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RADIOLOGY Catching Cancer Before It Takes Hold
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"This is the first time anyone has done this," says Weissleder, associate professor of radiology and director of the Center for Molecular Imaging Research at Massachusetts General Hospital. The probes are part of a new wave of diagnostic techniques emerging from the field of molecular imaging. Their novelty lies not just in their design but also in the specificity and range of information they yield.
Better Information
Until now, protein-based methods for detecting cancer, such
as the prostate specific antigen (PSA) test, have focused on free
circulating protein, which provides only indirect evidence of the
existence of cancer cells. Because Weissleder's probes track down
enzymes inside tumor cells, they provide much more direct evidence
not only about whether a tumor has formed, but where and what size.
Weissleder and his colleagues are currently developing
a range of enzyme-detecting probes that might someday be used to
screen people at risk for specific cancers—breast, prostate, colon—and
other diseases. In addition, cancers vary notoriously from person
to person, and they may demand different treatments. Probes capable
of detecting several tumor enzymes at once could be used to relay
detailed information about the metabolic state of particular tumor
cells, information that could be used to tailor individual therapy.
The probes might even be used to monitor those
treatments. For example, if a probe does not light up when it revisits
the tumor site, or does so only dimly, one might infer that the
cancer cells have been killed or inactivated. Indeed, Weissleder
considers this the real payoff of his approach. "Knowing whether
my therapies are working early on—that's the long-cherished goal
of imaging," he says.
Until recently, a satisfying solution might have
been considered beyond the pale by most radiologists. Methods like
MRI, PET, CT, and ultrasound had made it possible to image at very
high spatial resolutions. But the images rely on physical signals—magnetic
properties, proton density, ultrasound scatters—rather than actual
biological events. To image molecular events occurring inside the
cell required new probes.
Around ten years ago, Weissleder, a practicing
interventional radiologist, set about designing such probes. One
of his first consisted of ultrasmall iron oxide particles that could
signal whether primary cancers had metastasized to the lymph nodes.
Later, he and his colleagues created a molecular raft that when
introduced into the bloodstream, gravitates to the site of angiogenesis—new
blood vessel growth that often surrounds tumors. That raft, which
consists of linked amino acids (lysines), literally forms the platform
for his new probe.
Essentially, the probe consists of 10 to 20 peptide
stalks implanted in a lysine raft. Perched atop each stalk is a
tiny bulb of fluorescent dye, or fluorochrome. Normally the fluorochromes
fluoresce when hit with infrared light. But because they are spaced
tightly, they simply exchange energy among themselves. In fact,
it is only when their peptide stalks are broken by specific proteolytic
enzymes inside the tumor cells that the fluorochromes' energy is
released (see illustration).
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| Source: Dr. Weissleder Tumor enzyme–detecting probes shine a light on tumors. To create the probes, Ralph Weissleder and his colleagues plant 10 to 20 peptide stalks (NH) in a raft of lysines (Lys). To protect the stalks in the bloodstream, they surround them with polyethylene glycol shields (MPEG). The probes find and enter the tumor cell. Enzymes secreted by the lysosme cleave the peptide stalks, releasing detectable light. |
New Targets
Weissleder and his colleagues have developed a total of five
enzyme probes. In addition to enzymes, he and his colleagues are
also looking for other targets—receptors and proteins associated
with disease. Ultimately, they hope to design probes capable of
detecting several proteins at once. "With one molecule we could
look at PSA versus cathepsin versus some other protease. You would
do this with different peptide stalks and with different fluorochromes
that fluoresce at different levels," Weissleder says. "So we're
moving into a realm of new information that so far has not been
possible."
Weissleder hopes to bring his probes to clinical
trials before too long. The lysine raft has already passed phase
I safety trials. The fluorochromes and the peptide stalks are known
to be safe on their own. Now he plans to conduct preliminary toxicity
trials of the whole probe in ten patients with known tumors.
Other contributors to the study, all in the Department
of Radiology at MGH, are research fellow Ching-Hsuan Tung, clinical
fellow Umar Mahmood, and assistant professor Alexei Bogdanov.
—Misia Landau