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Because ferumoxtran-10 can stay in brain lesions for days - it can be administered to patients 24 hours before surgery - and can image other, non-cancerous lesions, it has some advantages over gadolinium, a metal used as an MR contrast agent for 20 years and which must be administered just before surgery. But Neuwelt doesn't believe iron oxide nanoparticles will necessarily replace gadolinium as an imaging tool.
"It will complement gadolinium, but not replace it," he said. "Gadolinium is the gold standard. But ferumoxtran-10 gives us additional information we can't get in some patients with gadolinium. Using both kinds of contrast agents, we can get better diagnostic information and that has the potential to improve the patient's outcome."
In the Neuropathology and Applied Neurobiology study, which followed seven patients with primary and metastatic malignant tumors, researchers used Combidex, a ferumoxtran-10 manufactured by Advanced Magnetics Inc. of Cambridge, Mass. Each iron oxide nanoparticle is the size of a small virus and is much smaller than a bacterium but much larger than an atom or standard gadolinium contrast molecule, Neuwelt said.
"It's an iron oxide crystal surrounded with a carbohydrate or 'sugar' coating," Neuwelt said. This coating, called dextran, gives the particle a longer plasma half-life, allowing it to slowly slip through the blood-brain barrier, or BBB, the tightly knit group of cells lining the walls of blood vessels in the brain. The BBB serves as a natural defense system by blocking the entry of foreign substances, including therapeutic agents.
"Anytime there's an injury, it induces inflammation," Neuwelt said. Ferumoxtran-10 is "taken up by inflammatory cells in the brain. You can see them in stroke and MS, you can see them in tumors. Gadolinium is basically the size of a large atom and does not enter cells, while this contrast agent is the size of a small virus and does enter cells."
In addition, ferumoxtran-10 can be detected with an iron stain in the tissue removed by biopsy or surgery, allowing physicians to see it in brain tissue samples under a microscope. "Unlike any other MR contrast agent, you can compare the images from an MR scan with the tissue taken out at surgery," Neuwelt said.
And it's relatively safe when diluted and administered as an infusion, although it can cause an allergic-type reaction when administered too quickly, he said.
Neuwelt says he first learned about iron oxide nanoparticles 11 years ago at a National Institutes of Health conference on new medical imaging techniques. "I heard this talk, and they were using it for liver and lymph nodes and I said to myself, 'Well, we ought to be able use it for the brain as well,'" he recalled.
Soon after, in April 1994, Neuwelt and colleagues published a study in the journal Neurosurgery showing that iron oxide nanoparticles could be delivered across the blood-brain barrier to the brain cells of rats and could be seen with MR.
