Magnetic resonance imaging‐based detection of glial brain tumors in mice after antiangiogenic treatment

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Abstract
Proper delineation of gliomas using contrast‐enhanced magnetic resonance imaging (CE‐MRI) poses a problem in neuro‐oncology. The blood brain barrier (BBB) in areas of diffuse‐infiltrative growth may be intact, precluding extravasation and subsequent MR‐based detection of the contrast agent gadolinium diethylenetriaminepenta‐acetic acid (Gd‐DTPA). Treatment with antiangiogenic compounds may further complicate tumor detection as such compounds can restore the BBB in angiogenic regions. The increasing number of clinical trials with antiangiogenic compounds for treatment of gliomas calls for the development of alternative imaging modalities. Here we investigated whether CE‐MRI using ultrasmall particles of iron oxide (USPIO, Sinerem®) as blood pool contrast agent has additional value for detection of glioma in the brain of nude mice. We compared conventional T1‐weighted Gd‐DTPA‐enhanced MRI to T2*‐weighted USPIO‐enhanced MRI in mice carrying orthotopic U87 glioma, which were either or not treated with the antiangiogenic compound vandetanib (ZD6474, ZACTIMA™). In untreated animals, vessel leakage within the tumor and a relatively high tumor blood volume resulted in good MRI visibility with Gd‐DTPA‐ and USPIO‐enhanced MRI, respectively. Consistent with previous findings, vandetanib treatment restored the BBB in the tumor vasculature, resulting in loss of tumor detectability in Gd‐DTPA MRI. However, due to decreased blood volume, treated tumors could be readily detected in USPIO‐enhanced MRI scans. Our findings suggest that Gd‐DTPA MRI results in overestimation of the effect of antiangiogenic therapy of glioma and that USPIO‐MRI provides an important complementary diagnostic tool to evaluate response to antiangiogenic therapy of these tumors.