Abstract

In the last decade, molecular ultrasound imaging has been rapidly progressing. It has proven promising to diagnose angiogenesis, inflammation, and thrombosis, and many intravascular targets, such as VEGFR2, integrins, and selectins, have been successfully visualized in vivo. Furthermore, pre-clinical studies demonstrated that molecular ultrasound increased sensitivity and specificity in disease detection, classification, and therapy response monitoring compared to current clinically applied ultrasound technologies. Several techniques were developed to detect target-bound microbubbles comprising sensitive particle acoustic quantification (SPAQ), destruction-replenishment analysis, and dwelling time assessment. Moreover, some groups tried to assess microbubble binding by a change in their echogenicity after target binding. These techniques can be complemented by radiation force ultrasound improving target binding by pushing microbubbles to vessel walls. Two targeted microbubble formulations are already in clinical trials for tumor detection and liver lesion characterization, and further clinical scale targeted microbubbles are prepared for clinical translation. The recent enormous progress in the field of molecular ultrasound imaging is summarized in this review article by introducing the most relevant detection technologies, concepts for targeted nano- and micro-bubbles, as well as their applications to characterize various diseases. Finally, progress in clinical translation is highlighted, and roadblocks are discussed that currently slow the clinical translation.

Highlights

  • Ultrasound (US) imaging, known as sonography, is used routinely in clinics for examining various organs of the body to diagnose, localize, and characterize diseases

  • This method favorably works for lipid-bound ligands such as phosphatidylserine [15] and phospholipid-heteropeptides binding to the vascular endothelial growth factor receptors 2 (VEGFR2) [16], because they can withstand harsh MB synthesis conditions

  • The results showed that the more aggressive tumor model (MDA-MB-231) had the higher total expression of VEGFR2 compared to MCF-7 according to VEGFR2-targeted US measurements and immunohistochemistry

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Summary

Introduction

Ultrasound (US) imaging, known as sonography, is used routinely in clinics for examining various organs of the body to diagnose, localize, and characterize diseases. The preclinical results indicate that actively targeted MB can detect angiogenesis, inflammation, and thrombus formation [3]. In this context, even small changes in marker expression can be quantified by molecular US. Drug or gene uptake is facilitiated by increasing the permeability of cell membranes and biological barriers with oscillating or bursting MB. This topic is already addressed in recent review articles [5,6,7]. In the context of the latter, this paper discusses challenges that have to be overcome to accelerate clinical translation

Detection Technologies
Functionalization of Contrast Agents
Angiogenesis
Inflammation and Atherosclerosis
Thrombosis
Multiple Targets
Targeted MB in The Clinics
Phase Shift Nanodroplets
Conclusions
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