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Feb 1, 2012 (Vol. 32, No. 3)

In Vivo Imaging Expands Niche

  • Spatial Coregistration

    Noninvasive in vivo imaging in animals has two useful utilities, according to University of California at Davis pathologist Alexander Borowsky, M.D., an expert in breast cancer. He makes extensive use of mouse models as a precursor to trials and therapy in humans.

    “Firstly, it allows us to use one mouse as its own control, which circumvents any issues in mouse-to-mouse variability,” he explained. “Secondly, compared to other technologies, it is immediately translatable to the clinic.”

    Dr. Borowsky highlighted a recent paper in PNAS in which small-animal high-resolution in vivo PET-imaging was demonstrated as a viable surrogate for more invasive standard histological measurements of tumor progression. The latter by their nature, he pointed out, cannot shed light on more subtle indices of tumor growth.

    “A great innovation in this study was what we call spatial coregistration,” said Dr. Borowsky. He defined this concept as “using high-resolution histology to achieve careful, anatomically registered validation of the imaging signals.”

    The technique has been combined with MRI to achieve more detailed characterization of amyloid plaques in mouse models of Alzheimer disease, which, since they contain iron, can generate confounding data in MRI studies.

    Relying on this two-pronged strategy—in vivo data collection and ex vivo validation—Dr. Borowsky’s longer-term goal is to assemble a catalog of associative data that correlates histology and microanatomy with the images collected in the live animal. “This is a problematic task, particularly in cancer,” explained Dr. Borowsky.

    Tumors are often a composite of many different cellular densities, angiogenic states, differentiation grades, and other variables. Dr. Borowsky is hopeful for the future, although, “it’s a matter of bringing the bioengineering behind the imaging platforms to a more sophisticated level that can address these subtleties.

    “Down the road I think you’re going to see an increasing convergence between the microscope slide and what can be achieved with in vivo imaging. I see plenty of space for more molecular and physiologically-based imaging methods, particularly in the area of optical imaging, that will gradually supplant methodologies with limited resolution, such as PET.”

  • IVIS Platform

    Click Image To Enlarge +
    PerkinElmer’s IVIS platform takes advantage of fluorescent and bioluminescent reporters to facilitate noninvasive longitudinal monitoring of a variety of processes in living animals. A. MDA-MB-231-luc2 mammary tumor cell line implanted into the mammary fat pad. B. Metastasis into the left ancillary lymph node. C. Ex vivo confirmation of lymph node burden. D. Multibiomarker characterization of breast tumor. Blue: DAPI; Green: Phospho-p-44/42 (Erk1/Erk2); Red: Phospho-Akt; Yellow: Phospho-S6.

    While MRI, PET, and x-ray are well-established types of in vivo imaging that offer the most clinical translational opportunities in preclinical models and patient imaging, optical imaging is gaining in importance. The IVIS platform initially developed by Caliper Life Sciences, which was recently acquired by PerkinElmer, takes advantage of fluorescent and bioluminescent reporters to facilitate noninvasive longitudinal monitoring of a variety of processes in living animals, including cellular trafficking and disease expression.

    “Caliper’s platform is applicable to a variety of therapeutic contexts, such as oncology, inflammation and metabolic disease, neuroscience and stem cell biology,” maintained Anna Christensen, product manager, life sciences and technology at PerkinElmer.

    The IVIS optical platform has grown to incorporate multispectral fluorescence imaging, 3-D tomography, fast kinetic imaging, integrated x-ray, and microCT.

    “Quantum FX microCT is a dedicated high-resolution longitudinal imaging platform for CT-focused applications and offers seamless co-registration with functional optical datasets,” added Christensen.

    On the translational side, the IVIS platform has already been leveraged in the progression of over 15 drugs into the clinic with many more in development, continued Christensen.

    “Optical imaging is quickly gaining acceptance within the clinic as a diagnostic tool for biopsy profiling and margin identification of resected tumors,” she observed.

    “Image-guided optical imaging can help surgeons not only define cleaner tumor margins intra-operatively, but identify metastatic lesions not visible with the naked eye all within the same surgical procedure.”

  • Novel In Vivo X-Ray Imaging System

    Officials at Carestream Molecular Imaging report that early adopters of the company’s In Vivo Xtreme instrument are carrying out research to study multiple pathways simultaneously within the same small animal.

    The pathways under investigation are myeloperoxidase (MPO) activity as it relates to inflammation and various apoptotic responses to the exposure of anionic membranes.

    The new high-resolution optical/x-ray system was specifically designed for applications in the preclinical, small animal research market and that require high sensitivity luminescence, fluorescence, radioisotopic, and radiographic imaging.

    In one application, the scientists have been studying a brain injury mouse model using luminol to longitudinally image neutrophil and macrophage activity in vivo, while simultaneously studying apoptosis and necrosis with a Zinc-DPA-NIR fluorophore conjugate. These probes have been previously validated in the literature to target MPO and anionic membranes respectively.

    The researchers relied on Xtreme’s x-ray signal to localize MPO activity and cell death utilizing bone structure in the skull of the mouse as landmarks. Using this same model, if researchers needed to quantify changes in brain metabolism, they could also image the subject using 18F-FDG in Carestream’s Albira PET/SPECT/CT system, according to a Carestream Molecular Imaging spokesperson.

    He added that the Xtreme, when paired with Albira, provides researchers with a combination of seven modalities for experiments requiring both high-throughput 2-D optical imaging and quantitative 3-D tomographic imaging.

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