Edward A. Neuwelt
MRI is a critical clinical tool that guides treatment decisions for patients with brain tumors and other clinical issues. The current standard gadolinium-based contrast agents (GBCA) have limitations in medical imaging concerning inconsistent and unreliable measurement of relative cerebral blood volume (rCBV), which is emerging as an important component in accurately diagnosing patients with CNS inflammatory disorders, lymphoma, vascular malformations, and especially CNS tumors. In addition, there are patient populations that cannot receive GBCA due to impaired kidney function and the risk of nephrogenic systemic fibrosis.
In recent years, there have been advances in utilizing iron oxide nanoparticles to further the diagnostic aid of MRI. Ultrasmall superparamagnetic iron oxide (USPIO) agents such as ferumoxtran-10 (Combidex) and ferumoxytol (Feraheme) are virus-sized, carbohydrate-coated particles that serve as more than just contrast agents for MRI: localization of the iron particles can also be easily identified histologically and ultrastructurally by standard and electron microscopy, respectively.
Ferumoxytol consists of an iron oxide core that is easily utilized and incorporated into the body’s iron stores, and a semi-synthetic carbohydrate coating. Ferumoxytol was originally developed for the treatment of iron-deficiency anemia, but we have found it to be a superior perfusion contrast agent for assessing brain tumors. Ferumoxytol, unlike GBCA, is both a high molecular BBB imaging agent and is taken up by inflammatory cells. MRI using ferumoxytol shows a good correlation with GBCA-enhanced scans 24 hours post–ferumoxytol injection, and ferumoxytol improves the visualization of tumor vasculature, CNS vascular malformations, tumor-associated inflammation, and rCBV measurements.
One of our earliest publications on iron oxide nanoparticles in brain tumors was a preclinical study in AJNR by Remsen et al1 using antibody-conjugated iron oxide nanoparticles after initial assessment of these particles to track virus-sized particles in the CNS.2 Originally designed to study the potential for specific diagnosis of brain tumors (ideally to separate metastatic disease from primary CNS glioma), the nanoparticle immunoconjugate achieved limited success but led to the subsequent exploration of iron oxide nanoparticle use for neuroimaging. Many years later, given interval technological advances, we are revisiting the potential of antibody-conjugated iron oxide nanoparticles to improve CNS tumor characterization using ferumoxytol. Meanwhile, 4 articles outline excellent progress with ferumoxytol for both anatomic and dynamic MR, which, hopefully, will extend FDA approval for iron replacement to MR CNS imaging that could lead to improved targeted therapy.3-6
Our experience highlights the benefits and limitations of the use of USPIO-based MRI, which provides relevant information in CNS inflammatory, vascular, and neoplastic diseases. Our findings of USPIO-enhanced imaging give anatomic and physiologic information about the BBB and CNS vascular parameters. Importantly, USPIO imaging provides a safe alternative for MRI in patients with renal failure. Based on these findings our group is working with the US Food and Drug Administration to further the use of USPIO agents in the setting of MRI.
