Dousset V, Brochet B, Deloire MSA, et al. MR Imaging of Relapsing Multiple Sclerosis Patients Using Ultra-Small-Particle Iron Oxide and Compared with Gadolinium. AJNR Am J Neuroradiol 2006;27:1000–05

Bronwyn Hamilton

Joao Prola Netto

Dousset et al provided an early demonstration of the utility of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles in clinical neuroradiology. This clinical study showed that ferumoxtran-10 could be used to image CNS lesions in multiple sclerosis and revealed different enhancement patterns compared with gadolinium-based contrast agents (GBCA) in the same patients. Enhancement was observed on T1-weighted sequences and areas of new hypointensity on T2-weighted sequences. Signal changes with ferumoxtran-10 appear to occur primarily in areas with macrophage infiltration, based on preclinical work predating this study.¹ Dousset’s study in humans showed that aside from areas of blood-brain barrier disruption, USPIO signal changes on T1 and T2 can identify inflammatory processes.

We subsequently demonstrated that ferumoxytol also shows signal changes on T1WI and T2WI sequences in demyelinating disease, as well as in primary CNS lymphoma (PCNSL) and lymphoproliferative disorder.²  Similar to the findings by Dousset et al, we observed different enhancement patterns compared to GBCA-enhanced scans in some patients. This supported differences in mechanism of enhancement (ie, intracellular uptake with iron oxide nanoparticles) between iron oxide nanoparticles and GBCA. Such differences might distinguish patients with differing degrees of inflammation that may have prognostic or therapeutic importance. Unlike ferumoxtran-10, ferumoxtyol can safely be used for dynamic susceptibility contrast perfusion imaging, and offers more reliable results than GBCA. We have used this for distinguishing lymphoid neoplasm from tumefactive demyelination. Our preliminary results showed rCBV values for PCNSL and lymphoproliferative disorders ranging from 1.3 to 4.1, while rCBV ratios for tumefactive demyelinating lesions ranged from 0.3 to 0.9. The T2WI signal changes characteristic of iron particles also improved neurosurgical targeting opportunities for biopsy (Figure 1).²

Trafficking of cell-based therapeutics such as hematopoietic stem cells, neural stem cells, or T cells could also be monitored noninvasively using ferumoxtyol. Currently, imaging detection of transplanted cell localization and viability require radionuclide labeling or incorporation of reporter genes into the cellular genome, with obvious limitations to FDA approval. We and others have shown that cells labeled with ferumoxides could be detected on MRI in vivo, but ferumoxytol was poorly taken up by cells.³ An alternative technique to label cells uses aggregation of ferumoxytol, heparin, and protamine to form “self-assembling nanocomplexes” that are taken up by a variety of human cells in vitro and could be used to monitor cell trafficking.⁴ The Thu et al preclinical study confirmed detection of transplanted cells with 3T MRI using T2*-weighted gradient echo, and intracellular localization within endosomes was visible on electron microscopy.⁴ The pathway to an investigational new drug application for clinical use of ferumoxytol for cell labeling could be shortened because each of the 3 components of the self-assembling complex are already FDA-approved medications. Alternatively, as just published in Radiology by Khurana et al,⁵ in vivo labeling of bone marrow was better than in vitro. Dr. Csanád Várallyay from our group just presented, at the 2013 ASNR 51st Annual Meeting, high levels of bone marrow uptake in 39 patients 24 hours after IV ferumoxytol, which was dose-dependent, supporting such in vivo labeling of hematopoietic stem cells.

An important way our research has impacted our own clinical practice has been the ability to provide ferumoxytol-enhanced MRI to patients with renal failure. Although this experience remains limited due to reimbursement issues, it could have a beneficial impact on patient care. One recent example is a young adult male with suspected multiple sclerosis or intracranial neoplasm based on an unenhanced MRI. He had significant renal failure that precluded GBCA-enhanced MRI due to risks for nephrogenic systemic fibrosis. He received ferumoxytol-enhanced MRI that provided a target lesion for stereotactic biopsy (Figure 2). Histology confirmed an entirely unsuspected diagnosis—in this HIV-negative individual with no history of natalizumab exposure—that completely changed the course of his workup: progressive multifocal leukoencephalopathy. A major obstacle to providing this service is the greater cost (approximately $400 per dose) and lack of insurance coverage for using ferumoxytol contrast in routine MRI compared with GBCA. One caveat: if the radiologist is not aware that ferumoxytol has been given prior to an MR exam, interpretation of the MR study can be compromised as stated on the package insert.

Our group has met independently with the FDA in order to try and secure an imaging labeling indication for ferumoxytol, something usually only feasible through pharmaceutical industry funding. We previously achieved orphan designation for ferumoxytol as an imaging agent for cerebral glioma and intracranial metastatic disease, and hope to move it forward to broader market approval as a complementary contrast agent to GBCA. If successful, we believe doing so will significantly advance research in this area and promote the use of ferumoxytol in the clinical arena.

References

1. Muldoon LL, Manninger S, Pinkston KE, et al. Imaging, distribution, and toxicity of superparamagnetic iron oxide magnetic resonance nanoparticles in the rat brain and intracerebral tumor. Neurosurgery 2005;57:785–96. doi: 10.1227/01.NEU.0000175731.25414.4c
2. Farrell BT, Hamilton BE, Dósa E, et al. Using iron oxide nanoparticles to diagnose CNS inflammatory diseases and PCNSL. Neurology 2013;81:256–63. doi: 10.1212/WNL.0b013e31829bfd8f
3. Wu YJ, Muldoon LL, Várallyay C, et al. In vivo leukocyte labeling with intravenous ferumoxides/protamine sulfate complex and in vitro characterization for cellular magnetic resonance imaging. Am J Physiol Cell Physiol 2007;293:C1698–708. doi: 10.?1152/?ajpcell.?00215.?2007
4. Thu MS, Bryant LH, Coppola T, et al. Self-assembling nanocomplexes by combining ferumoxytol, heparin and protamine for cell tracking by magnetic resonance imaging. Nature Medicine 2012;18:463–67. doi: 10.1038/nm.2666
5. Khurana A, Chapelin F, Beck G, et al. Iron Administration before Stem Cell Harvest Enables MR Imaging Tracking after Transplantation. Radiology July 12, 2013. [Epub ahead of print]. doi: 10.1148/radiol.13130858