A research team from Oregon Health & Science University and the Portland Veterans Affairs Medical Centre is demonstrating some of the world’s first clinical applications for nanometer-size particles in the brain.
The OHSU scientists have shown that an iron oxide nanoparticle as small as a virus can outline not only brain tumours under magnetic resonance imaging, but also other lesions in the brain that may otherwise have gone unnoticed, according to a study published in the journal Neuropathology and Applied Neurobiology.
The iron oxide nanoparticle, ferumoxtran-10, can be viewed as a contrast agent under MR for more than 24 hours, sometimes as long as five days, said the study’s lead author, Edward Neuwelt, MD, professor of neurology and neurological surgery, OHSU School of Medicine, and the Portland VA Medical Centre.
In a parallel study by Neuwelt and colleagues, to be presented in June to the American Society of Neuroradiology, ferumoxtran-10 also was found to provide a “stable imaging marker” during surgery to remove brain tumours, and it remains in the brain long enough for post-operative MR, even after surgical manipulation.
The studies’ findings have the potential to assist image-guided brain surgery and improve diagnosis of lesions caused by multiple sclerosis, stroke and other neurological disorders, in addition to residual tumours.
“This is one of the first biologically specific nanoparticles to be used in clinical trials,” said Neuwelt, director of OHSU’s Blood-Brain Barrier Program, which studies ways of outwitting the brain’s natural defence to treat people with brain tumours. “This is the first time it’s been applied to look at inflammatory lesions in the brain, not just tumours. They’re very interesting particles and they’re safe.”
Study co-author Gary Nesbit, MD, associate professor of diagnostic radiology and neurological surgery, and the Dotter Interventional Institute, OHSU, agreed the nanoparticles show potential for providing insight into a variety of brain pathologies.
“We’re learning that disease in the brain is a complex system that has active involvement with cells and membranes, so there’s a lot of interest in other areas as well,” Nesbit said.
He said this early research on ferumoxtran-10 must be expanded to a larger group of patients to help scientists learn more about how the material reaches certain tumours and lesions, and why.
“This contrast agent provides a completely different way of looking at enhancement patterns on MRI,” Nesbit added. There are distinct differences in how tumours enhance with contrast agents. “The way the contrast agent gets there is completely different. What we need to find out is what the specific pattern of enhancement with this contrast agent means.”
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 tumours, researchers used Combidex, a ferumoxtran-10 manufactured by Advanced Magnetics Inc. of Cambridge, Massachusetts. 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 defence 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 tumours. 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 added.