Diagnostics & Imaging Week Washington Editor

BETHESDA, Maryland — We’ve heard of “personalized” medicine. More recently, it’s been called “predictive” medicine. And we can now add a new synonym for the type of medicine that hopes to look into the cellular and genetic crystal balls to foresee those diseases we may be most susceptible to: “preemptive” medicine.

“Imaging Molecules: The Promise of Preemptive Medicine” was one of the forward-looking presentations last week at a symposium held by the National Institute of Biomedical Imaging and Bioengineering — one of the newer institutes of the National Institutes of Health — a commemorative event serving to look at the history of advanced imaging systems and take a peek at the institute’s mission.

The presentation was made Ralph Weissleder, MD, director of the Center for Molecular Imaging Research at Massachusetts General Hospital/Harvard Medical School (Boston), who said that molecular medicine will require further development of bioimaging, quantitative analytical techniques and the chemical probes used to visualize chemical pathways. The other two ingredients are nanotechnology and gene sequencing, for both the individual and all of humanity.

Weissleder said that current bioimaging — such as 3D imaging that “allows us to fly through the human body” — is the antecedent of imaging that will examine the body on “a cellular and sub-cellular level.” This will, he said, “allow us to unravel biology that we will never be able to unravel by in vitro technology” because so many processes change when taken out of the human body.

He said that one of the biggest growth areas in imaging involves emerging optical technologies that are based on lasers. Among these is fluorescence molecular tomography (FMT), also known as optical positron-emission tomography (PET).

“This methodology, after five to seven years, is now entirely quantitative,” Weissleder said, and gives a spatial resolution of about half a millimeter or less.

To make practical use of FMT, Weissleder and his colleagues developed probes that are sensitive to proteases that “are highly up-regulated in lung cancer development” and give an early indication of the disease.

This technique compares with Western blotting for accuracy and eliminates the need for a biopsy. Substantial effort is going into combined FMT/CT systems, similar to a PET/CT, which “will have tremendous implications for how we do biomedical research,” Weissleder said.

As for intraoperative imaging, Weissleder’s institution has developed a fiber optic for microscopic imaging that includes a confocal lens attached to fibers less than 300 microns in diameter.

“We have used this in mice to phenotype” certain tumors, he said, thus permitting his team to image T-cell lymphocytes by introducing fluorescent proteins that attach to the lymphocytes.

“Another area of tremendous interest to us is the ability to pair diagnostic and therapeutic planning,” which Weissleder said is abetted by pairing white-light and infrared imaging, but early efforts have not always allowed a physician to distinguish cancerous cells from normal and pre-cancerous cells. A fluorochrome stain embedded in nanoparticles imparts different colors to each cell type, which gives a doctor “the ability to image all three processes at the same time.”

As for the need to “zap” the tumor, Weissleder’s lab is working on platforms using near infrared light at between 800 nm and 900 nm for diagnosis and another wavelength to essentially ablate the tumor after it absorbs the fluorochrome.

Some of these will be “a hundred-fold better than the best photodynamic agent out there,” he said, because of the use of nanomaterials to add amplifying contrasts in a more targeted fashion, allowing physicians to “completely eradicate tumors.”

Weissleder and others have had success in forcing various chemicals into nanoparticles to form very small assay instruments. The possible use of such nanomaterials in nanoscale sensing is of great interest because many biomarkers are present in blood.

However, any technology that can read these nano-assays must be “much more sensitive than is currently there, must be simple, scalable, and ideally, you have to be able to detect DNA, protein, metabolites and drugs all at the same time in order to have an impact on clinical medicine,” Weissleder said.

Some current examples “do some of these better than others, but there are very few technologies that do all of these,” Weissleder said. However, “we believe we have stumbled across one of the technologies” that can do the job, namely magnetic resonance (MR).

Weissleder said that in this use of MR, “we’re using a nanoparticle proximity assay to measure the T-2 relaxation time of water proteins around magnetic nanoparticles,” an approach that is “based on an observation we had about five years ago” that a change in the organization of nanoparticles in such a setting will exert different effects on the surrounding water. Those measurable effects can influence “billions and billions of water molecules.”

This type of assay and can be used on a wide range of tissue types, including sputum.

Picking up this effect does not require the latest million-dollar machine, Weissleder said, but currently available systems that are smaller than the standard MRI are still too bulky or otherwise impractical. “We need a handheld imaging system or a chip.”

Weissleder quipped that the devices in use in his lab “are currently being fabricated at a cost of $5,” but admitted, after the laughter subsided, that it is difficult to anticipate the final cost of such a device. However, he said that the device “has a little chip three centimeters across, [and] the magnet is about a hundred dollars and can be bought at a toy store.”

To establish whether this device could measure bacteria, Weissleder and his team inserted vancomycin into nanoparticles to induce a reaction in Staphylococcus aureus. The instrument was almost sensitive enough to detect a single bacterium per microliter, and Weissleder said that the device is able to detect a single mammalian cancer cell in a blood sample.

“The concept ultimately would be to put a drop of blood and get a readout of all these different markers,” he said, adding that “this technology is very fast” and turns around a reading “in about a minute.” Such a device could even be developed as an implantable for 24/7 detection of tumor markers in diagnosed patients.

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