Metabolic Imaging Using Hyperpolarized Agents at Tracer Concentrations

Abnormal metabolism is characteristic of nearly all disease states, whether in pathway or extent, and often precedes changes accessible to anatomical medical imaging. Although several methods have been proposed and implemented to realize this potential for sensitivity to early disease, or to the immediate impact of a therapeutic regimen, each has a shortcoming that prevents metabolic imaging from being the general purpose diagnostic tool with broad clinical or research impact. This is equally true of solution state hyperpolarization, an MRI-based technique that enhances the signal per nucleus of selected biomolecules by >10,000x. Despite the large sensitivity gains, the technology of hyperpolarization has thus far been limited to rapid administration of high concentrations of imaging agent, limiting the accessible set of agents along with the amount that can be administered and metabolized in the short time during which the hyperpolarized state remains. In this project, we build on recent technical advances to produce a low cost, continuous flow device capable of producing highly polarized agents of clinical importance, at concentrations suitable for continuous infusion into in vitro cell culture and small animal preclinical experiments. We note that this scheme 1) maximizes metabolic signal by avoiding transporter and metabolic enzyme saturation, as well as cofactor pool depletion, while supporting greater safe total doses of the administered agent, and 2) simplifies analysis by operating under steady state conditions and allowing practical implementation of traditional MRI contrast techniques (e.g., metabolite signal saturation/inversion, diffusion encoding, etc.). We then demonstrate this utility in a series of studies in the SNU-449, comparing the metabolism of the adherent, perfused cells under a variety of conditions to similar results in induced tumors in immunocompromised mice. These studies, at `tracer' (e.g., relevant to normal physiological) concentrations will be the first of their kind using hyperpolarized agents, and are made possible using the apparatus developed in the first aim. Justified by these initial results, we anticipate that scaling up to large animal or human operation will be straightforward, and that eventual clinical adoption may be made easier by the ability to verify agent safety in steady state before infusion. Project Number: 1R21CA297468-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: STEPHEN KADLECEK | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $415,623 | Activity Code: R21 | Study Section: Imaging Probes and Contrast Agents Study Section[IPCA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11303907