Preclinical MRI
The IVIF Magnetic Resonance Imaging (MRI) modality provides comprehensive, economical, and state-of-the-art MRI services that enable real-time in vivo analyses of physiological, cellular, and molecular processes as well as in vivo analyses of responses to medical interventions.
Services provided by the MRI modality include:
- molecular and cellular imaging techniques, pulse sequence design and implementation, imaging protocol development, contrast agent synthesis, and data analysis;
- expert consultation in the design and application of relevant MRI methods, enabling the selection of the most suitable technique for research studies; and
- guidance by trained personnel who have the technical skills and expertise to facilitate and implement the necessary MRI research protocols.
MR Imaging
Compared with survival studies, MRI gives UPCI investigators both earlier end points for assessing the efficacy of new treatments and insight into the molecular reasons why these new treatments may or may not work. This information provides specificity with respect to the treatment's effect on the tumor and can even be used to identify the onset of tumor resistance to a given therapy.
The methodologies offered include:
- Tumor volume measurements, which are simple measurements that directly assess the effect of a new treatment on a particular tumor type. Unlike survival studies, tumor volume studies allow an investigator to observe partial effects, and even temporary remission, with the implicit subsequent development of tumor resistance.
- Tumor capillary transfer rates or permeability surface area products, tumor vascular plasma fraction, and extracellular volume space measurements, which can give physiological information about a treatment protocol at earlier stages than even tumor volume measurements. For example, these measurements provide insights into the molecular mechanisms and the efficacy of anti-VEGF and anti-angiogenesis treatments. They also enable in vivo analyses of drugs targeted to disrupt specific signaling cascades in endothelial cells and whether the drugs affect the end points of these signaling cascades. In the case of brain tumors, these types of measurements are one of the few that can differentiate between radiation-induced scarring and recurrent or residual tumor.
- Measurement of tumor metabolites and drug concentrations with MRI and Magnetic Resonance Spectroscopy (MRS) enables the in vivo monitoring of drug pharmacokinetics, drug activation, and tumor biology. It provides vital information on the actual conversion of prodrugs into active drugs or drugs into inactive metabolites and the intratumoral concentration of these drugs. These methods also allow investigators to monitor changes in tumor biochemistry as a function of treatment, growth, or metastatic potential.
Synthesis of targeted and macromolecular MR contrast agents. The use of macromolecular contrast agents provides better methods for monitoring tumors in organs other than the brain when combined with measurements of tumor capillary physiology and function. The existence of the blood brain barrier in healthy brain tissue creates a zero baseline value for tumor capillary transfer rates and tumor extracellular extravascular space measured with water soluble MRI contrast agents. Brain tumor capillaries have a significant increase in these parameters from zero. In other organs, the tumor capillary transfer rates and tumor extracellular extravascular space have values well above zero for standard MRI contrast agents, and this obscures small changes associated with tumor capillaries and their responses to therapy in these organs.
Macromolecular agents have tumor capillary transfer rates or permeability surface area products that vary with the size and charge of the agent, and the relative changes above background are larger, making them a better choice for tumors outside of the brain. Tumor-specific agents provide an additional means of directly monitoring tumor response, differentiating tumor types, confirming secondary tumors, and a method for differentiating tumors from scar tissue.
- Applications and development of techniques based on single and multiple quantum methods, for the measurement of low sensitivity nuclei, low concentration metabolites, and for directly detecting low concentrations of drugs. These methods provide a means of studying tumor biochemistry, drug activation, intra—tumoral drug concentrations, and intra-tumoral drug pharmacokinetics.
- Monitoring and measuring cell movement into and recruitment by tumors in vivo. Lymphocyte, adoptively transferred immune cell, and stem cell tracking provides a means of monitoring different types of immunotherapy, how the tumor environment affects immune cells, if a treatment protocol attracts immune cells to the tumor, and if stem cells home to specific targets.
- Custom methods development. Services are developed with user input and by surveying the UPCI community. Examples include regional blood volume measurements and perfusion studies. All of these methods provide UPCI investigators with tools that generate more information, and also have the potential to greatly benefit cancer research, clinical trials, and cancer treatments.
The UPCI has a large number of investigations that involve biological therapeutics, anti-angiogenesis therapies, drug pharmacokinetic studies, MRS of breast cancer, and earlier biochemical markers of the transformed phenotype. The custom MRI methods may lead to quicker noninvasive strategies for diagnosing and staging primary or metastatic tumors and better monitoring of tumor responses to therapeutic protocols or standard treatments.
MRI Consultation Services
Most UPCI investigators lack exposure to and experience with MRI. To provide researchers with important awareness of the full capabilities of MRI, and to better identify the MRI/MRS methods that best fit their needs, the IVIF provides one-on-one consultative services.
Interested UPCI animal researchers should first contact Dr. Erik Wiener to discuss their research objectives and long term goals. Dr. Wiener will bring these needs to the attention of a joint MRI-PET internal advisory committee, and the group will discuss and identify the appropriate modality or modalities. The appropriate MRI expert will then meet with the UPCI investigator and Dr. Wiener to discuss the specifics of the tumor models and the implementation of the particular MRI methods that meet those objectives.
MRI Equipment
The development of MRI contrast agents and multimodal platforms, which are utilized as biomarker assessment tools for preclinical research, continues to grow with custom synthesis providing a significant contribution to UPCI members. The Hillman Cancer Center houses a 7T ClinScan small animal clinical magnet, which has the same clinical operating system and research agreement that is installed on the Human 3 and 7T magnets housed in the Magnetic Resonance Research Center (MRRC) to facilitate translation of new biomarkers. This 7T imaging system enables the use of novel, ultra-short echo time (TE) protocols, including twisted planer imaging (TPI) and spiral acquisition methods. In addition to enabling rapid imaging of systems with extremely short T2s, bone and lung tissues, these techniques also enable Na and Rb imaging. Intracellular Na is a marker of cell division, like KI67, and Rb is a K surrogate. There are only a few groups in the world capable of imaging Rb.
