In vivo imaging technology developers and providers gear new features toward the drug discovery and development process.
Imaging continues to be a burgeoning tool of the pharmaceutical industry. Tools such as magnetic resonance imaging (MRI) and positron emission tomography (PET), which were at one time only used to image humans for medical purposes, have made their way into pharmaceutical labs. Optical imaging (i.e., microscopy) has also become a major tool of the industry, especially with advancements in labeling and detection technologies. Imaging of animal models to the assay efficacy and safety of candidate pharaceuticals has become commonplace. Moreover, growth and development of in vivo imaging technologies, which allow the user to capture biological events in real time in live animals, does not show signs of waning.
There have been a few advancements in in vivo imaging technologies just in the last year. Caliper Life Sciences (Hopkinton, Mass.), developer of the IVIS imaging platform, made multiple changes in its in vivo imaging technology in 2008. For example, the company expanded its capabilities in fluorescence labeling and detection. "With in vivo imaging using optical technologies, we’re using either bioluminescence or fluorescence [labeling] technology," says Stephen Oldfield, PhD, director of marketing at Caliper Life Sciences. Over the last year, he says, fluorescence has become increasingly important. Additionally, the integration of an electron multiplying charge coupled device (EMCCD) camera into the IVIS system has accelerated its response time in capturing biological events in real time.
Capturing kinetic events in vivo in real time is the name of the game for any in vivo imaging system, and this is especially true for the new IVIS Kinetic system. "With this new system, you can look at cellular signaling, track molecular movement, perfusion into tissues, diffusion rates, differential response after drug treatment—applications that you would not necessarily see if you were just looking at the tissue at normal time points," says Oldfield. The IVIS Kinetic is built to capture biological events that occur on the millisecond scale, which is impossible without an in vivo imaging system.
From cell to animal
As life science has grown into a mega-field, imaging technologies have seemingly grown along with it. In recent years, imaging has even advanced enough to detect interactions between single protein molecules. Although the IVIS system does track biological events at the molecular level, it does not have the capability to do so at the level of the single molecule. There is too much scatter of photons for that to happen, says Oldfield. However, the IVIS system is sensitive enough to detect events in a single cell. This level of detection is possible with the use of their brightly bioluminescent cell lines called BioWare Ultra. This application has been very useful for drug discovery applications, which is explained by Oldfield with the following story. "Last year at the American Association for Cancer Research’s annual meeting, we showed data where we implanted a single cell under the skin of a mouse and were able to detect that using bioluminescence. … So that gets interesting when thinking of a drug discovery application in oncology, where, from say five cells implanted, you can see the development of the tumor and track it much earlier in the developmental process, which can reduce the time to analysis from weeks to days."
But imaging of cell biology is not the primary use of the IVIS system—it is mainly used to image biological events in small animals such as mice and rats. But imaging in animals has its own challenges. Oldfield points out that one of these challenges has to do with what part of the animal is imaged. "You might want to image deep within a tissue. So with fluorescence, we’ll use a transillumination technique where we illuminate at one side of the animal and detect at the other side in order to image things that are deep within the animal. But there are still limitations as to how big that distance can be because of the scatter and absorption of photons."
The IVIS system also contains integral anesthetic manifolds that enable the user to anesthetize the animal prior to analysis. However, Oldfield says that, in some instances, allowing the animal to remain conscious during detection is necessary for a study. "People have said they want to look at moving animals because they may want to look at a nerve stimulus or, for some infectious disease models, the disease progression actually changes in a sedated animal and so it is less useful to work in a sedated animal," says Oldfield, who adds that such conscious animal studies are possible using the IVIS Kinetic system.
Over the next year or so, Caliper plans to expand the use of some of the features on the IVIS system. One of those features, the capability to create a 3D reconstruction of captured images, has been an available, yet underutilized, feature on the IVIS. "So if you are doing transillumination of a mouse to get the fluorescent signal, you could reconstruct that into a 3D representation where you could find the source of the signal and accurately quantify how many molecules were in that signal. So this is important information in terms of the quantification, it is useful in linking to computed tomography (CT) or MRI or one of those more translational modalities … ," says Oldfield. Over the next year plus, Caliper plans to tap into this market. Additionally, it plans to increase the use of multiple reporters (e.g., green fluorescence protein, luciferase, and fluorescence-labeled antibodies) in drug discovery efforts.
Medical imaging’s new role
In the last year, Charles River (Wilmington, Mass.) expanded its imaging capabilities with the acquisition of Molecular Imaging Research. Patrick McConville, PhD, is director of imaging at Charles River. "What we do here is focus on running imaging studies for our clients, which are pharmaceutical companies, from start to finish," says McConville. And the imaging modalities used? The atypical imaging tools include MRI, PET, and CT, while a less complex imaging tool used is optical imaging of bioluminescence reporter-labeled and fluorescence reporter-labeled cells or molecules. Although most of the imaging services are performed using cancer models, Charles River’s imaging services span across therapeutic areas.
The imaging services are conducted using small animal models, some of which are the intellectual property of Charles River, which puts them in a unique position as an imaging provider. "Some of these models, especially the metastatic and orthotopic tumor models, are difficult to study without imaging because the tumor is inaccessible to external measurements," says McConville, who adds that there is increasing demand for these models by their pharmaceutical clients.
Charles River uses what has become known as functional imaging. That is, the use of imaging technology to track a biomarker for disease progression. Several of the company’s imaging services fall into this category, including the measurement of tumor metabolism with fluorodeoxyglucose positron emission tomography (FDG-PET) imaging or the use of MRI to measure blood flow or tissue perfusion.
In summary, it is difficult to imagine performing a biological assay these days without some kind of imaging component. And the widespread availability of imaging tools makes their use very tempting. In vivo imaging has opened the door to the wonderous world of live-animal drug studies. No longer will it be necessary to sacrifice an animal to perform bioassays on its internal organs. With the increasing power of in vivo imaging, drug development can become more animal-friendly.
Published in Drug Discovery & Development magazine: Vol. 12, No. 3, March, 2009, pp.19-21.