Liver dysplasia: US molecular imaging with targeted contrast agent enables early assessment

• Published in: Radiology Vol. 267; no. 2; pp. 487 - 495
• Main Authors: Grouls, Christoph, Hatting, Maximillian, Rix, Anne, Pochon, Sibylle, Lederle, Wiltrud, Tardy, Isabelle, Kuhl, Christiane K, Trautwein, Christian, Kiessling, Fabian, Palmowski, Moritz
• Format: Journal Article
• Language: English
• Published: United States 01.05.2013
• Subjects: Animals; Contrast Media; Liver - diagnostic imaging; Liver - metabolism; Liver - pathology; Mice; Mice, Transgenic; Molecular Imaging; Phospholipids; Sensitivity and Specificity; Statistics, Nonparametric; Sulfur Hexafluoride; Ultrasonography; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 0033-8419; 1527-1315
• DOI: 10.1148/radiol.13120220

To investigate the ability of vascular endothelial growth factor receptor type 2 (VEGFR2)-targeted ultrasonographic (US) microbubbles for the assessment of liver dysplasia in transgenic mice. Animal experiments were approved by the governmental review committee. Nuclear factor-κB essential modulator knock-out mice with liver dysplasia and wild-type mice underwent liver imaging by using a clinical US system. Two types of contrast agents were investigated: nontargeted, commercially available, second-generation microbubbles (SonoVue) and clinically translatable PEGylated VEGFR2-targeted microbubbles (BR55). Microbubble kinetics was investigated over the course of 4 minutes. Targeted contrast material-enhanced US signal was quantified 5 minutes after injection. Competitive in vivo binding experiments with BR55 were performed in knock-out mice. Immunohistochemical and hematoxylin-eosin staining of liver sections was performed to validate the in vivo US results. Groups were compared by using the Mann-Whitney test. Peak enhancement after injection of SonoVue and BR55 did not differ in healthy and dysplastic livers (SonoVue, P = .46; BR55, P = .43). Accordingly, immunohistochemical findings revealed comparable vessel densities in both groups. The specificity of BR55 to VEGFR2 was proved by in vivo competition (P = .0262). While the SonoVue signal decreased similarly in healthy and dysplastic livers during the 4 minutes, there was an accumulation of BR55 in dysplastic livers compared with healthy ones. Furthermore, targeted contrast-enhanced US signal indicated a significantly higher site-specific binding of BR55 in dysplastic than healthy livers (P = .005). Quantitative immunohistologic findings confirmed significantly higher VEGFR2 levels in dysplastic livers (P = .02). BR55 enables the distinction of early stages of liver dysplasia from normal liver.