Muldoon LL, Pagel MA, Kroll RA, et al. A Physiological Barrier Distal to the Anatomic Blood-Brain Barrier in a Model of Transvascular Delivery. AJNR Am J Neuroradiol 1999;20:217–22

We investigated the delivery of ferumoxide (Feridex) iron oxide nanoparticles across the BBB in rats. The original goal was to use the MR contrast agent as a marker of viral-sized particle delivery to the brain. We administered Feridex intra-arterially (IA) in conjunction with hypertonic mannitol, a technique to safely and transiently open the BBB. MRI showed increased signal throughout the disrupted cerebral hemisphere, indicating global delivery of nanoparticles throughout the brain. In contrast, electron microscopy showed that the iron oxide nanoparticles were located at the basement membrane of cerebrovascular endothelial cells (Figure 1). Thus, the nanoparticles had crossed the BBB but had not actually entered brain parenchyma. This is important for clinical practice regarding the use of nanoparticles, such as encapsulated drugs, as delivery vehicles. Our results show that the presence of these agents in the brain does not necessarily indicate their accessibility to the target cells, either neurons or tumor cells.

This AJNR paper was the first of many preclinical studies in my lab investigating multiple aspects of imaging with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles. In 2005, we assessed delivery and toxicity of Feridex and alternative USPIO nanoparticle agents, including ferumoxtran-10 (Combidex) and ferumoxytol, in rat brain.¹ In this study, Feridex was stuck at the basement membrane for at least a month after transvascular delivery, while ferumoxytol was dispersed through brain tissue and could no longer be detected 1 week later (Figure 2). It is important for the use of ferumoxytol in neuroradiology that delivery directly to brain tissue was safe and gave relatively transient (1 week) signal changes.

We next looked at leakage of ferumoxtran-10 USPIO nanoparticles across the dysfunctional BBB in rat brain tumor models.¹ At 24 hours after IV administration of ferumoxytol, signal changes in brain tumors were highly dependent on the tumor model, with significantly more enhancement in a lung cancer brain metastasis model compared with a glioblastoma model (Figure 3A). Histochemistry for iron showed that the ferumoxytol nanoparticles were located in macrophages and activated glial cells in and around the tumors, rather than within the tumor cells (Figure 3B). This finding is clinically relevant because it shows that the delayed signal changes in tumor with ferumoxytol may define the inflammatory component of the tumor, a completely different mechanism than vascular leakiness visualized by gadolinium-based contrast agents.

In subsequent studies we used the blood-pool characteristics of the ferumoxytol USPIO with dynamic susceptibility-weighted contrast-enhanced MRI to measure relative cerebral blood volume (rCBV) in rat brain tumor models.^2.3  Tumor blood volume is a powerful tool to assess active tumor versus necrosis or treatment-related changes in tumor vasculature. Accurate measurement of rCBV requires that the contrast agent be confined to the vasculature. Our ferumoxytol rCBV measurements showed that bevacizumab (Avastin) anti-angiogenic agent decreased tumor blood volume as well as or better than high-dose steroid treatment.²  Because ferumoxytol does not leak from tumor blood vessel at early times (<30 minutes), we found that neither contrast pre-load techniques nor leakage correction were necessary for accurate and consistent rCBV measurements. The current direction of our research is to move away from low-resolution dynamic MRI to high-resolution steady-state MRI with ferumoxytol, as a mechanism to increase the spatial localization of active tumor growth in brain tumors.

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. Várallyay CG, Muldoon LL, Gahramanov S, et al. Dynamic MRI using iron oxide nanoparticles to assess early vascular effects of antiangiogenic versus corticosteroid treatment in a glioma model. J Cereb Blood Flow Metab 2009;29:853–60. doi: 10.1038/jcbfm.2008.162
3. Gahramanov S, Muldoon LL, Li X, et al. Improved perfusion MR imaging assessment of intracerebral tumor blood volume and antiangiogenic therapy efficacy in a rat model with ferumoxytol. Radiology 2011;261:796–804. doi: 10.1148/radiol.11103503