Non-invasive, high-resolution contrast-enhanced MRI techniques are useful tools to characterize physiological changes in the vasculature and inflammatory processes in brain tumors and CNS lesions. Our recent studies have focused on the iron oxide nanoparticle contrast agent ferumoxytol (Feraheme, AMAG Pharmaceuticals). Ferumoxytol acts as a blood pool agent at early times (minutes to hours) after IV infusion, decreasing leakage artifact and improving measurements of relative cerebral blood volume (rCBV) in brain lesions compared to GBCA. We have directly compared dynamic susceptibility-weighted contrast-enhanced (DSC) MRI using ferumoxytol and GBCA. The new technique of steady-state T2*-weighted MRI with ferumoxytol further improves blood volume measurements by providing high resolution CBV maps without image distortions (Varallyay 2013). Ferumoxytol provides an additional advantage to neuroimaging because the nanoparticles traverse the blood-tumor barrier over hours to days after infusion and are taken up by phagocytic cells (macrophages and activated microglia) in and around brain tumors and CNS lesions. Finally, we use dynamic contrast-enhanced (DCE) MRI with GBCA to measure the permeability of the blood-brain barrier and the neurovascular unit.

Our pre-clinical studies have used dynamic and steady-state neuroimaging techniques to evaluate tumor vasculature changes during therapy in animal models of primary and metastatic brain tumors. Ferumoxytol improved the consistency of rCBV measurements in a rat model of glioblastoma treated with the anti-VEGF monoclonal antibody bevacizumab (Gahramanov 2011). Importantly, perfusion imaging with ferumoxytol does not require contrast preload, leakage correction, or the technical and mathematical manipulations that are necessary with rapidly extravasating GBCA. In a lung cancer brain metastasis model, treatment with bevacizumab decreased tumor rCBV while treatment with an antibody targeting αv integrin cell adhesion proteins increased tumor rCBV (Muldoon 2011). Blood volume measurements on MRI correlated with vascular markers on immunohistochemistry and with areas of treatment-induced necrosis (high and low rCBV, respectively). Bevacizumab decreased tumor vascular permeability to a low molecular weight marker in a lung adenocarcinoma brain metastasis model (Pishko 2015). This study showed that Ktrans measurements of drug permeability correlated with radiolabeled drug delivery only after vascular normalization with bevacizumab.

In rat brain tumor models as well as a rat model of acute neuroinflammation, 24h delayed MRI shows ferumoxytol uptake as signal dropout in and around the lesion. Immunohistochemistry for the dextran-based coating on ferumoxytol localizes ferumoxytol to macrophages within necrotic areas and astrocyte processes and endfeet surrounding cerebral vessels, but not tumor cells.

In patients with malignant brain tumors, radiographic worsening after radiochemotherapy can be caused by true tumor progression or by treatment-induced inflammatory changes called pseudoprogression that is associated with a favorable prognosis. Differentiating tumor progression from pseudoprogression is crucially important for clinical decisions such as continuing effective therapy or moving patients to experimental treatment. High rCBV on DSC-MRI or steady-state MRI with ferumoxytol is associated with tumor progression while low rCBV is indicative of pseudoprogression (Gahramanov 2014, Nasseri 2014, Varallyay 2013). We have shown that delayed imaging changes after ferumoxytol may provide a tool to evaluate inflammatory changes in patients with brain tumors and other neurological lesions such as MS and vascular lesions such as cavernomas, arterio-venous malformations and stroke (Dosa 2011, Farrell 2013). Our colleagues are studying pediatric imaging, lymph node imaging and diabetic foot ulcers outside the CNS and the list is growing.

We have introduced the concept of dual-contrast imaging during a single MRI session: GBCA for BBB integrity assessment, and ferumoxytol for CBV assessment, and 24 h later assessment of inflammation. Dual-contrast imaging may mark the beginning of a multicontrast imaging era when different contrast agents are applied for specific purposes to confirm or rule out certain tumor types. Using different contrast agents for specific applications in patients conforms to recent recommendations for “high-value MRI exams”, and entails specifically tailored imaging sessions for each patient. In 2011, we gained orphan drug designation for use of ferumoxytol in MRI for the management of brain tumors and for imaging in brain metastases. We are working with AMAG Pharma and the FDA to move toward market approval of ferumoxytol for brain MRI imaging with ferumoxytol. We have developed multiple clinical trials to assess ferumoxytol as a MRI contrast agent for anatomic, dynamic, and steady-state MRI of intracerebral tumors. We anticipate that based on this work, improved and specific neuroimaging will be incorporated into standard of care for assessing therapy-induced changes in brain tumor vasculature and improving detection of brain tumor response to therapy.