Establishment of Functional and Molecular Ultrasound for Breast Cancer Xenograft Imaging

Correspondence Frau Dr. Jessica Bzyl Institute for Experimental Molecular Imaging, RWTH Aachen University Pauwelsstraße 20 52074 Aachen Germany Tel.: ++ 49/2 41/8 080116 Fax: ++ 49/2 41/8 03382006 [email protected] The present work was originally published in European Radiology [1, 2] and as a PhD thesis at the RWTH Aachen University [3] and was conducted at the Institute for Experimental Molecular Imaging at the RWTH Aachen University. Among women, breast cancer is the most frequently diagnosed cancer worldwide. Accurate and sensitive imaging techniques are needed to help decrease the mortality rate by early detection of breast cancer. Contrast-enhanced ultrasound with non-targeted microbubbles in patients was shown to possibly help to predict prognosis and to noninvasively detect highly aggressive breast cancers [4]. This technique is called functional ultrasound. Due to their size of 2–5μm, the microbubbles stay strictly intravascular and the relative blood volume (rBV) of a tumor can be determined, reflecting its angiogenic activity und thus, the tumor’s aggressiveness. A further technique for the characterization of the breast cancer’s aggressiveness may be molecular ultrasound imaging. The microbubbles, now targeted to tumor-endothelial angiogenic markers, bind to their specific target upon injection and a relative quantification of marker expression within the tumor endothelium can be performed noninvasively. In the present work two types of microbubbles were used [1, 2]. For molecular ultrasound this was BR55. A heterodimer selectively binding to human and murine vascular endothelial growth factor receptor type 2 (VEGFR-2) was conjugated to DSPE-PEG-2000-NH2 which was then incorporated into the microbubbles’ lipid shell. A detailed description can be found in [5]. VEGFR-2 is one of the most characterized tumor-angiogenic markers. For functional ultrasound BR38 was applied, consisting of non-targeted, PEGylated microbubbles, i. e. microbubbles with a Polyethylenglycol (PEG) brush. Their lipid shell contains DPPE-MPEG 5000 that contributes to a long persistence of the microbubbles in the blood system [6]. Both, BR38 and BR55 were designed for clinical application. In the first study the circulating characteristics of BR55 and BR38 microbubbles in healthy mice and their ability to characterize the angiogenic activity of differently aggressive human breast adenocarcinomas were evaluated [1]. BR38 showed a long blood half-life of more than ten minutes and a relatively slow uptake by the liver. For clinical use the long circulation time of BR38 might be beneficial because it allows an intensive examination of one or even several different organs. The VEGFR-2 targeted BR55 microbubbles had a relatively short blood half-life of about 4min. An early accumulation of these microbubbles was obPromotionspreis 2013 377