1. ¹Department of Neuroradiology, Universitätsklinikum Würzburg, Würzburg, Germany
2. ²Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA
3. ³Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon, USA
4. ⁴Advanced Imaging Research Center, Oregon Health and Science University, Portland, Oregon, USA
5. ⁵Department of Neurosurgery, Oregon Health and Science University, Portland, Oregon, USA
6. ⁶Veterans Administration Medical Center, Portland, Oregon, USA

Correspondence: Dr EA Neuwelt, Department of Neurology and Blood Brain Barrier Program, Oregon Health and Sciences University, 3181 Sam Jackson Parkway Road, L603, Portland, OR 97239, USA. E-mail: neuwelte@ohsu.edu

Received 9 September 2008; Revised 20 November 2008; Accepted 30 November 2008; Published online 14 January 2009.

Abstract

The vascular effects of antiangiogenic treatment may pose problems for evaluating brain tumor response based on contrast-enhanced magnetic resonance imaging (MRI). We used serial dynamic contrast-enhanced MRI at 12 T to assess vascular responses to antiangiogenic versus steroid therapy. Athymic rats with intracerebral U87MG human glioma (n=17) underwent susceptibility-weighted perfusion MRI with ferumoxytol, a solely intravascular ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle, followed by T1-weighted dynamic gadodiamide-enhanced MRI to measure vascular permeability. Rats were imaged before and after 24, 48, and 72 h of treatment with the antiangiogenic agent bevacizumab or the corticosteroid dexamethasone. Contrast agent extravasation was seen rapidly after gadodiamide, but not with ferumoxytol administration. Bevacizumab significantly decreased the blood volume and decreased permeability in tumors as determined by increased time-to-peak enhancement. A single dose of 45 mg/kg bevacizumab resulted in changes analogous to dexamethasone given in an extremely high dose (12 mg/kg per day), and was significantly more effective than dexamethasone at 2 mg/kg per day. We conclude that dynamic perfusion MRI measurements with ferumoxytol USPIO to assess cerebral blood volume, along with dynamic gadodiamide-enhanced MR to assess vascular permeability, hold promise in more accurately detecting therapeutic responses to antiangiogenic therapy.