March 31, 2008

Stanford researchers develop tool that 'sees' internal body details 1,000 smaller

Stanford University School of Medicine researchers has developed a new type of imaging system that can illuminate tumors in living subjects—getting pictures with a precision of nearly on nanometer (one-trillionth of a meter).

This technique, called Raman spectroscopy, expands the available toolbox for the field of molecular imaging, said team leader Sanjiv Sam Gambhir, MD, PhD, professor of radiology. signals from Raman spectroscopy are stronger and longer-lived than other available methods, and the type of particles used in this method can transmit information about multiple types of molecular targets simultaneously.

“Usually we can measure one or two things at a time,” he said. “With this, we can now likely see 10, 20, 30 things at once.”

Gambhir said he believes this is the first time Raman spectroscopy has been used to image deep within the body, using tiny nanoparticles injected into the body to serve as beacons.

When laser light is beamed from a source outside the body, these specialized particles emit signals that can be measured and converted into a visible indicator of their location in the body.

Technology Review also has some information on this new imaging technology.

There are several techniques that employ the Raman effect, but this study used SERS (surface enhanced Raman scattering), which relies on roughened surfaces of metal nanoparticles to greatly boost the Raman effect. To create Raman nanoparticles, scientists attach small dye molecules, which scatter light, to these molecular amplifiers. They can then affix molecules that allow them to target the particles to a location in the body, such as antibodies that bind to specific proteins in cells.

The key advantage of this technique is that it allows for what imaging researchers call multiplexing: creating images of several different molecules at once. "One of the problems with imaging is, we tend to only be able to look at one or two things at a time," says Sanjiv Sam Gambhir, lead author of the study and codirector of the Molecular Imaging Program at Stanford. Multiplexing is important in complex diseases like cancer, in which several events occur within tumor cells, each of which could give information about the tumors' status and the likelihood that it will spread. As a first demonstration of multiplexing, Gambhir's team injected mice simultaneously with four kinds of Raman nanoparticles at different concentrations and showed that it is possible to locate the different particles and calculate their concentrations based on their Raman signal.

The most widely used molecular imaging technique in the lab is fluorescence. What makes Raman spectroscopy unique is that "you get a very sharp signal back, unlike [with] fluorescence, where you get a broad spectrum of energy," Gambhir says.

Claudio Vinegoni, an imaging specialist at the Center for Molecular Imaging Research at Harvard and at the Massachusetts General Hospital, who was not involved in the study, says that although scientists can use fluorescent molecules of different colors to see more than one molecule at a time, the ability to multiplex is limited because their signals quickly begin to overlap. In contrast, with Raman spectroscopy, "every molecule has its own Raman spectrum," Vinegoni says, so there is no possibility of the signals interfering. Because of their specificity, Raman nanoparticles can also be imaged at concentrations a thousand times lower than what can be detected using fluorescent quantum dots.

One of the major shortcomings of this technique, as in all optical imaging methods, is the limited ability of light to penetrate deep into tissue. Although it can be used to visualize the internal organs of a mouse, Gambhir says that in humans, the technique would be more useful for visualizing tumors close to the surface of the skin, such as melanomas or even breast cancer. The technique could also be used in conjunction with endoscopes that probe inside the body. Gambhir's team is planning a clinical trial to test the use of Raman particles in conjunction with colonoscopies for detecting early-stage cancers. In this procedure, the nanoparticles could simply be sprayed onto the surface of the colon rather than injected into the body. But a key challenge for bringing this technique into the clinic will be determining the safety of nanoparticles as probes--studies that Gambhir's group is currently undertaking.

Imaging of animals and humans can be done using a few different methods, including PET, magnetic resonance imaging, computed tomography, optical bioluminescence and fluorescence and ultrasound. However, said Gambhir, none of these methods so far can fulfill all the desired qualities of an imaging tool, which include being able to finely detect small biochemical details, being able to detect more than one target at a time and being cheap and easy to use.

Postdoctoral scholars Shay Keren, PhD, and Cristina Zavaleta, PhD, co-first authors of the study, found a way to make Raman spectroscopy a medical tool. To get there, they used two types of engineered Raman nanoparticles: gold nanoparticles and single-wall carbon nanotubes.

First, they injected mice with the some of the nanoparticles. To see the nanoparticles, they used a special microscope that the group had adapted to view anesthetized mice exposed to laser light. The researchers could see that the nanoparticles migrated to the liver, where they were processed for excretion.

Using a microscope they modified to detect Raman nanoparticles, the team was able to see targets on a scale 1,000 times smaller than what is now obtainable by the most precise fluorescence imaging using quantum dots.

When adapted for human use, they said, the technique has the potential to be useful during surgery, for example, in the removal of cancerous tissue. The extreme sensitivity of the imager could enable detection of even the most minute malignant tissues.

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