The cellular pathophysiology that underlies diseases, such as cancer, cardiovascular disease, and diabetes, begins to change long before disease symptoms become apparent. Moreover, current imaging techniques typically only visualize morphology and structure. Therefore, imaging techniques that can characterize metabolic changes have the potential to detect disease processes long before disease symptoms are pronounced. Metabolic and functional imaging thus allows much earlier diagnosis and treatment. In vivo metabolic imaging, which distinguishes changes in the chemical reactions that make up cellular processes, can be used to better understand the mechanisms underlying disease onset and progression. Current metabolic imaging techniques, such as PET and SPECT, are expensive, difficult, and not conducive for longitudinal studies due to the use of radioactive contrast agents. Therefore, the broad clinical utilization of these techniques is limited in scope. In preclinical models, other techniques, such as tissue slicing of sacrificed animals for mass spectrometry analysis, need to be employed to study cellular metabolism, resulting in a very large translational gap between preclinical animal models and clinical studies. Vizma Life Sciences has developed a novel easy-to-operate tool to prepare contrast agents that enable noninvasive, cost-saving, and repeatable in vivo preclinical imaging and is amenable to clinical translation. The tool prepares hyperpolarized metabolites that can be used as injectable contrast agents visible to conventional MRI systems. The hyperpolarized metabolites, such as [1-13C]-pyruvate, have signal-boosted spins and can be tracked in real time and report on metabolic transformations and pathways. Vizma's tool can be easily adapted for broad use in animal facilities and in longitudinal studies in the same animals, thus reducing experimental variability and the number of animals required as the animals do not need to be sacrificed for metabolic imaging. This tool will directly improve the translation of animal research to clinical validation. The overall goal of this Phase I SBIR is to make the Vizma hyperpolarization process fully biocompatible. This involves adapting the [1-13C]-pyruvate hyperpolarization process from an alcohol-based solution to an aqueous solution, determining sensitivity limits, and then measuring residual solvent and catalyst contamination. The in vivo feasibility and safety of the technology will be examined by assessing the levels of detection of acute injections of the aqueous solution with chemical shift imaging in animals and monitoring another set of animals receiving hyperpolarized injections of the aqueous solution once a week for two weeks. Successful completion of this Phase I SBIR will result in in vivo proof-of-concept and support Phase II investigations of its use in imaging multiple animal models of disease in multiple species. The ultimate goal of this project is to commercialize this technology for broad use in preclinical and clinical settings.
Public Health Relevance Statement: PROJECT NARRATIVE Because disease-related alterations in cellular mechanisms occur long before disease symptoms, in vivo imaging of biomolecular transformations can be used to detect cellular dysfunction at an early pre-diagnosis stage, be it in preclinical animal models or a clinical setting, and thereby provide a better understanding of the onset and progression of disease mechanisms. Current cellular imaging techniques are expensive, difficult, and often require radioactivity, thus limiting their use in research animal models and clinical practice. In this proposal, we examine the safety and feasibility of our novel easy-to-operate tool that is used to prepare contrast agents for metabolic imaging in research animal models and that has a clear path to clinical translation because it enables safe longitudinal visualization of biochemical cellular mechanisms and metabolic pathways in any organ for early stage detection and in-depth monitoring of disease.
Project Terms: Alcohol Chemical Class; Alcohols; Animal Experimental Use; Animal Research; animal experimentations; Animal Experimentation; Animals; Biological Sciences; Biologic Sciences; Bioscience; Life Sciences; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cardiovascular Diseases; cardiovascular disorder; Cell physiology; Cell Function; Cell Process; Cellular Function; Cellular Physiology; Cellular Process; Subcellular Process; Clinical Research; Clinical Study; Contrast Media; Contrast Agent; Contrast Drugs; Radiopaque Media; Dedications; Diabetes Mellitus; diabetes; Diagnosis; Disease; Disorder; Animal Disease Models; Euthanasia; Mercy Killing; Filtration; Filtration Fractionation; Goals; Heart Diseases; Cardiac Diseases; Cardiac Disorders; heart disorder; Longevity; Length of Life; life span; lifespan; Longitudinal Studies; long-term study; longitudinal outcome studies; longterm study; Magnetic Resonance Imaging; MR Imaging; MR Tomography; MRI; MRIs; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; NMR Imaging; NMR Tomography; Nuclear Magnetic Resonance Imaging; Zeugmatography; Metabolism; Intermediary Metabolism; Metabolic Processes; Methods; Study models; Positron-Emission Tomography; PET; PET Scan; PET imaging; PETSCAN; PETT; Positron Emission Tomography Medical Imaging; Positron Emission Tomography Scan; Rad.-PET; positron emission tomographic (PET) imaging; positron emission tomographic imaging; positron emitting tomography; Precipitation; precipitations; Radioactivity; radioactivities; Wistar Rats; Rodent; Rodentia; Rodents Mammals; Safety; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Solvents; Mass Spectrum Analysis; Mass Photometry/Spectrum Analysis; Mass Spectrometry; Mass Spectroscopy; Mass Spectrum; Mass Spectrum Analyses; Technology; Time; Tissues; Body Tissues; single photon emission computed tomography; SPECT; SPECT imaging; Single-Photon Emission-Computed Radionuclide Tomography; Translating; Translations; translation; Weight; weights; Work; Imaging Techniques; Imaging Procedures; Imaging Technics; Measures; Cost Savings; Injectable; catalyst; animal care; Organ; improved; Acute; Clinical; Residual; Residual state; Phase; Biochemical; Chemicals; insight; Licensing; Chemical Shift Imaging; Measurement; Disease Progression; Pyruvate; Dysfunction; Physiopathology; pathophysiology; Functional disorder; disease onset; disorder onset; Onset of illness; Metabolic; Morphology; tool; Intravenous; Adopted; Investigation; Complex; Clinic; Techniques; System; biomaterial compatibility; biocompatibility; chemical reaction; Early Diagnosis; early detection; longitudinal animal study; success; Animal Model; Animal Models and Related Studies; model of animal; aqueous; Toxic effect; Toxicities; Structure; skills; novel; Disease model; disorder model; Reporting; animal facility; NMR Spectroscopy; NMR Spectrometer; nuclear magnetic resonance spectroscopy; image-based method; imaging method; imaging modality; Metabolic Pathway; preventing; prevent; Symptoms; Detection; Imaging Device; Imaging Instrument; Imaging Tool; Pre-Clinical Model; Preclinical Models; Radioactive; in vivo; Functional Imaging; Physiologic Imaging; physiological imaging; Laboratory Animal Production and Facilities; Research Animal Facility; Slice; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Validation; validations; Monitor; Preparation; preparations; Molecular; Process; cellular imaging; cell imaging; molecular imaging; molecule imaging; Image; imaging; Pathway interactions; pathway; pre-clinical; preclinical; cost; model of data; model the data; modeling of the data; data modeling; preclinical research; pre-clinical research; early therapy; Early treatment; commercialization; clinical practice; imaging in vivo; in vivo imaging; noninvasive imaging; non-invasive imaging; safety and feasibility; clinically translatable; clinical translation; metabolic imaging; Injections; Infrastructure; animal safety; Visualization; pre-clinical imaging; preclinical imaging; detection limit
