Traditional imaging studies such as X-ray (CT), MRI and ultrasound have hugely influenced clinical decision making in the last few decades in a large variety of disease entities. They improve and accelerate the diagnostic and treatment response pathway for the individual patient and patient groups as a whole. Novel imaging techniques allow for guidance towards more accurate and effective medical, surgical and radiotherapy related therapies. Therefore, these studies can be a crucial factor to improve patient selection prior to surgery or (neo-)adjuvant chemoradiotherapy and eventually patient outcome. Moreover, current innovative technical developments allow for the assessment of not only the standard anatomical information, but also provide biological disease related information by using molecular imaging. Molecular imaging is the so-called future of imaging. The combination of anatomical and biological information in molecular imaging studies allows for improvements of the diagnostic trajectory and the possibility for monitoring disease progression and drug accumulation over time. This is highly valuable in drug development, as it identifies the working mechanism and effects of new diagnostic and therapeutic drugs.
Two types of molecular imaging techniques.
Two main imaging techniques are used in preclinical and clinical molecular imaging studies: nuclear imaging and optical imaging. The most widely used nuclear imaging techniques are Positron Emission Tomography/Computed Tomography (PET/CT) and Single-Photon Emission Computed Tomography (SPECT). These modalities use radioactive labeled imaging agents to detect disease-specific characteristics. This allows for the detection of tumors, metastatic lesions after the detection of a primary tumor, infectious and inflammatory diseases. Additionally, it allows for follow-up imaging after for example (neo)adjuvant chemotherapy to evaluate the response for a certain treatment schedule.
The combination of PET with CT has not only improved medical diagnosis by combining anatomical with functional/biological imaging, but opens up a world of new potentials to track drug distribution. This is highly relevant to assess for example new chemotherapeutic targets and corresponding new therapeutic drugs. Nuclear imaging can provide whole body biological information and accurate quantification. However, a disadvantage is that the resolution of the images is relatively low and comes with the use of ionizing radiation.
On the other hand, optical imaging modalities like fluorescence and optoacoustic imaging can increase disease detection, as both modalities have a much higher spatiotemporal resolution. Nevertheless, they come with a limited field of view of just a few centimeters and limited penetration depth. Optical imaging techniques do allow for real-time surgical and endoscopic imaging, where visualization of small disease lesions is highly relevant and delivers information ‘on-the-spot’.
Nuclear and optical imaging modalities are complementary in a clinical setting to improve patient outcome. Both modalities are extensively used during preclinical and clinical research. You can read more about the use of nuclear and optical molecular imaging in drug development in our previous blog.
Molecular imaging studies in drug development.
The application of medical imaging studies, especially in the early phase of drug development, can shorten the current and future development phases. The goal is to translate preclinical results towards clinical studies using a standardized workflow. This allows for a quick and accurate assessment of drug behavior in vivo. Specifically, molecular imaging enables the monitoring of pharmacodynamic changes and the pharmacokinetic properties of drugs in vivo. Molecular clinical imaging studies provide an accurate qualification and quantification of drug mechanism. Therefore, they can, especially when used during surgery, influence decision making right on the spot.
In a clinical setting, both in vivo and ex vivo imaging techniques can be used to classify and quantify biological activity. In medical oncology, this means that tumor response towards chemotherapy can be monitored. In surgery, fluorescence intensities of a tumor-targeted tracer can provide information about the margin status and the malignant nature of tissue and/or the presence of locoregional metastases. Both settings are equally extremely important for pharmaceuticals in the field of oncology. Additionally, and unique in its nature, labeling drugs with a fluorescent or radioactive substrate allows for tracking of the drug on a cellular setting and for whole-body biodistribution and pharmacodynamic evaluation. Needless to state that delivery of a drug in the tissue of interest is key to provide personalized medicine now and in the future.
Another major advantage of clinical molecular imaging studies is the possibility to detect diseases in a very early stage. For most medical imaging devices, the resolution is too low to detect tumors or premalignant tissue smaller than 0.5-1 centimeter. The goal of real-time imaging studies is to provide the physician information that is not visible with the naked eye. For example, for gastroenterologists it is mostly hard to distinguish between benign and (pre-)malignant tissue. Tumor-specific imaging agents, labeled with a fluorophore, are used to detect this (pre-)malignant tissue during endoscopy to increase visualization and decrease the number of false-negative biopsies. In turn this will eventually lead to early-stage therapy for malignancies.
Effective multidisciplinary collaborations to produce high quality imaging studies.
Clinical imaging significantly overlaps with pathology, a combination that is essential for biological information of the tissue of interest. Histopathological information is combined with the imaging results and allows for noninvasive visualization of biochemical processes at the molecular level. Disease behavior and drug responses, adequately correlated with histopathological data after surgical or endoscopic excision, can be assessed in detail. Therefore, a standardization of acquiring and analyzing imaging results is essential and key to achieve high level imaging studies. At TRACER, we focus on a standardized analytical imaging framework as described by Koller et al (Nature Communications, 2018). This framework focusses on all aspects of tumor visualization. It starts at real-time in vivo fluorescence imaging during surgical excision and moves up towards ex vivo imaging taking into account all steps of histopathological assessment. Furthermore, the framework allows for adequate, precise and reproducible correlation studies between surgical results and the final histopathological outcome.
Molecular imaging studies are a result of a major multidisciplinary collaboration. Namely, they are influenced by the needs of medical physicians, biologists, chemists, engineers and pharmacists. TRACER has extensive expertise in conducting molecular imaging clinical trials and has the right state-of-the-art network of all key facilitators in the field. Therefore, we are able to provide both quality nuclear and optical imaging studies towards our clients.
To conclude, clinical imaging studies provide a broad spectrum of opportunities for physicians, pharmacists, chemists, but most importantly drug developers. Imaging studies, both optical and nuclear, have the opportunity to provide biological information and track and navigate the selected drug to speed up the first phases of drug discovery. Additionally, they can provide researchers with human tissue, and therefore, biological information after surgical excision.