Double-takes with a dual-modality probe
Novel contrast agent suits MR and optical imaging
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
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.
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,”
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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