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Double-takes with a dual-modality probe

Aug 2006
Novel contrast agent suits MR and optical imaging

Gary Boas

The past few decades have seen the emergence of a variety of imaging modalities, each with its own strengths and weaknesses. For instance, one technique might offer high resolution but relatively low sensitivity, and another, just the opposite. In recent years, investigators have sought to combine modalities to take advantage of their respective, complementary strengths. Such multimodality imaging offers tremendous potential for both research and clinical applications.

Investigators with the National Institutes of Health’s National Cancer Institute in Bethesda, Md., wanting to combine the respective strengths of MRI and optical imaging, have recently developed a nanoprobe for both modalities. “We were trying to ‘marry’ the resolution of MRI with the sensitivity of optical imaging to obviate the shortcomings of each modality,” said Martin W. Brechbiel, the principal investigator of the study.

A probe that combines the spatial resolution of MRI and the sensitivity of optical (fluorescence) imaging has been developed. It was demonstrated in multimodality imaging of lateral thoracic lymph nodes in a mouse model, showing its ability to provide complementary information that could ultimately contribute to improvements in intraoperative imaging, for example.

Brechbiel and colleagues — Vladimir S. Talanov, Celeste A.S. Regino, Hisataka Kobayashi, Marcelino Bernardo and Peter L. Choyke — focused on using treelike dendrimer molecules. These have played an increasingly prominent role in biomedical research, largely because of their well-defined structures, discrete sizes and potentially large number of treelike branches. In fact, the researchers have spent the better part of a decade studying dendrimers for use with MRI, exploring where they go when introduced into the body and what the effects of their size on biology are, and looking at different administration methods and tumor models. Ultimately, Brechbiel explained, they wanted to know what kind of MRI contrast agents they could make with dendrimers.

The researchers had acquired exquisite images of dendrimer-based contrast agents in mouse models using significantly less gadolinium than is typically required by small-molecular-weight contrast agents in clinical imaging. Although MRI provided superior images and better resolution, absolute sensitivity remained quite low, leading the researchers to consider multimodal imaging with fluorescence methods, which offer relatively low resolution but much higher sensitivity. This in turn led them to develop the dual-modality dendrimer-based probes reported in the July issue of Nano Letters.

They designed a probe that consisted of a number of gadolinium-chelate moieties and near-infrared fluorescent dye units to contribute to MR and fluorescence imaging. They used Cy5.5 as the fluorescence dye unit, and because fluorescence imaging offers a much higher sensitivity than MRI, they used more gadolinium-chelate moieties than fluorescent dye units to balance the performance of the two imaging modalities. The low surface concentration of dye moieties also may have helped minimize self-quenching of the fluorescence.

Validating reproducibility

Characterizing the probes proved challenging. Because the macromolecular probes were so complex, the researchers couldn’t use traditional means, so they relied on a combination of analytical tools to understand the chemical composition of the probes and to affirm their reproducibility. “We need to validate that we can replicate the chemistry that we have developed to make these probes, to ensure that we remain capable of their clinical translation,” Brechbiel said.

To demonstrate use of the probes, the researchers performed MR and fluorescence imaging of sentinel lymph nodes in normal mice. They acquired MR images 10, 20 and 30 minutes postinjection with a 3-T clinical scanner made by GE Medical Systems of Waukesha, Wis., outfitted with a modified Alderman-Grant mouse coil. They immediately performed optical imaging with a Maestro in vivo optical imaging system made by Cambridge Research Instrumentation Inc. of Woburn, Mass. For this they used a 615- to 665-nm excitation bandpass filter and a 720-nm liquid crystal emission filter. They acquired images in 10-nm steps in the range of 650 to 950 nm.

They successfully performed MR and optical imaging with the probes. In fact, the sentinel node was equally visible with the two modalities, even though there were 145 gadolinium ions as opposed to just one fluorescent dye molecule.

Ultimately, the researchers would like to develop the probes for clinical applications, such as intraoperative imaging. Doctors could acquire presurgical 3-D MR maps of the lymphatics and nodes, and then perform optical imaging to locate the fluorescent dye within that map to distinguish the nodes from the malignant tissue to be removed.

The next step toward this goal is to develop probes of different sizes and test them in further animal studies. For the current study, the researchers determined the optimal size probe for the particular application; next they want to design probes of various sizes for other applications, and make the probes active targetable agents. “Our current library of probes are passive agents,” Brechbiel said. “There is no disease recognition built into them. We want to target breast cancer and other diseases; we want to be able to direct and choose where our probes go.”

Another option for future research is to incorporate fluorescent dyes that respond to their environment, so that they not only would illuminate a specific location, but also provide a readout of important biological information such as pH or O2 status, Brechbiel said.

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