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Multipurpose Molecule for Cancer Surgery

The fluorescent molecule targets tumors to guide surgeons and provide pre- and post-op imaging.

A new molecule designed to seek out and label cancer cells could help guide surgeons to hidden pockets of disease–a technology that could one day allow for more complete tumor removal and increase a patient’s chances of survival.

Seeing red: Infrared fluorescent labels, targeted to cancerous tumor cells, provide a luminescent guide for surgeons trying to remove the lethal tissue.

The molecular label, developed by researchers at the University of California at San Diego (UCSD), works in two ways. It tags cancer cells with a fluorescent marker to highlight tumors for identification and removal during surgery, and it contains a magnetic marker that can be used to evaluate the disease via magnetic resonance imaging.

In two papers published recently by The Proceedings of the National Academy of Sciences, the UCSD researchers describe a novel marker that fluoresces in the near-infrared, which has wavelengths long enough to make their way through layers of opaque human tissue and can help surgeons find buried tumor cells. In studies in mice, the researchers were able to find and remove 90 percent more residual cancer cells than was possible with visible light alone. And depending on the type of cancer, they were able to increase the animals’ long-term survival rates by as much as fivefold.

When cancerous tumors take hold, a person’s fate often rests in the surgeon’s hands–the more completely a surgeon is able to remove a tumor, the better the patient’s chances of survival. But even the best surgeons work under limiting conditions, extracting only what they can see and feel and hoping that they got it all. They send the tissue to the lab while the patient is still on the operating table and, if the lab deems that the tumor is surrounded by healthy cells, they close the patient back up. If not, they must continue cutting until lab samples come back clean.

With the new molecule, “we can not only do guided surgery, but we can show an increase in survival,” says Roger Tsien, a biochemist at UCSD and the project’s lead researcher.

A small number of researchers are working to provide cancer surgeons with a visual aid to help track down tumor cells that have separated from the main mass–those wound around nerve fibers, for instance, or tucked out of sight. But while some near-infrared methods seem promising, other approaches rely on viruses to insert a fluorescent marker (a gene-therapy like approach, with questionable safety), or don’t fluoresce strongly enough to glow through human tissue.

Tsien, who shared the 2008 Nobel Prize in chemistry for his work on green fluorescent protein, and colleagues created a two-peptide structure. One peptide acts as both a fluorescent and magnetic label, and the other keeps the molecule neutral. In the presence of tumor cells, enzymes called matrix metalloproteinases (MMPs) snip off the neutralizing peptide and allows the labeled one to enter the cell. Once there, the dual probe remains for as long as four or five days.

The new marker not only provides a visual aid during surgery, but can be used to assess the presence of a tumor both before and afterward. Radiologists could localize tumors magnetically during a pre-operative MRI scan, surgeons could then follow the infrared map to remove all traces of glowing tumor, then radiologists could perform a post-operative MRI to ensure there’s no remaining evidence of disease.

Scott Hilderbrand, a chemist at Massachusetts General Hospital’s Center for Molecular Imaging Research, is also developing targeted fluorescent probes. He notes that the individual pieces of the technique developed by Tsien’s team have been shown to work by other researchers, “but to be able to do this with one agent is one of the more major advances of this approach.”

The researchers hope they may be able to add yet another feature to their molecule. “We’d love to think that with this fluorescence we’ve gotten 100 percent of the cells, but that’s not the case,” says surgeon Quyen Nguyen, one of the papers’ first authors. She says they’re working to attach a third branch to the molecule, one that becomes toxic in the presence of bright light. “At the end of the surgery, you could shine a bright light that targets the fluorescent molecule and makes it phototoxic. That way, I can kill the residual cells,” Nguyen says.

One of the drawbacks of using MMPs, however, is that they are not expressed in all cancers, and are present in some noncancerous tissues, too, including the liver and in areas of inflammation. “The mice they tested this in have only normal tissue and cancer tissue, but the human body is not so simple” says Hisataka Kobayashi, a molecular imaging specialist at the National Cancer Institute in Bethesda, MA, and another person working on the targeting cancer with fluorescent probes.

That is why the researchers are targeting their probe for use in surgical guidance, where an experienced surgeon can distinguish between cancerous tissue and inflamed areas elsewhere in the body. Nguyen says the same team is working on using the molecule to deliver therapeutics targeted directly to cancer cells, but notes that this is going to be a bit trickier.

The researchers are looking into other potential uses for their molecule, such as lighting up arterial plaques in order to identify ones most at risk of causing a stroke or heart attack. Avelas Biosciences, a new startup based in San Diego, has licensed the probe technology in 2009 and hopes to have something ready for human testing within two to three years.

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