Molecular Ultrasound Imaging

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.

InVivo Molecular Ultrasound Assessment of Glioblastoma Neovasculature with Endoglin-Targeted Microbubbles

Objectives. Glioblastoma, as one of the most malignant cancer in the world, usually shows substantially increased angiogenesis. Endoglin (CD105), which is an alternative proangiogenic growth factor, has been remarkably upregulated on the proliferating glioblastoma neovasculature. However, little is known on the noninvasive assessment of the expression levels of CD105 during glioblastoma progression. Herein, we investigated the potential of the molecular ultrasound imaging for the noninvasive assessment of the expression levels of the biomarker CD105 during the glioblastoma progression. Materials and Methods. The CD105-targeted perfluorocarbon-containing lipid-shelled microbubbles (MBs) were prepared. A parallel flow chamber was employed, in which the CD105-targeted and non-targeted MBs were tested across the CD105 ± expression cell lines. In vivo molecular US imaging was conducted based on a subcutaneous xenograft tumor model (n=9). Finally, the statistical analysis was conducted to quantitatively correlate the attachment numbers of MBs in the parallel flow chamber test with the CD105 expression levels of the cells in the flow cytometry test and the in vivo molecular ultrasound signals with the ex vivo expression levels of CD105 in the immunohistochemical test. Results and Discussion. The attachment numbers of the CD105-targeted MBs significantly correlated with the CD105 expression levels of the cells in the parallel flow chamber test. There was a good correlation between the in vivo molecular ultrasound signals with the CD105-targeted MBs and the ex vivo expression levels of CD105 in the immunohistochemical test. The results indicate that the molecular US imaging is much potential to assess the progression of the glioblastoma neovasculature noninvasively.