Purpose

To demonstrate simultaneous hyperpolarization and imaging of three (13)C-labeled perfusion MRI contrast agents with dissimilar molecular structures ([(13)C]urea, [(13)C]hydroxymethyl cyclopropane, and [(13)C]t-butanol) and correspondingly variable chemical shifts and physiological characteristics, and to exploit their varying diffusibility for simultaneous measurement of vascular permeability and perfusion in initial preclinical studies.

Methods

Rapid and efficient dynamic multislice imaging was enabled by a novel pulse sequence incorporating balanced steady state free precession excitation and spectral-spatial readout by multiband frequency encoding, designed for the wide, regular spectral separation of these compounds. We exploited the varying bilayer permeability of these tracers to quantify vascular permeability and perfusion parameters simultaneously, using perfusion modeling methods that were investigated in simulations. "Tripolarized" perfusion MRI methods were applied to initial preclinical studies with differential conditions of vascular permeability, in normal mouse tissues and advanced transgenic mouse prostate tumors.

Results

Dynamic imaging revealed clear differences among the individual tracer distributions. Computed permeability maps demonstrated differential permeability of brain tissue among the tracers, and tumor perfusion and permeability were both elevated over values expected for normal tissues.

Conclusion

Tripolarized perfusion MRI provides new molecular imaging measures for specifically monitoring permeability, perfusion, and transport simultaneously in vivo.

This first-in-man imaging study evaluated the safety and feasibility of hyperpolarized [1-¹³C]pyruvate as an agent for noninvasively characterizing alterations in tumor metabolism for patients with prostate cancer. Imaging living systems with hyperpolarized agents can result in more than 10,000-fold enhancement in signal relative to conventional magnetic resonance (MR) imaging. When combined with the rapid acquisition of in vivo ¹³C MR data, it is possible to evaluate the distribution of agents such as [1-¹³C]pyruvate and its metabolic products lactate, alanine, and bicarbonate in a matter of seconds. Preclinical studies in cancer models have detected elevated levels of hyperpolarized [1-¹³C]lactate in tumor, with the ratio of [1-¹³C]lactate/[1-¹³C]pyruvate being increased in high-grade tumors and decreased after successful treatment. Translation of this technology into humans was achieved by modifying the instrument that generates the hyperpolarized agent, constructing specialized radio frequency coils to detect ¹³C nuclei, and developing new pulse sequences to efficiently capture the signal. The study population comprised patients with biopsy-proven prostate cancer, with 31 subjects being injected with hyperpolarized [1-¹³C]pyruvate. The median time to deliver the agent was 66 s, and uptake was observed about 20 s after injection. No dose-limiting toxicities were observed, and the highest dose (0.43 ml/kg of 230 mM agent) gave the best signal-to-noise ratio for hyperpolarized [1-¹³C]pyruvate. The results were extremely promising in not only confirming the safety of the agent but also showing elevated [1-¹³C]lactate/[1-¹³C]pyruvate in regions of biopsy-proven cancer. These findings will be valuable for noninvasive cancer diagnosis and treatment monitoring in future clinical trials.

This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) ¹³C magnetic resonance imaging's (MRI's) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized ¹³C MRI in 2011, preclinical studies involving [1-¹³C]pyruvate as well a number of other ¹³C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1-¹³C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP ¹³C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind.