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IMAGING
Study Sheds Light on Cancer's Spread--LiterallyQuantum Dots Shine Through Tissue to Illuminate Sentinel Lymph NodesWhen a patient has been diagnosed with cancer, one of the first questions that comes up is, Has it spread? And one of the surest ways to find the answer is by examining the lymph system for metastatic cells. The sentinel lymph node in particular, which is the first to drain a tumor site, can provide crucial diagnostic information. Finding and removing these tiny nodes, however, is often difficult. Yet what if they fluoresced so brightly that they could be seen beneath the skin?
Sentinel lymph nodes can be mapped in large animals, in this case in the colon of a 35 kg Yorkshire pig, using near-infrared quantum dots (pseudo-colored green). Quantum dots injected into the wall of the colon, near the putative site of a tumor, can be visualized in real time as they flow through the fine lymph channels. The sentinel lymph node, the faint concentration of dots to the left of the injection site, becomes bright after approximately 3 minutes. This permits image guided resection, and inspection of the surgical site. (Image courtesy of John Frangioni) In December's Nature Biotechnology, HMS assistant professor of medicine and of radiology John Frangioni at Beth Israel Deaconess Medical Center, and HMS assistant professor of surgery Tomislav Mihaljevic at Brigham and Women's Hospital, together with Moungi Bawendi, a professor of chemistry at MIT, and colleagues, describe how quantum dots--small, intensely fluorescent metal particles--may be used to light up lymph nodes like a beacon. "The fluorescence is so intense," said Frangioni, "that the nodes can be clearly seen through at least a centimeter of tissue." Let There Be LightQuantum dots are nano-sized crystals composed of transition metals such as cadmium, selenium, and technetium. First described about five years ago, they get their name from a property called quantum confinement, which results from the squeezing of electrons and electron-negative areas (or holes in semiconductor lingo) into nanometer-sized spheres. It is this confinement that allows energized electrons to emit photons as they relax, rather than shed energy as heat.
Over the last few years, Frangioni and Bawendi have been optimizing the dots for use in a variety of imaging applications, including sentinel lymph node mapping. Now, by exploiting the sieving properties of the lymph system, Frangioni, with the aid of first author and MIT postdoc Sungjee Kim, has created dots that are small enough to travel through lymph ducts, but too large to pass through the nodes. Instead, they get trapped there, and when exposed to visible light, fluoresce brightly, providing a stark contrast to the background. Dot DesignDesigning these nanocrystals was a challenge. First the particles had to be rendered soluble, which Kim achieved by using a polydentate phosphene coating that had been developed by Bawendi's lab. The researchers then engineered the dots to emit near-infrared light, a part of the spectrum that is transmitted through biological tissue with minimal scattering. For this, the crystals had to be built to optimal proportions. "One of the intriguing properties of quantum dots," Frangioni explained, "is that their emission can be 'tuned' by changing their size and chemical composition."
Once the team had hit on the correct core and shell makeup, they tested the dots in mice. Five minutes after injecting as little as 10 pmol of the crystals into one paw, the mouse axillary lymph node could be seen clearly fluorescing under the skin. Buoyed by this success, the team turned to larger animals. A 400 pmol intradermal injection in the groin area of pigs led to intense fluorescence in the lymph node, visible up to about a centimeter below the surface of the skin. The high visibility of the node allowed Edward Soltesz, a surgeon at BWH, to remove it with minimal dissection. "The technique is a remarkable improvement on the current technologies, which rely on either a dye or a radioactive tracer to identify sentinel nodes," said Mihaljevic. The traditional methods often require considerable dissection before the node is found, because when these currently used tracers are injected at the site of a tumor, they travel beyond the sentinel node. This imprecision makes it difficult to contrast the node against other tissues. Radioactive imaging has the added complication that counters used for detection have relatively poor spatial resolution. "With quantum dots, we have for the first time a method that can be used in real time with a high degree of sensitivity, and which can detect the smallest lymph nodes with exquisite precision," he said. The next step is to develop dots that can be used safely in human trials. Because the dots in the study are composed of heavy metals, which can be toxic, they have not yet been approved for use in humans. "This is currently under review," said Frangioni. "One has to weigh the risk of the heavy metals versus the benefit of obtaining vital information," commented Mihaljevic. For someone with a particularly aggressive form of cancer, the scales may come down heavily on the side of better information. In the meantime, Frangioni is pursuing less toxic near-infrared fluorescent molecules that might someday approach the performance of the quantum dots. --Tom Fagan |
John Frangioni and his research team, including chemists and surgeons, found that the fluorescent quantum dots they designed could precisely delineate sentinel lymph nodes. The fluorescence is so bright that in animal models the nodes are visible prior to surgery. From left above are Sungjee Kim; Rita Laurence, a surgical technician at Brigham and Women's; Lawrence Cohn, the Virginia and James Hubbard cardiac professor of surgery at BWH; Alec DeGrand, software programmer at Beth Israel Deaconess; Tony Parker, HMS associate professor of radiology at BID; Tomislav Mihaljevic; Frangioni; and Edward Soltesz. (Photo by Steve Gilbert)