Imaging of hyperpolarized nuclei provides significant new insights into previously inaccessible aspects of disease biology. Many of the biomolecules crucial for understanding and monitoring metabolism are present in low concentration and are often beyond the detection threshold of traditional magnetic resonance spectroscopy and imaging. A solution is to improve sensitivity by a factor of 10,000 or more by temporarily redistributing the populations of nuclear spins in a magnetic field, a process termed “hyperpolarization”. Hyperpolarized Carbon-13 MR is an emerging molecular imaging approach that has been applied to directly investigate key cellular enzymatic pathways in vivo through hundreds of preclinical studies and recently in human studies at four sites (and increasing) world-wide. Hyperpolarized C-13 imaging using the dissolution DNP (dynamic nuclear polarization) method provides 5-orders of magnitude signal enhancement for detecting C-13 probes of endogenous, nontoxic, nonradioactive substances such as pyruvate to monitor metabolic fluxes through multiple key biochemical pathways (glycolysis, citric acid cycle and alanine transaminase). The hyperpolarization of [1-13C]pyruvate has demonstrated the ability to not only detect pyruvate uptake but also the in vivo enzymatic conversion to 13C-lactate through the enzyme lactate dehydrogenase (LDH), 13C-alanine through the alanine transaminase (ALT) pathway; and 13CO2 & 13C-bicarbonate through the pyruvate dehydrognase (PDH) catalyzed metabolic pathway. The value of this powerful metabolic imaging technique for cancer imaging was shown first by Golman et al and we have applied it in a number of preclinical animal studies for detecting presence, progression and response to therapy in cancer models and in animal studies of liver and kidney disease. The first National Cancer Institute-sponsored white paper describing the potential of this new molecular imaging technique was published five years ago and over 60 biomolecules have been hyperpolarized and tested in pre-clinical studies. Moreover, a phase 1 clinical trial of hyperpolarized [1-13C]pyruvate in prostate cancer patients has demonstrated that this powerful technology can be translated to the clinic. This Phase 1 clinical trial in prostate cancer patients, published in Science Translational Medicine (2013), demonstrated feasibility and safety for this MR metabolic imaging technique. There are now over 50 dissolution DNP systems being used for in vivo studies world-wide and being applied for a wide variety of applications including cardiac studies, liver disease, diabetes, renal pathologies, infectious diseases, and numerous cancers.

We have conducted preclinical studies in multiple cancers including prostate, liver, kidney and brain. While 13C-pyruvate is the first to studied in humans, other hyperpolarized substrates including bicarbonate, glutamine, lactate, urea, alanine, bicarbonate, ketobutyrate, and dehydroascorbate have also been investigated in preclinical studies to probe cancer metabolism, perfusion and physiology. These studies have demonstrated significant metabolic changes with cancer presence, aggressiveness and response to therapy. The detection of a significant correlation with grade for up-regulated LDH-conversion to lactate by HP MRI is of great potential clinical value since there is no accurate current imaging technique to identify aggressive prostate cancers (which should be treated) from indolent cancers that may be managed through “active surveillance”. In addition to metabolic pathway information, hyperpolarized probes can provide valuable physiological information such as perfusion information (with HP 13C-urea) and pH (with HP C-13 sodium bicarbonate). In a special double-transgenic mouse model, we have performed preclinical studies of specific human oncogene expressions demonstrated highly elevated pyruvate to lactate conversion with significant correlations to up-regulated lactate dehydrogenase (LDH) activity and mRNA over-expression. This study also showed significant reductions in HP 13C-lactate detection in 3 days following oncogene inhibition demonstrated the potential of this technology for the early detection of therapeutic response in these preclinical models.

In addition to basic science and animal studies utilizing HP C-13 MRI, we have also focused on research to develop and translate hyperpolarized C-13 methods for ongoing clinical trials. Specialized carbon-13 MRI techniques were developed to provide extremely rapid volumetric imaging and serial dynamic acquisitions to monitor temporal metabolic changes in cancer patients following the injection of HP 13C-pyruvate. Led by the UCSF Cancer Center Investigational Therapeutics group, our multidisciplinary research group designed and initiated the world’s first clinical trial of hyperpolarized carbon-13 MRI. This study received FDA-IND approval and a total of 31 patients were studied using this new metabolic imaging method. All exams demonstrating feasibility and safety with no dose-limiting toxicity up to 0.42ml/kg of 250mM HP pyruvate which is the selected dose for current and future trials that now have FDA and IRB approval to conduct clinical research HP C-13 MRI studies in prostate cancer, brain tumors, and metastases to liver.