Research by scientists based at the University of Illinois at Urbana-Champaign may lead to the development of a new breed of "multimodal" contrast agents that could work within a host of medical imaging platforms — from ultrasound and computed tomography (CT) to magnetic resonance imaging and molecular imaging.
Use of these new agents may, in turn, significantly improve the diagnosis and treatment of cancer, according to Kenneth Watkin, a professor in the department of speech and hearing science and the Beckman Institute for Advanced Science and Technology.
Watkin’s findings, the result of work with former graduate student Michael McDonald, who is now completing a postdoctoral fellowship at Stanford University, were published recently in the journal Academic Radiology.
"The goal of this work for me was to be able to create advanced methods for the treatment of disease, specifically cancer, that reduce the toxic effects that we see with our current treatments," Watkin said. "And to do that, I had to develop really, really, really small carriers.
"I got into this field — which is really nanomedicine — because my area of interest is imaging and head and neck cancer," he said. "And as I would do imaging studies, I would see the true devastation of chemotherapy and radiation therapy to individuals from a psychosocial and a body point of view. So I got to thinking, ‘How could we treat head and neck cancers differently — using fewer chemotoxins?’ "
The tiny carriers Watkin and McDonald are proposing would, in effect, zero in on tumors in much the same way that smart bombs take aim at strategic targets.
Watkin’s transport system of choice are nanoparticles of gadolinium oxide.
The best way to visualize these nanoparticles, Watkin said, is to think of them as "exceptionally tiny pouches." Or better yet, "like the trailer on a semi-truck. The deliverer is the targeting body and the trailer is the little shell that contains the material."
To put things in perspective: The width of a single human hair measures about 80,000 nanoparticles.
In their work with gadolinium oxide nanoparticles, Watkin and McDonald started by breaking nanoparticles down into even smaller particles. Next, they successfully coated the particles with dextran, a naturally occurring carbohydrate.
The chemical coating — which Watkin compares to the thin, outer shell of an M&M candy — functions as a spacer, preventing the nanoparticle from undergoing a chemical reaction when it comes in contact with water. It also keeps the nanoparticles from clumping and behaving erratically.
"The M&M analogy is really a great one because it says you can put things on the outside and you can have something on the inside," Watkin said. "And in the case of gadolinium oxide, it’s really a metallic ion."
Watkin said gadolinium oxide is a superb imaging agent because of its superparamagnetic properties — "meaning that they work well within a magnetic resonance imaging machine."
Its properties as an effective emitter of radiation sources also make it well-suited for use with a type of cancer therapy called neutron capture therapy.
"What it means," Watkin said, "is that these little particles capture the neutrons and emit alpha and gamma rays, and that energy — sent out from an accelerator — is what can be used to kill cancer cells.
"In looking at this, we both said, ‘Holy … cow!’ These little gadolinium particles capture neutrons at four times a greater rate than boron, and yet boron is what is (currently) used for neutron capture. This means it (gadolinium oxide) is potentially a multimodal agent" … in other words, a contrast agent that would work with a number of different medical imaging techniques.
Among the most promising applications for using gadolinium oxide nanoparticles as a neutron capture therapy agent is in the treatment of brain tumors.
"Treating brain tumors — typically called glioblastomas — is very difficult," Watkin said. "Irradiating them is really difficult because you alter all kinds of tissues in the brain. And getting little bubbles like this or other kinds of contrast agents into the brain is difficult because the holes that allow plasma and other substances to flow through the brain are very small — about 25 nanometers. With such a small opening, "you’ve got to have something pretty tiny to get in there. So these little gadolinium oxide particles can be really useful."
Watkin noted that another reason the researchers initially chose to investigate the effects of adding a dextran coating was because it makes it possible to "target" the nanoparticle.
"By that, we mean we put a ligand — an organic substance, such as a monoclonal antibody — on the outside that searches out in the bloodstream. Antibodies seek their antigens. So we target something to seek out a substance that’s expressed by cells — cancer cells, in my work. Cancer cells express particular antigens to which an antibody attaches itself. So, if we put the appropriate glioblastoma antibody on the end of a particle, as it passes through the bloodstream it will attach to the tumor cell."
In experiments with other types of nanoparticles, Watkin has loaded the particles with cancer-fighting drugs such as Doxorubicin or Taxiter. He also is investigating using them to deliver genetic material such as RNA inhibitor.
Watkin acknowledges that it could be years before the work results in diagnostic or treatment methods used in clinical practices.
"We have a lot of potential research directions ahead of us," he said. "I think one of the directions this is going to take is exploring its use at the molecular level with various types of other high-resolution imaging systems. And if it’s of interest for use within humans in the end, all of the pharmacological attributes of this will have to be explored. That is, its distribution in the body … where do the nanoparticles go? What are its effects? How long does it last? All of those kinds of things are part of the preclinical work, before people can even consider using it."
