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Vol. 4 • Issue 4 • 2010 • 4
the newsletter of the snm center for molecular imaging innovation and translation
Molecular and Cellular Imaging with Ultrasound Contrast
Agents
T
oday, ultrasound imaging generally
plays a minor role in molecular imaging. Most of the clinical activities are
focused on PET and SPECT, and most of
preclinical research is expanded to the
areas of optical imaging and MRI. However,
with proper contrast agents designed for
molecular imaging, ultrasound can play an
essential role both in research and clinical
applications.
Historically, ultrasound contrast imaging was suggested for visualization of
blood flow patterns (1). Early-generation
ultrasound contrast agents comprised air
bubbles prepared by rapidly mixing air
with aqueous saline, albumin or X-ray
contrast media immediately (seconds) before intravascular administration (2). Air
bubbles were echogenic but would quickly
dissolve in the blood; bubbles would not
pass through the pulmonary circulation,
hence monitoring blood flow following
intravenous administration had not been
feasible with those contrast particles. Oth-
er, sometimes exotic, microbubble preparation approaches were investigated, such
as intravenous administration of H2O2 to
generate oxygen bubbles in vivo, but they
did not gain widespread use (3). Next,
so-called first-generation contrast materials were much more stable and circulated
longer than uncoated air bubbles because
they were stabilized with a surfactant or
a protein shell (4). They were capable of
transpulmonary passage, so blood flow
characterization after intravenous administration became feasible, although circulation time of air-filled bubbles was generally
quite short and these contrast agents did
not gain much recognition in clinical use.
Significant clinical use of microbubbles for
blood pool enhancement became possible
less than a decade ago, with the approval of
second-generation contrast agents, which
contained water-insoluble fluorinated gases (5, 6) (7). These materials stayed in the
bloodstream for minutes, not seconds, so,
viable in vivo imaging studies have been
performed. The features (such as circulation time) and structure (such as the shell
to which targeting ligands can be coupled)
of these second-generation microbubbles
are quite acceptable for the design of the
molecular ultrasound imaging contrast materials, which target the specific molecular
markers of disease.
Particle size constraints apply to the
design and applicability of molecular imaging ultrasound contrast agents to achieve
successful imaging. In most cases, these
materials are gas-filled microbubbles with
the size of several microns. These particles,
with a picogram mass, are detected by ultrasound very well, to the level of imaging individual particles in the suspended
state and even after binding to the target
(8). Submicron gas bubbles possess much
worse stability and circulation time; they
are not as echogenic as larger bubbles.
Therefore, preferred contrast particle size is
2-4 um (larger microbubbles may lodge in
the capillaries, e.g., in the lungs). It means
Amyloid in the Brain
Continued on page 2. See Ultrasound Contrast Agents.
PET Drugs and Part 212
Requirements
T
PET drug
he FDA, taking into consideration the unique nature of PET drugs and
production, published the final rule, 21 CFR Part 212 “Current Good Manufactur
ing Practice (CGMP) for PET drugs” on December 10, 2009 (Federal Register/Vol.74/
December 10, 2009, p.65409). Part 212 is the rule (or regulation) and contains binding
guidance
requirements for the CGMP for PET drugs and is enforceable in the courts. The
“PET drugs…CGMP” published at the same time as Part 212 describes FDA’s current
thinking on specific approaches to comply with Part 212 requirements (Federal Register/
Vol.74/December 10, 2009, p.65538). Part 212 requires that producers of PET drugs for
clinical use must be compliant with the rule by December 12, 2011––and that is only
Continued on page 5. See PET Drugs and Part 212.
in this issue
Images of Interest
3
Tech Sector
4
YI Contribution
5
Donor Corner
6
MI Calendar
8
Ultrasound Contrast Agents. Continued from page 1.
2011 Molecular
Imaging Meetings
Multimodality Molecular
Imaging of Prostate Cancer
Friday, January 21, 2011
Palm Springs, California
Part of the SNM 2011
Mid-Winter Meetings
www.snm.org/prostate2011
Clinical Trials Network
Workshop
January 20–21, 2011
Palm Springs, California
www.snm.org/ctn2011
Breast Cancer Imaging:
State of the Art 2011
Diagnosis, Therapy and
Beyond
April 21-22, 2011
Bethesda, Maryland
2
The Natcher Center
National Institutes of Health
www.snm.org/breast2011
Lost and Found in
Translation: Translating
Your Optical and Radiopharmaceutical Agents into
the Clinic, a Categorical
Seminar
June 4, 2011
San Antonio, Texas
SNM Annual Meeting
www.snm.org/am
m i images of interest
Ultrasound Contrast Agents. Continued from page 1.
that successful molecular imaging with current generation of microbubble contrast
agents is possible only for intravascular markers, and ultrasound contrast detection
of a specific cellular marker is not feasible if that marker is not exposed to the bloodstream and is located at the interstitial space or inside the target cell.
Design of Microbubbles for Molecular Imaging
Over the past 15 years, dozens of papers describing molecular imaging with ultrasound contrast have appeared, presenting targeting to a variety of the disease marker
molecules. General design of the particle has not changed significantly since its first
presentation (9). Targeting ligand is attached to the microbubble shell-forming material, then microbubbles are generated from insoluble gas during high-shear mixing,
e.g., with a probe-type sonicator. During the preparation procedure, microbubbles
are immediately covered with the shell. After removal of excess ligand by centrifugal
flotation, microbubble targeting is either tested in vitro or injected intravenously in
the experimental animals with the appropriate disease models.
Most successful and popular targeted microbubble shell design is based on a lipid
monolayer shell decorated with a grafted brush of the water-soluble polyethylene
glycol. The thickness of the lipid monolayer is ~2 nm. This thin shell does not interfere significantly with microbubble expansion and contraction in the ultrasound
field, providing good contrast echogenicity without the need to destroy the particles
by cracking the shell with high-power ultrasound. This shell does not serve as a significant barrier for gas diffusion in and out of the bubble. PEG chains extend from
the microbubble surface into the surrounding aqueous environment by ~10-30 nm,
which is not very significant when compared with a 2-3 um particle diameter (10).
Targeting ligand is usually attached to the exterior of the PEG brush in the same extended “fishing line” manner as it was earlier proposed for liposomes (11). This ligand
coupling technique facilitates ligand-receptor interaction and improves microparticle
targeting in a flow-through scenario (12). Peptides/mimetics, carbohydrates, glycosulfopeptides, small and large proteins (such as antibodies) were successfully tested
as ligands for ultrasound molecular imaging. Most of such tests required biotinylated
ligand that would attach to the bubble via a streptavidin spacer (13); many biotinylated ligands are available commercially or can be prepared easily. The advantage of
biotin-streptavidin ligand linking technique is in its simplicity; bubbles can be easily
centrifuged to remove excess of free ligand. This approach is especially useful if the
ligand is a large protein that could become denatured and inactivated during microbubble preparation by sonication as described in the previous paragraph. However,
there is a very significant disadvantage. Streptavidin, as a foreign protein, will not
be approved for clinical application in human setting. Therefore, chemical coupling
between ligand and shell has to take place, either before (as described above) or after
bubble preparation.
The choice of ligands for microbubble targeting may be determined not just by
the specificity and affinity of ligand-receptor interaction for the respective molecular
markers (thermodynamics), but also by how fast the ligand-receptor interaction takes
place (kinetics). Antibodies are usually selected via ELISA, by the value of equilibrium
affinity, often described as equilibrium dissociation constant, Kd; however, the act of
interaction of ligand-microbubble with the receptor on the vessel wall is a rather timeconstrained event, and if the kinetics of association between the ligand and receptor
is slow, the microbubble would be transported away from the target area and would
not attach to the intended target. Therefore, the choice of fast-binding ligands, such
as glycosulfopeptide portion of the natural molecule P-Selectin Glycoprotein Ligand 1
(PSGL-1, (14)) or even simpler molecules such as sialyl Lewis X, (15) could be considContinued on page 3. See Ultrasound Contrast Agents.
www.molecularimagingcenter.org/ mi
Molecular Ultrasound Imaging of Tumor Angiogenesis
Visistar-Integrin microbubbles
(cRGD peptide)
Visistar-Integrin Control microbubbles
(cRAD peptide)
8 min after intravenous injection of 50 million microbubbles.
Sequoia 512 imaging system with 15L8 probe, operated in CPS mode
Ultrasound molecular imaging of tumor angiogenesis in an orthotopic mouse model of breast cancer (Met-1 cells implanted in mammary fat pad).
Microbubbles bearing a cyclic RGD peptide ligand (Visistar-Integrin, directed at avb3 integrin on tumor vascular endothelium) or a control ligand (cyclic
RAD peptide) covalently conjugated to the bubble shell were administered intravenously and allowed to circulate and clear from the bloodstream over
eight minutes. Targeted microbubbles accumulated within the tumor. Control microbubbles exhibited negligible accumulation. Dotted line delineates tumor
borders, as determined by B-mode ultrasound.
Images courtesy of Xiaowen Hu and Katherine Ferrara (University of California, Davis); Visistar-Integrin microbubbles provided by Joshua Rychak (Targeson,
San Diego).
Ultrasound Contrast Agents. Continued from page 2.
ered. Interestingly, the latter has equilibrium Kd ~ 1mM for P- or
E-selectin. Such low affinity is not useful for targeting of small
molecules. However, successful particle targeting is possible via a
combination of rapid association between the ligand and receptor,
and cooperative multipoint interaction between large number of
ligand and receptor molecules. Placing over a million small ligand
molecules per single microbubble is feasible. Only ~105 (or less)
antibody molecules attached per microbubbles is typically reported (13). Using full IgG molecule (MW=150,000) for immobilization on the microbubble surface may not be the best strategy as
compared with the use of smaller ligands: larger molecules carry
much more than just the target binding sequence. Fc fragment of
the antibody may be quite immunogenic, so the use of humanized
(or fully human) antibodies is required. Furthermore, Fc receptors on phagocytic cells (e.g., in the liver) may alter microbubble
biodistribution in an undesirable way. Overall, the use of smaller
molecules as ligands for molecular ultrasound imaging should be
preferred.
In Vivo Molecular Imaging with Microbubble
Contrast Agents
There are many useful intravascular molecular targets that mark
disease tissue location; most of them are affiliated, directly or indirectly, with endothelial cells, and constitute markers of inflammation (such as ICAM-1 (16), VCAM-1 (17), MAdCAM-1 (18), P- or
E-selectin (13)) or angiogenesis (VERFR2 (19), αvβ3 (20)). Blood
clot markers, such as platelet GPIIbIIIa (21) and P-selectin (22)
and activated form of endothelial von Willebrand Factor (23) can
also serve as useful targets of disease. A wide array of molecular
imaging ultrasound contrast studies have been performed to date
in animal models. Imaging procedure is quite straightforward, but
somewhat different when compared with other molecular imaging
modalities. Targeted microbubble construct aqueous dispersion
(or control non-targeted preparation) is injected intravenously as
a bolus, and low-power contrast ultrasound imaging of the region
of interest is performed immediately. Contrast inflow imaging provides real-time information of the blood flow patterns in the tissue
of interest, and may be useful for immediate understanding of the
target tissue physiology. Several minutes later, imaging of microbubbles that have accumulated in the tissue can be performed.
By that time, repeated circulation of the injected microbubbles
through the body vasculature results in the selective binding of a
fraction of the injected bubbles to the target, e.g., disease tissue.
Continued on page 7. See Ultrasound Contrast Agents.
3
Ultrasound Contrast Agents. Continued from page 1.
2011 Molecular
Imaging Meetings
Multimodality Molecular
Imaging of Prostate Cancer
Friday, January 21, 2011
Palm Springs, California
Part of the SNM 2011
Mid-Winter Meetings
www.snm.org/prostate2011
Clinical Trials Network
Workshop
January 20–21, 2011
Palm Springs, California
www.snm.org/ctn2011
Breast Cancer Imaging:
State of the Art 2011
Diagnosis, Therapy and
Beyond
April 21-22, 2011
Bethesda, Maryland
2
The Natcher Center
National Institutes of Health
www.snm.org/breast2011
Lost and Found in
Translation: Translating
Your Optical and Radiopharmaceutical Agents into
the Clinic, a Categorical
Seminar
June 4, 2011
San Antonio, Texas
SNM Annual Meeting
www.snm.org/am
m i images of interest
Ultrasound Contrast Agents. Continued from page 1.
that successful molecular imaging with current generation of microbubble contrast
agents is possible only for intravascular markers, and ultrasound contrast detection
of a specific cellular marker is not feasible if that marker is not exposed to the bloodstream and is located at the interstitial space or inside the target cell.
Design of Microbubbles for Molecular Imaging
Over the past 15 years, dozens of papers describing molecular imaging with ultrasound contrast have appeared, presenting targeting to a variety of the disease marker
molecules. General design of the particle has not changed significantly since its first
presentation (9). Targeting ligand is attached to the microbubble shell-forming material, then microbubbles are generated from insoluble gas during high-shear mixing,
e.g., with a probe-type sonicator. During the preparation procedure, microbubbles
are immediately covered with the shell. After removal of excess ligand by centrifugal
flotation, microbubble targeting is either tested in vitro or injected intravenously in
the experimental animals with the appropriate disease models.
Most successful and popular targeted microbubble shell design is based on a lipid
monolayer shell decorated with a grafted brush of the water-soluble polyethylene
glycol. The thickness of the lipid monolayer is ~2 nm. This thin shell does not interfere significantly with microbubble expansion and contraction in the ultrasound
field, providing good contrast echogenicity without the need to destroy the particles
by cracking the shell with high-power ultrasound. This shell does not serve as a significant barrier for gas diffusion in and out of the bubble. PEG chains extend from
the microbubble surface into the surrounding aqueous environment by ~10-30 nm,
which is not very significant when compared with a 2-3 um particle diameter (10).
Targeting ligand is usually attached to the exterior of the PEG brush in the same extended “fishing line” manner as it was earlier proposed for liposomes (11). This ligand
coupling technique facilitates ligand-receptor interaction and improves microparticle
targeting in a flow-through scenario (12). Peptides/mimetics, carbohydrates, glycosulfopeptides, small and large proteins (such as antibodies) were successfully tested
as ligands for ultrasound molecular imaging. Most of such tests required biotinylated
ligand that would attach to the bubble via a streptavidin spacer (13); many biotinylated ligands are available commercially or can be prepared easily. The advantage of
biotin-streptavidin ligand linking technique is in its simplicity; bubbles can be easily
centrifuged to remove excess of free ligand. This approach is especially useful if the
ligand is a large protein that could become denatured and inactivated during microbubble preparation by sonication as described in the previous paragraph. However,
there is a very significant disadvantage. Streptavidin, as a foreign protein, will not
be approved for clinical application in human setting. Therefore, chemical coupling
between ligand and shell has to take place, either before (as described above) or after
bubble preparation.
The choice of ligands for microbubble targeting may be determined not just by
the specificity and affinity of ligand-receptor interaction for the respective molecular
markers (thermodynamics), but also by how fast the ligand-receptor interaction takes
place (kinetics). Antibodies are usually selected via ELISA, by the value of equilibrium
affinity, often described as equilibrium dissociation constant, Kd; however, the act of
interaction of ligand-microbubble with the receptor on the vessel wall is a rather timeconstrained event, and if the kinetics of association between the ligand and receptor
is slow, the microbubble would be transported away from the target area and would
not attach to the intended target. Therefore, the choice of fast-binding ligands, such
as glycosulfopeptide portion of the natural molecule P-Selectin Glycoprotein Ligand 1
(PSGL-1, (14)) or even simpler molecules such as sialyl Lewis X, (15) could be considContinued on page 3. See Ultrasound Contrast Agents.
www.molecularimagingcenter.org/ mi
Molecular Ultrasound Imaging of Tumor Angiogenesis
Visistar-Integrin microbubbles
(cRGD peptide)
Visistar-Integrin Control microbubbles
(cRAD peptide)
8 min after intravenous injection of 50 million microbubbles.
Sequoia 512 imaging system with 15L8 probe, operated in CPS mode
Ultrasound molecular imaging of tumor angiogenesis in an orthotopic mouse model of breast cancer (Met-1 cells implanted in mammary fat pad).
Microbubbles bearing a cyclic RGD peptide ligand (Visistar-Integrin, directed at avb3 integrin on tumor vascular endothelium) or a control ligand (cyclic
RAD peptide) covalently conjugated to the bubble shell were administered intravenously and allowed to circulate and clear from the bloodstream over
eight minutes. Targeted microbubbles accumulated within the tumor. Control microbubbles exhibited negligible accumulation. Dotted line delineates tumor
borders, as determined by B-mode ultrasound.
Images courtesy of Xiaowen Hu and Katherine Ferrara (University of California, Davis); Visistar-Integrin microbubbles provided by Joshua Rychak (Targeson,
San Diego).
Ultrasound Contrast Agents. Continued from page 2.
ered. Interestingly, the latter has equilibrium Kd ~ 1mM for P- or
E-selectin. Such low affinity is not useful for targeting of small
molecules. However, successful particle targeting is possible via a
combination of rapid association between the ligand and receptor,
and cooperative multipoint interaction between large number of
ligand and receptor molecules. Placing over a million small ligand
molecules per single microbubble is feasible. Only ~105 (or less)
antibody molecules attached per microbubbles is typically reported (13). Using full IgG molecule (MW=150,000) for immobilization on the microbubble surface may not be the best strategy as
compared with the use of smaller ligands: larger molecules carry
much more than just the target binding sequence. Fc fragment of
the antibody may be quite immunogenic, so the use of humanized
(or fully human) antibodies is required. Furthermore, Fc receptors on phagocytic cells (e.g., in the liver) may alter microbubble
biodistribution in an undesirable way. Overall, the use of smaller
molecules as ligands for molecular ultrasound imaging should be
preferred.
In Vivo Molecular Imaging with Microbubble
Contrast Agents
There are many useful intravascular molecular targets that mark
disease tissue location; most of them are affiliated, directly or indirectly, with endothelial cells, and constitute markers of inflammation (such as ICAM-1 (16), VCAM-1 (17), MAdCAM-1 (18), P- or
E-selectin (13)) or angiogenesis (VERFR2 (19), αvβ3 (20)). Blood
clot markers, such as platelet GPIIbIIIa (21) and P-selectin (22)
and activated form of endothelial von Willebrand Factor (23) can
also serve as useful targets of disease. A wide array of molecular
imaging ultrasound contrast studies have been performed to date
in animal models. Imaging procedure is quite straightforward, but
somewhat different when compared with other molecular imaging
modalities. Targeted microbubble construct aqueous dispersion
(or control non-targeted preparation) is injected intravenously as
a bolus, and low-power contrast ultrasound imaging of the region
of interest is performed immediately. Contrast inflow imaging provides real-time information of the blood flow patterns in the tissue
of interest, and may be useful for immediate understanding of the
target tissue physiology. Several minutes later, imaging of microbubbles that have accumulated in the tissue can be performed.
By that time, repeated circulation of the injected microbubbles
through the body vasculature results in the selective binding of a
fraction of the injected bubbles to the target, e.g., disease tissue.
Continued on page 7. See Ultrasound Contrast Agents.
3
SNM is now accepting abstracts for the 2011 Annual Meeting, June 4-8 in San Antonio, TX.
This premier event offers physicians, scientists, technologists, lab professionals, and
educators/course directors in the field of nuclear medicine and molecular imaging the
ideal platform to present scientific research to an audience of medical imaging professionals from
around the world.
call
Abstracts
Abstract
Submission
Deadline:
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2011
for
DONOR CORNER
MI Innovations Increase Efficiency
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Compromise
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M
olecular imaging has the potential to transform health care by shifting the focus
from treating disease to enabling early health. At RSNA 2010, GE Healthcare
demonstrated several innovative molecular imaging technologies designed to increase
workflow efficiency and overall image quality, while reducing exam times and improving dose management. By combining the power of anatomical and functional scanning
with biological tracers, GE is helping health care providers to detect and diagnose
disease earlier, and to evaluate treatment efficacy more quickly.
Molecular imaging also directly impacts patient care by allowing physicians to tailor
specific treatments to individual patients, which in turn will mean that health care
dollars are more efficiently spent to save lives. With tri-modality imaging, researchers
and clinicians have the potential to improve small lesion detection, image quality and
therapy response monitoring to understand disease from the beginning.
It is important to demonstrate industry commitment to improving the patient experience while maintaining clinical excellence and quality. By applying innovation, we can significantly
shorten traditional exam times and reduce dose to improve the
patient experience without compromising a clinician or researcher’s ability to understand and treat disease effectively.
Terri Bresenham
Vice-President of Molecular Imaging at GE Healthcare
www.molecularimagingcenter.org/ mi
2011 Annual Meeting
San Antonio, TX
June 4-8, 2011
SNM 2011 Mid-Winter
Meetings Offer
Comprehensive
Prostate Cancer
Symposium
SNM’s Center for Molecular Imaging
Innovation and Translation (CMIIT) is
hosting the Multimodality Molecular Imaging of Prostate Cancer Symposium on Jan.
21, 2011. This one-day symposium brings
together individuals from multiple clinical and scientific disciplines to provide an
up-to-date survey of best practices for the
diagnosis and treatment of patients with
prostate cancer. The symposium will address the need for synergism between
diagnostic radiology, nuclear medicine and
the new molecular imaging modalities.
Lectures will emphasize the role of imaging
in enabling better treatment selection and
evaluation and, importantly, the ideal approach to assessing response to treatment.
Ultrasound Contrast Agents. Continued from page 3.
The majority of contrast agent is not likely to adhere to the molecular marker of disease and is recirculating with the blood flow.
Microbubble shell is too thin to be a good barrier for air diffusion
into the bubble and fluorocarbon diffusion out of the bubble. As
microbubble contrast passes through the lungs, gas exchange with
the surrounding medium takes place; most of the fluorocarbon gas
is exchanged out of the bubbles and exhaled within minutes of
intravenous administration. Residual air in the bubbles does not
support good stability in vivo, it diffuses out and shell collapses,
making the particle non-echogenic. Targeted bubbles, adhered
e.g., to tumor vasculature, are not exposed to fast flow convection
conditions that support rapid gas exchange during circulation, so
we can hypothesize that loss of gas from targeted bubbles would be
slower. This process can contribute to the improvement of signalto-noise (e.g., target-to-blood) localization ratio.
So at 5-15 minutes after microbubble administration, most of
the circulating bubbles have cleared from the bloodstream, and
imaging of adhered bubble can be performed. Modern contrast
modes (such as Contrast Pulse Sequencing or Pulse Inversion Amplitude Modulation) implemented on many ultrasound imaging
systems allow to suppress the signal from the tissue itself, and observe microbubbles with excellent detection sensitivity in real time
at low power without contrast destruction (ultrasound Mechanical Index <0.2). After observing the targeted bubble in the particular imaging plane(s), ultrasound power can be increased, and
adhered bubbles destroyed. Reduction of the acoustic backscatter
signal after destructive pulse can serve as an additional proof of
microbubble targeting; within seconds after reduction of Mechanical Index, we can observe residual circulating bubbles still present
in the bloodstream.
Nearly all of the molecular ultrasound imaging studies described
in the literature so far have been performed in rodent animal
models. Publications of molecular ultrasound imaging studies on
larger animals are quite rare. There is one exception––a clinically
approved agent that is routinely used for Kupffer cell targeting,
Sonazoid (perflubutane microbubbles). It is approved for targeted
ultrasound contrast in the liver radiology setting in Japan. It is estimated that several hundred thousand patients have received this
contrast agent since its approval. Sonazoid accumulation in normal liver parenchyma is achieved via phosphatidylserine targeting:
Sonazoid microbubble consists of phosphatidylserine shell and
perfluorobutane gas. As phosphatidylserine is the natural marker
of apoptosis, its presence on the outer surface of a particle or a cell
makes that surface an immediate target for phagocytic uptake (24)
(25, 26). In the normal liver tissue but not in the lesion foci, Kupffer
cells are present and can capture circulating microbubbles and allow better disease characterization by “negative” target enhancement, as compared with unenhanced ultrasound or dynamic CT
(27). This “late-phase” ultrasound imaging is performed to detect
bubbles that have targeted to the normal liver tissue of interest following the clearance of circulating bubbles from the bloodstream,
several minutes after bolus intravenous administration.
As phosphatidylserine-targeted microbubbles are taken up by
any phagocytic cells, they can be applied not only for liver radiology, but also for imaging of adherent neutrophils in the acute
inflammation (28) or ischemia/reperfusion injury scenarios (29).
Cell Labeling for Ultrasound Contrast Imaging
As described in the previous paragraph, in vivo cell-specific labeling is already becoming a useful clinical tool in liver radiology
studies. It serves as proof that ex vivo cell labeling with microbubble agents can also be performed, e.g., for stem cell or dendritic cell therapy research, as is now popular for optical, MRI and
SPECT imaging modalities. Several groups by now have presented
ultrasound contrast materials such as microbubbles and liquid
fluorocarbon nanoparticle emulsions (30) for contrast labeling of
cells for ultrasound contrast imaging. One interesting example of
in vivo selective cell labeling is provided for circulating cells that
are tagged with ligand-carrying microbubbles after intravenous administration (31). The ability to detect microbubbles by ultrasound
even after their uptake in the cell has been proven experimentally
a decade ago (32); we can expect that after intracellular uptake,
microbubbles will not lose their gas core as rapidly as free circulating or even target-adherent bubbles; anecdotal evidence suggests
that echogenicity of microbubbles in the liver have significant longevity, perhaps due to intracellular uptake. Currently, this area is
rapidly developing, with the general goal of preparing labeled cell
samples to be monitored by ultrasound imaging for an extended
period of time (days).
Conclusion
In conclusion, molecular/cellular imaging with ultrasound contrast agents represents a rapidly developing area of research. A
combination of equipment portability, low cost and excellent contrast detection sensitivity by ultrasound imaging, in concert with
the ability to detect molecular markers of disease in real time, will
very likely lead to the development of molecular imaging contrast
agents for widespread clinical application for diagnostic imaging
and image-guided therapy.
A complete list of references for this article can be found at
http://www.molecularimagingcenter.org/docs/Gateway_Lead_
Article_US_Contrast-Klibanov.pdf
Alexander (Sasha) L. Klibanov, PhD
Associate Professor, Division of Cardiovascular Medicine and
Department of Biomedical Engineering, University of Virginia
7