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Magnetic Resonance Imaging Visualization of Hyaluronidase in Ovarian Carcinoma

Departments of ¹ Biological Regulation, ² Molecular Cell Biology, and ³ Chemical Research Support, The Weizmann Institute of Science, Rehovot, Israel and ⁴ Department of Pathology, School of Medicine, University of California at San Francisco, San Francisco, California

Requests for reprints: Michal Neeman, Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel. Phone: 972-8-9342487; Fax: 972-8-9342487; E-mail: michal.neeman{at}weizmann.ac.il.

Hyaluronan, a high molecular weight, negatively charged polysaccharide, is a major constituent of the extracellular matrix. High molecular weight hyaluronan is antiangiogenic, but its degradation by hyaluronidase generates proangiogenic breakdown products. Thus, by expression of hyaluronidase, cancer cells can tilt the angiogenic balance of their microenvironment. Indeed, hyaluronidase-mediated breakdown of hyaluronan correlates with aggressiveness and invasiveness of ovarian cancer metastasis and with tumor angiogenesis. The goal of this work was to develop a novel smart contrast material for detection of hyaluronidase activity by magnetic resonance imaging (MRI). Gadolinium-diethylenetriaminepentaacetic acid (GdDTPA) covalently linked to hyaluronan on the surface of agarose beads showed attenuated relaxivity. Hyaluronidase, either purified from bovine testes or secreted by ES-2 and OVCAR-3 human epithelial ovarian carcinoma cells, activated the hyaluronan-GdDTPA-beads by rapidly altering the R₁ and R₂ relaxation rates. The change in relaxation rates was consistent with the different levels of biologically active hyaluronidase secreted by those cells. Hyaluronan-GdDTPA-beads were further used for demonstration of MRI detection of hyaluronidase activity in the proximity of s.c. ES-2 ovarian carcinoma tumors in nude mice. Thus, hyaluronan-GdDTPA-beads could allow noninvasive molecular imaging of hyaluronidase-mediated tilt of the peritumor angiogenic balance.

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