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.