Marybeth Anne Pysz PhD, Abstract Co-Author: Nothing to Disclose

Michel Schneider, Abstract Co-Author: Employee, Bracco Group

Sanjiv S. Gambhir MD, PhD, Abstract Co-Author: Board of Directors, Lumera Corporation Stockholder, Lumera Corporation Stockholder, Pfizer Inc Consultant, Spectrum Dynamics Ltd Stockholder, Spectrum Dynamics Ltd Grant, Johnson & Johnson Committee member, Amgen Inc Scientific Advisory Board, Novartis AG Scientific Advisory Board, Siemens AG Royalties, Reed Elsevier Scientific Advisory Board, Genentech, Inc Scientific Advisory Board, General Electric Company Grant, General Electric Company Research collaboration, GlaxoSmithKline plc Scientific Advisory Board, GlaxoSmithKline plc Scientific Advisory Board, Intronn Inc Research collaboration, Intronn Inc Grant, Intronn Inc Scientific Advisory Board, Lumen Therapeutics Consultant, MediGene AG Scientific Advisory Board, MediGene AG Consultant, Millennium Pharmaceuticals, Inc Research collaboration, Pfizer Inc Grant, Pfizer Inc Consultant, Koninklijke Philips Electronics NV Scientific Advisory Board, Koninklijke Philips Electronics NV Consultant, Pathwork Diagnostics Grant, Bayer AG Speaker, Siemens AG Scientific Advisory Board, Varian Medical Systems, Inc Scientific Advisory Board, VisualSonics Inc

Juergen Karl Willmann MD, Presenter: Nothing to Disclose

KDR, the human vascular endothelial growth factor receptor type 2 (VEGFR2), is overexpressed on angiogenic vessels in many cancers. Previous studies have shown that molecular ultrasound using targeted contrast microbubbles allows VEGFR2 imaging at the molecular level. However, many targeted microbubbles are constructed with streptavidin-biotin chemistry that is toxic in humans. Since non-invasive molecular ultrasound imaging for detection and treatment monitoring of cancer holds large potential for clinical translation, the purpose of this study was to develop and test novel human KDR-targeted contrast microbubbles using binding chemistry that allows a future use in patients.

A peptide that binds to KDR with high affinity was isolated with phage display and coupled onto the surface of perfluorobutane-filled, lipid-shelled contrast microbubbles (KDR-MB). Binding specificity of KDR-MB compared to control MB was tested on KDR-positive and -negative cells under flow stress conditions (100 s-1) in a parallel plate flow chamber. In vivo binding specificity of KDR-MB was tested in human LS174T colon carcinoma tumor xenografts in mice (n=6) using a high-resolution (40 MHz) ultrasound system. In addition, in vivo imaging signal in mice with (n=4) and without (n=4) anti-angiogenic treatment was recorded every 24h for a total of 3 days and correlated with ex vivo KDR vascular expression levels and microvessel density (MVD) analysis using immunofluorescence.

Flow chamber experiments confirmed KDR binding specificity of KDR-MB compared to control MB (P<0.05). In vivo imaging signal was significantly higher (P<0.001) with KDR-MB compared with control MB, and significantly (P<0.007) dropped by 60% following receptor blocking with an antibody, thus, confirming in vivo binding specificity of KDR-MB. In vivo imaging signal was significantly (P<0.03) reduced in anti-angiogenic treated tumor-bearing animals compared with non-treated animals. Ex vivo analysis confirmed both reduced MVD and KDR expression levels in treated versus non-treated tumors.

Our results suggest that human KDR-targeted microbubbles can be developed that allow detection and quantification of KDR expression at the molecular level in vivo.

Our study is a further step towards a future clinical translation of molecular ultrasound imaging in cancer patients.

Pysz, M, Schneider, M, Gambhir, S, Willmann, J, Development and Preclinical Characterization of Novel Clinically Translatable Contrast Microbubbles for Molecular Ultrasound Imaging of KDR Expression in Cancer.  Radiological Society of North America 2009 Scientific Assembly and Annual Meeting, November 29 - December 4, 2009 ,Chicago IL. http://archive.rsna.org/2009/8005261.html