In order to pinpoint tumors in the body and successfully remove them, surgeons rely heavily on medical imaging–x-ray, MRI, and CT scans–to light the way. From these images, a surgeon can tell a tumor’s location and anatomy, or its size and shape. However, in many cases, medical images don’t paint a clear enough picture. These images may light up healthy tissue surrounding a tumor, along with the tumor itself, and may leave smaller tumors, particularly at the millimeter scale, in the dark. Surgeons who depend on these images may end up leaving behind smaller tumors that could later grow and spread or removing healthy tissue that appeared to be cancerous.
Now a team of researchers at the National Cancer Institute (NCI) and the University of Tokyo have developed a new imaging probe that specifically targets and illuminates tumors, even at the submillimeter scale. The scientists designed the fluorescent probe to seek out and grab on to specific receptors on a tumor’s surface, and activate, or light up, only when the probe has made it inside a cancer cell. The researchers reasoned that this targeted infiltration ensures that nothing but tumors are illuminated. The team injected the fluorescent probe into mice and was able to see live breast-cancer cells that had spread to their lungs.
“The first time we got this result, it was really exciting,” says Hisataka Kobayashi, chief scientist of NCI’s Molecular Imaging Program. “Only the tumor lit up, and nothing else, sort of like a sign in the dark sky, and it was really a beautiful view.”
Kobayashi and his colleagues are part of a growing number of researchers who are taking a molecular approach to medical imaging. Termed molecular imaging, the concept is based on identifying specific molecules that signal disease and using them as beacons to identify early stages of, for example, cancer. Laboratories around the world are developing fluorescent compounds that seek out and bind to such molecules, from cancer-related enzymes to macrophages that signal inflammation.
One main hurdle in all these efforts is what’s referred to in the field as target-to-background ratio. That is, scientists have found it difficult to illuminate just the target tissue or tumor, and not the background. Kobayashi says that’s partly because the fluorescent probes used are “always on,” meaning always lit, regardless of whether a probe is bound to its target. That could be a problem, particularly in identifying tumors.
“Cancer tissue is really leaky,” says Kobayashi. “Some of these fluorescent probes can easily be leaked out into the tissue and stay on, and we can misread cancer in those tissues.”
To get around this problem, the researchers picked a fluorescent agent that’s only activated in highly acidic conditions, or environments with low pH. Kobayashi recognized that within a cancer cell is a highly acidic compartment called the lysosome, which digests large molecules. He predicted that the pH-sensitive probe would only light up once it reaches the lysosome, remaining dark in the less acidic environment outside cancer cells. This “activatable” probe would theoretically improve the target-to-background ratio.
Before testing his theory, Kobayashi’s team added a targeting agent to the fluorescent compound, to help it home in on cancer cells. The researchers chose to attach the cancer drug Herceptin, an antibody that binds to HER2 receptors found on certain early-stage breast-cancer cells. The idea is that once the compound binds to HER2 receptors, the cancer cell absorbs the compound, which then comes in contact with the acidic lysosome, which activates the fluorescent agent.
The team injected the compound into mice with HER2-positive tumors, and used an endoscope to capture images of lit areas. Researchers found that the pH-sensitive probe detected tumors with 99 percent accuracy, lighting up just the tumors, compared with an “always on” fluorescent probe, which only detected 85 percent of the tumors, and also lit up nontumor tissue in the background.
Kobayashi found that a pH-sensitive probe could have other advantages. Cancer cells that are weakened or dead cannot maintain cellular processes, so the lysosomes often become less acidic. Therefore, a probe sensitive to pH levels may be able to tell a live cell from a dead one.
The researchers took biopsies from rats treated with the pH-sensitive probe and the “always on” probe, then washed the tissues with alcohol, killing the cells. In the aftermath, they found that tissue with the pH-sensitive probe had gone dark, but they found little change with the “always on” probe.
“Once the cell is dead, the fluorescence is gone,” says Kobayashi. “So we can potentially monitor cancer therapy in real time.”
Kobayashi acknowledges that the system has its limitations. The pH-sensitive probe is based on green light, which doesn’t penetrate very deep into the body, meaning it cannot be used for noninvasive imaging. A more practical application may be imaging during surgery, when an endoscope could come in close contact with tissue. For example, the fluorescent probe could be injected into a patient presurgery. After a surgeon has taken out large tumors, an endoscope could be threaded through the area to illuminate residual cancer cells.
In the future, Kobayashi says, the pH-sensitive probe could be tailored to target other cancers, by attaching agents that bind to molecules that signal specific tumor types. He believes that such a targeted imaging strategy could be used in humans within the next five years.
Scott Hilderbrand, a researcher at Massachusetts General Hospital’s Center for Molecular Imaging Research, is also developing fluorescent probes using molecular targeting strategies. He says that in the future, Kobayashi’s team may want to consider working with probes in the near-infrared spectrum, which are able to illuminate deeper into the body.
“This specific system may have limited application, especially in regards to taking this forward into the clinic,” says Hilderbrand. “But the concept and approach are definitely very relevant towards the area of enhanced tumor detection at the molecular level.”
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