Once basic research has established a solid understanding of an isolated cellular process or molecular function, the next challenge is to expand this knowledge to the interactions that occur within a living organism. More complexities come into play once a process is viewed in its natural environment. How does activation occur? What other processes does it interact with in the body and where? At what steps in the process can it be deactivated and by what? How do drug interactions come into play? All of these questions and more become the basis for a reliance on imaging.
Preclinical molecular imaging using small animal models is a key tool in drug discovery and development, providing an approach to monitoring a potential drug compound or disease progression live and over a period of time. This noninvasive technology allows experimental evaluation longitudinally in vivo without invasive tissue dissection, fixation, and sectioning, and delivers a comprehensive data set across a group of animals, while also analyzing the time-lapsed response within the same animal. The end result is the use of fewer animals and the collection of more complete and multidimensional data sets.
Recent advances in small animal imaging have helped to accelerate biomedical sciences in a way that provides valuable insights into the physiology and pathology of an organism that can be translated to clinical application. Using new small animal imaging technologies to gain a deeper understanding of disease states or mode of action of potential therapies allows improved conversion to the clinic for more rapid and accurate diagnostics and treatment options.
A strong foundation
Individual imaging techniques including optical, positron emission tomography (PET), single-photon emission computed tomography (SPECT), and magnetic resonance (MR) offer high specificity and wide applicability to small animal research. Improvements in instrumentation, imaging chemistry, and software development have yielded new efficiencies to the lab, allowing increased throughput and refining ease of use.
Improvements in instrumentation, imaging chemistry, and software development have yielded new efficiencies to the lab, allowing increased throughput and refining ease of use.
Optical imaging is one of the most widely used preclinical modalities due to the ability to record multiple fluorescent and bioluminescent signals in vivo, relatively low cost, and high-throughput capabilities. Analytik Jena focuses its imaging development on fluorescence and bioluminescence imaging for small animal applications, and has made a move toward instruments that automatically adjust settings for optimal contrast imaging. Automating technology to be more user-friendly with the ability to composite different imaging modalities together greatly enhances where imaging can take research.
“We develop tools that can be used as the underpinning for translation to clinical applications,” explains Sean Gallagher, director of research and development at Analytik Jena, “and provide the research foundation for strategies that can be moved to the clinic.”
As an example of where this technology can go, Analytik Jena’s UVP Scientia Small Animal Imager, which allows optical imaging of multiple mice at the whole animal level is currently being employed in preclinical to clinical studies at AntiCancer, Inc.
Analytik Jena works with Robert Hoffman at AntiCancer, a company specializing in mouse models for cancer research as they apply to drug discovery and evaluation. Using Analytik Jena’s iBox imaging systems, AntiCancer has developed mouse models that express various colors of fluorescent protein to enable scientists to observe tumor behavior in real-time. These mice can then be coupled with implanted tumors labeled with different fluorescent proteins to create technicolor and multiplex imaging options. By adding in near-infrared (IR) labeled drug delivery systems, the approach provides a method to study drug distribution in live models, offering a substantial amount of very valuable information in a short period of time.
Using an approach that applies multiple wavelengths and automated composition of images provides high-contrast imaging that can be directed to detailing drug response. Approaches such as these can also be used with nanoparticles or lipid vesicles employed for drug delivery to watch in real time how a drug travels through the body and where it accumulates.
Translating probes from lab to clinic
While molecular imaging publications are numerous, the number of new molecular probes approved for clinical use in the last few years is few and far between. Taking a probe from the bench to the clinic depends on successful preclinical efficacy and reproducibility, overall safety and effectiveness, and regulatory risk management.
Though the development of an optical probe seems simple enough, it requires a lot of expertise in a lot of different areas. With dye development, synthesis, conjugation, purification, specificity of the probe to the target, clearance and biodistribution, and scale-up and cGMP manufacturing, there is a drive for collaboration across chemistry, biology, manufacturing, and physics in order to address each area of expertise.
While many of these issues seem irrelevant to basic research and early application of a novel molecular probe, understanding the unique obstacles to clinical imaging encourages better initial design of molecular probes and in turn better preclinical studies.
“Fluorescent optical imaging has made very large strides in the in vivo imaging community as it relates to movement toward clinical applications,” says Jeff Harford, senior product manager at LI-COR. “The development of near-infrared optical imaging probes can easily translate from the lab to the clinic, commonly done for clinical applications such as image guided surgery, photoimmunotherapy, or optoacoustic imaging. Currently, there are over 16 clinical trials in process that are making use of LI-COR’s IRDye infrared dye technology.”
A presently ongoing clinical trial involving the IRDye technology is testing the probe as a tumor biomarker for recurrent high-grade glioma. The clinical trial is set to determine if a fluorescence signal can be detected by wide-field imaging technology with a relevant signal-to-noise ratio necessary for subsequent assessment of diagnostic performance of the probe sufficient to guide surgical resection in the future.
To supplement LI-COR’s imaging chemistry, LI-COR’s Odyssey CLx and other plate-based assays provide specificity testing of optical probes, offering high-throughput and highly reproducible results so researchers can push forward only the most promising candidates into animals.
Preclinical to clinical multimodal imaging
Not only have there been technological advances in the instrumentation, physics, and chemistry of individual modalities, but also integration of modalities to create an increasingly comprehensive view of drug response, diseases pathways, and cellular processes. Combining a number of imaging modalities using the same instrument transforms research by facilitating the use of complementary techniques to realize more from each experiment.
Bruker offers one of the widest ranges of preclinical imaging modalities for a broad spectrum of applications, providing researchers with several technologically advanced options that mirror what could be done in the clinic with different combinations of systems to fit their focus. One specific area of preclinical to clinical application is the transition from PET only to PET/CT multimodal systems, and most recently to PET/MR. Both preclinical research and clinics are now able to use these multimodal imaging systems for better contrast with soft tissue imaging in particular, including brain and cardiac imaging.
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“Bruker is allowing the researcher to replicate the types of detections that are being done in the clinic with PET/MR, and interrogate any questions regarding benefits and strengths of these combined systems for clinical use,” explains Todd Sasser, product marketing manager of molecular imaging at Bruker BioSpin.
By using a multimodal imaging system like PET/MR, researchers and clinicians alike can apply simultaneous or sequential configurations as needed for different applications or patient needs. Simultaneous multimodal imaging not only saves time, a critical factor for both preclinical and clinical situations, but also offers the exceptional benefit of synchronized data, where intersecting images can be put together to get multiparametric datasets and garner more information from each scan.
Image: Analytik Jena
Imaging Accessories
In addition to greatly improved instrumentation, advances in imaging accessories have helped expand small animal imaging when examining a specific area on the animal or investigating anti-tumor effects and early vascular events. APJ Trading develops imaging accessories for an increased number of compatible systems such as MRI for a look into specific organs and tissue areas such as dorsal, abdominal, or brain scans.