusive thrombi, or occlusions, with the exception of two studies, which were set forth in detail in this comprehensive summary

Summary

Introduction

Thrombosis (i.e., localized formation of a clot) in the vasculature can occur within the arterial or venous system when pathological factors compromise normal hemostasis, which is the complex process that maintains vascular integrity (e.g., in response to stasis, injury, or hypercoagulability) by regulating blood flow via platelet recruitment, fibrin formation, and blood coagulation (Rasche, 2001; Arnout et al, 2006; Tynngård et al, 2015; Stone et al, 2017; Yusof et al, 2019; Zhao Z. et al, 2020).

Results

Conclusion