Despite its potential, however, molecular imaging is not without its technical challenges. For one thing, researchers are working hard to ensure that the images it produces are clear. Imaging agents are always on-always emitting radioactivity, like Apomate, or always glowing, in the case of some others. That works fine when there is an abundance of target molecules for the agents to bind to. The trouble is, sometimes the molecules characterizing a problem are so scarce that the few imaging agents that do reach and bind to them are lost in a haze generated by unbound agents floating nearby. That makes it hard to pick out a few precancerous cells in an otherwise healthy organ, for instance. And other times the agents collect in locations such as the liver, where they give off a bright but meaningless glow.To address these problems, Northwestern’s Meade and other researchers are inventing chemistry designed to keep the imaging agents invisible until they find their target molecules. “We’re making molecular beacons that respond to physiological conditions,” explains Meade. “They’re off when injected, and only turned on by the presence of an enzyme target.” That simple-sounding goal will nonetheless demand considerable basic research and complex chemistry.
Meade, for one, has come up with a novel scheme in which a target enzyme chews off the equivalent of a cap on the imaging agent, allowing it to beam out its signal. He hopes the approach will allow diagnosticians to use high-resolution MRI and computed-tomography scanners to probe ailments such as stroke, schizophrenia, and Alzheimer’s disease.
Researchers at Massachusetts General Hospital are putting some of these same principles to work to improve the diagnosis of colon cancer-the second most common cause of cancer death in the United States, with more than 50,000 fatalities each year. Colonoscopy has helped physicians find colon cancer earlier. However, it can have difficulty differentiating between dangerous and more benign polyps. In a lab at Mass. General headed by Ralph Weissleder, scientists have found that an enzyme called cathepsin-B appears in higher concentrations in the most dangerous polyps than it does in nearby tissue and in other polyps.
Armed with this biological insight, the researchers designed a clever new imaging agent, taking advantage of the fact that cathepsin-B is an enzyme that cuts up specific proteins. They constructed the agent out of a fluorescent protein fragment attached to another molecule that keeps the fluorescence quenched. When the imaging agent finds cathepsin-B, the enzyme cleaves off the quenching arm, freeing up the probe to glow brightly. Since targets like cathepsin-B exist in very small quantities, turning off extraneous unbound agent molecules is like darkening the stars in a night sky to better spot a passing comet.
Because light scatters as it penetrates deep into tissues, it would be difficult to scan a human patient’s colon optically from outside the body. But the technology could be paired with conventional colonoscopy. In the future, doctors may inject a patient with a fluorescent imaging probe designed to find the enzyme, and then examine the colon using a fiber-optic scope that picks up the fluorescence (see “Molecular Colonoscopy,” below). This will allow doctors to distinguish between the different kinds of polyps in real time, with a minimally invasive approach, instead of having to cut out sample tissue and send it to a pathology lab, then wait days or weeks for the results.
As a next step, says Mass. General’s Mahmood, the researchers are now performing test colonoscopies on lab mice using the new imaging agent. According to Mahmood, the technique could make it possible to avoid many colon biopsies in five to ten years.
In the near term, optical imaging could also help improve the accuracy of breast biopsies. These procedures now can miss malignant cells because it’s difficult for physicians working off of two-dimensional mammograms to know exactly where in the breast to place their needles. Experts estimate that in the United States alone, some 50,000 to 100,000 breast biopsies each year don’t find existing cancer cells-and so do not properly diagnose the women’s cancers.
To address the problem, University of Wisconsin-Madison biomedical engineer Nimmi Ramanujam is exploiting the fact that biological tissues naturally fluoresce in response to stimulation by certain wavelengths of light-and that healthy and cancerous tissues fluoresce differently. Ramanujam scaled down optical imaging technology to create a tiny fiber-optic sensor that can be threaded right through a biopsy needle. When the doctor inserts the needle into the breast, the device sends light into the tissue and collects the fluorescence emitted by cells at the needle’s tip; algorithms developed by Ramanujam analyze this fluorescence in real time to distinguish between the telltale optical signatures of healthy and cancerous tissues.
Ramanujam and her colleagues at the University of Wisconsin Medical School are already testing the technology on women undergoing breast cancer surgery and plan trials with women undergoing breast biopsy within the next year.