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Research Articles: Therapeutics, Targets, and Development

Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects

¹ Department of Diagnostic Radiology, Ruprecht-Karls University; ² Junior Group Molecular Imaging, ³ Department of Medical Physics in Radiology, German Cancer Research Center, Heidelberg, Germany; ⁴ Department of Neurology, University of Erlangen, Germany; ⁵ Global Drug Discovery, Bayer Schering Pharma AG, Berlin, Germany; and ⁶ Group Tumor and Microenvironment, and ⁷ Clinical Cooperation Unit Radiotherapy, German Cancer Research Center, Heidelberg, Germany

Requests for reprints: Fabian Kiessling, Junior Group Molecular Imaging, German Cancer Research Center, INF 280, D-69120 Heidelberg, Germany. Phone: 49-6221-422533; Fax: 49-6221-422572. E-mail: f.kiessling{at}dkfz.de

Abstract

Molecular ultrasound is capable of elucidating the expression of angiogenic markers in vivo. However, the capability of the method for volumetric "multitarget quantification" and for the assessment of antiangiogenic therapy response has rather been investigated. Therefore, we generated cyanoacrylate microbubbles linked to vascular endothelial growth factor receptor 2 (VEGFR2) and _vβ₃ integrin binding ligands and quantified their accumulation in squamous cell carcinoma xenografts (HaCaT-ras-A-5RT3) in mice with the quantitative volumetric ultrasound scanning technique, sensitive particle acoustic quantification. Specificity of VEGFR2 and _vβ₃ integrin binding microbubbles was shown, and changes in marker expression during matrix metalloproteinase inhibitor treatment were investigated. In tumors, accumulation of targeted microbubbles was significantly higher compared with nonspecific ones and could be inhibited competitively by addition of the free ligand in excess. Also, multimarker imaging could successfully be done during the same imaging session. Molecular ultrasound further indicated a significant increase of VEGFR2 and _vβ₃ integrin expression during tumor growth and a considerable decrease in both marker densities after matrix metalloproteinase inhibitor treatment. Histologic data suggested that the increasing VEGFR2 and _vβ₃ integrin concentrations in tumors during growth are related to an up-regulation of its expression by the endothelial cells, whereas its decrease under therapy is more related to the decreasing relative vessel density. In conclusion, targeted ultrasound appears feasible for the longitudinal molecular profiling of tumor angiogenesis and for the sensitive assessment of therapy effects in vivo. [Mol Cancer Ther 2008;7(1):101–9]

Grant support: BMBF (Quantitative molekulare Bildgebung mit spezifischen Ultraschallkontrastmitteln) and DFG (SFB TR23).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: M. Palmowski and J. Huppert contributed equally to this work.

Received 6/15/07; revised 10/22/07; accepted 12/ 4/07.

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