The use of dynamic nuclear polarization (13)C-pyruvate MRS in cancer

Abstract

In recent years there has been an immense development of new targeted anti-cancer drugs. For practicing precision medicine, a sensitive method imaging for non-invasive, assessment of early treatment response and for assisting in developing new drugs is warranted. Magnetic Resonance Spectroscopy (MRS) is a potent technique for non-invasive in vivo investigation of tissue chemistry and cellular metabolism. Hyperpolarization by Dynamic Nuclear Polarization (DNP) is capable of creating solutions of molecules with polarized nuclear spins in a range of biological molecules and has enabled the real-time investigation of in vivo metabolism. The development of this new method has been demonstrated to enhance the nuclear polarization more than 10,000-fold, thereby significantly increasing the sensitivity of the MRS with a spatial resolution to the millimeters and a temporal resolution at the subsecond range. Furthermore, the method enables measuring kinetics of conversion of substrates into cell metabolites and can be integrated with anatomical proton magnetic resonance imaging (MRI). Many nuclei and substrates have been hyperpolarized using the DNP method. Currently, the most widely used compound is (13)C-pyruvate due to favoring technicalities. Intravenous injection of the hyperpolarized (13)C-pyruvate results in appearance of (13)C-lactate, (13)C-alanine and (13)C-bicarbonate resonance peaks depending on the tissue, disease and the metabolic state probed. In cancer, the lactate level is increased due to increased glycolysis. The use of DNP enhanced (13)C-pyruvate has in preclinical studies shown to be a sensitive method for detecting cancer and for assessment of early treatment response in a variety of cancers. Recently, a first-in-man 31-patient study was conducted with the primary objective to assess the safety of hyperpolarized (13)C-pyruvate in healthy subjects and prostate cancer patients. The study showed an elevated (13)C-lactate/(13)C-pyruvate ratio in regions of biopsy-proven prostate cancer compared to noncancerous tissue. However, more studies are needed in order to establish use of hyperpolarized (13)C MRS imaging of cancer.

Keywords: 13C-pyruvate; Dynamic nuclear polarization; MR; MRS; cancer; response monitoring.

Figure 1

A key metabolic fingerprint in cancer cells is the switch to glycolysis with production of lactate even in the presence of sufficient oxygen (reproduced with permission from ref [68]).

Figure 2

Color maps representing ¹³C-lactate and ¹³C-pyruvate peak intensities obtained from ¹³C chemical-shift images in the same mouse before and after treatment with etoposide. The images were acquired between 20 and 25 s after intravenous injection of 0.2 ml 75 mM hyperpolarized ¹³C-pyruvate and 20 h after injection of the mice with 67 mg/kg etoposide. Tumor margins are indicated by the white lines. Reprinted with kind permission from Nature Medicine [30].

Figure 3

View of HyperPET and description of the Warburg effect. Increased ¹⁸F-FDG uptake is a composite quantity of numerous hallmarks of cancer, e.g. metabolic changes, cell proliferation and hypoxia. While measured ¹³C-pyruvate to ¹³C-lactate switch probably expresses the Warburg per se. Modified from [68].

Figure 4

Showing Hyper PET images of a canine cancer patient with a sarcoma on the back. Demonstrating the agreement of ¹⁸F-FDG and ¹³C-lactate in the tumor region. Unpublished data.