Newly equipped molecular probes may improve early detection of cancer, other diseases

BOSTON - August 19, 2002 - Researchers at Massachusetts General Hospital (MGH) have created key components for near-infrared probes that could be used to pinpoint the exact location of cancer and other diseases in the body. These noninvasive, molecular tools work by lighting up in the presence of certain enzymes involved in a range of disease processes. The new components, near-infrared optical quenchers and fluorescent dyes, increase the probes' accuracy and range of use. The light emitted by the probes, near-infrared radiation, has attracted much interest recently for its ability to image relatively deep tissues in the body.

These and related findings were reported in poster and oral presentations at the August meeting of the American Chemical Society by Wellington Pham, PhD, Yuhui Lin, PhD, Ching-Hsuan Tung, PhD, and Ralph Weissleder, MD, PhD, who is the director of the Center for Molecular Imaging Research at MGH and professor of radiology at Harvard Medical School (HMS).

The refined probes are part of a new wave of molecular imaging techniques being developed for diagnostic and other purposes by researchers led by Weissleder and Tung, who is HMS assistant professor of radiology at MGH. Until now, most molecular methods for detecting diseases like cancer have focused on proteins in the blood such as prostate-specific antigen, providing only indirect evidence of disease. By zeroing in on specific tissues and tracking down enzyme activity associated with cancer, the use of probes provides more direct evidence and information about the presence and location of disease.

The probes the researchers work with consist of a raft implanted with 10 to 20 closely spaced peptide stalks, each of which may be cut by a specific enzyme. Perched on top of each stalk is a tiny bulb of fluorescent dye. Normally, these closely spaced bulbs, or fluorochromes, exchange energy among themselves, giving off little or no light when hit by near-infrared radiation. If their peptide stalks are snapped - for example, by enzymes present in a cancer cell - the fluorochromes separate and release their energy in the form of light.

The new quencher compounds help to absorb near-infrared radiation when the peptide stalks are intact, and they do so without emitting light. "So the signal is quenched," said Pham, an HMS research fellow in radiology at MGH. Quenching activity in the inactive state helps produce a clearer distinction between the presence and absence of enzyme activity, more accurately detecting associated diseases.

By varying the peptide stalks, the researchers have developed a whole fleet of enzyme-detecting probes. They believe that the quencher is versatile enough to be used in a variety of probes. They have tested it in several of them, including one for caspase-3, a cancer-associated cell-death enzyme.

In related research presented at the American Chemical Society meeting, Lin, a former HHS research fellow at MGH, joined Weissleder and Tung to develop fluorochromes that emit different colors under near-infrared light. The researchers used fluorescent dyes that give off redder hues than the ones currently in use and attach to probes targeting enzymes overexpressed in cancer cells. With a broader palette of colors in hand, it will be possible to use various fluorochromes to detect the expression of several enzymes at once and gather more information about tumors and other tissues. The team has used these approaches to image more than 10 different enzymes expressed in cancer and various diseases.

Media Contact: Sue McGreevey, MGH Public Affairs

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