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Nanoparticles as Beacons
Apr 2008
STANFORD, Calif., April 1, 2008 -- Raman spectroscopy has been used to take images deep within the human body, after injecting tiny nanoparticles to serve as beacons. The method is expanding the available tools for molecular imaging, enabling illumination of tumors in living subjects and pictures with a precision of nearly one-trillionth of a meter, said a team at Stanford University Medical School.

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, Stanford said in a statement.

“This is an entirely new way of imaging living subjects, not based on anything previously used,” said Sanjiv Sam Gambhir, MD, PhD, a professor of radiology who directs the Molecular Imaging Program at Stanford University School of Medicine. He said signals from Raman spectroscopy are stronger and longer-lived than other available methods and that the type of particles used in this method can transmit information about multiple types of molecular targets simultaneously. Gambhir is the senior author of a paper describing the method published in the March 31 online issue of Proceedings of the National Academy of Sciences.

“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 for that purpose.
Setup of the Raman microspectroscopy system and schematic of Raman nanoparticles used for in-vivo imaging. a) Photograph of Raman microscope adopted for small animal imaging with mouse positioned supine on an x-y translation stage. The liver is illuminated with a 785-nm excitation laser. b) Schematic of SERS (surface-enhanced Raman scattering) active nanoparticles (Nanoplex biotag) showing a gold core and a layer of Raman tag encapsulated in a glass shell. c) Schematic (not drawn to scale) of a single-wall nanotube showing a mean diameter of 3 nm and a length of approximately 200 nm. (Image courtesy National Academy of Sciences, PNAS, Copyright 2008)
Gambhir compared the Raman spectroscopy work to the development of positron emission tomography discovered 20 or 30 years ago. PET has become a routine hospital imaging technique that uses radioactive molecules to generate a 3-D image of body biochemistry.

“Nobody understood the impact of PET then,” he said, referring to its discovery. “Ten or 15 years from now, people should appreciate the impact of this.”

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.

Gambhir’s group turned to making good use of the Raman effect, the physical phenomenon that occurs when light from a source such as a laser is shined on an object. When the light hits the object, roughly one in 10 million photons bouncing off the object’s molecules has an increase or decrease in energy -- alled Raman scattering. This scattering pattern, called a spectral fingerprint, is unique to each type of molecule and can be measured.

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 accomplish that, 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.
Raman image of liver acquired in a mouse after injection of surface-enhanced Raman scattering (SERS) nanoparticles. These artistically rendered nanoparticles each have their own spectral fingerprint as depicted in the spectral line graph to the right. Each color represents a different Raman active molecule incorporated into the nanoparticle that gives off its own unique Raman spectrum, which allows for biomedical multiplexing imaging capabilities. (Image courtesy Jim Strommer, Cristina Zavaleta, and Sanjiv Gambhir)
To be able to detect molecular events, said Zavaleta, they labeled separate batches of spectrally unique Raman nanoparticles with different “tags” -- peptides or antibodies -- then injected them into the body simultaneously to see where they went. For example, if each type of particle migrated to a different tumor site, the newly developed Raman microscope would enable the researchers to separate the signals from each batch of particles.

As part of this proof-of-principle work, Gambhir’s team tagged the gold nanoparticles with different pieces of proteins that homed in on different tumor molecules.

“We could attach pretty much anything,” said Gambhir. The Raman effect also lasts indefinitely, so the particles don’t lose effectiveness as indicators as long as they stay in the body.

Using a microscope that they modified to detect Raman nanoparticles, the team was able to see targets on a scale 1000 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, they said.

Gambhir’s lab is further studying these Raman nanoparticles to follow their journey throughout the body over the course of several days before they are excreted. They are also optimizing the particle size and dosage and are evaluating the particles for potential toxicity. ( Gambhir published findings in the March 30 issue of Nature Nanotechnology indicating that the carbon nanotubes are not likely toxic in mice.)

A clinical trial is planned to test the gold nanoparticles in humans for possible use in conjunction with a colonoscopy to indicate early-stage colorectal cancer.

Their work was funded by the National Institutes for Health, including the Center for Cancer Nanotechnology Excellence. Other Stanford researchers who contributed are: Zhen Cheng, PhD, assistant professor of diagnostic radiology; graduate student Adam de la Zerda; and Oliver Gheysens, PhD, a former postdoctoral scholar.

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Basic ScienceBiophotonicsCommunicationsindustrialMicroscopymolecular imaginenanonanoparticlesNews & FeaturesphotonicsradiologyRamn spectroscopySam GambhirStanford University

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