Tumor imaging using hyperpolarized ¹³C magnetic resonance spectroscopy

Abstract

Dynamic nuclear polarization is an emerging technique for increasing the sensitivity of magnetic resonance imaging and spectroscopy, particularly for low-g nuclei. The technique has been applied recently to a number of 13 C-labeled cell metabolites in biological systems: the increase in signal-to-noise allows the spatial distribution of an injected molecule to be imaged as well as its metabolic product or products. This review highlights the most significant molecules investigated to date in preclinical cancer models, either in terms of their demonstrated metabolism in vivo or the biological processes that they can probe. Key words: hyperpolarized carbon-13; dynamic nuclear polarization; imaging; metabolism; tumor; pyruvateThe application of magnetic resonance in medicine has been dominated by imaging of tissue anatomy. However, one of the great strengths of magnetic resonance (MR) is spectroscopy, which allows imaging of tissue biochemistry; this was recognized in the earliest applications of MR to intact biological systems (1). Although magnetic resonance imaging (MRI) has become a routine clinical tool, the use of magnetic resonance spectroscopy (MRS) in patients has lagged far behind; this has been primarily due to a lack of sensitivity, which leads to long measurement times and poor image resolution (2-5). In spite of this, 1 H-MRS measurements of cellular metabolites in a variety of tumor types have been shown to provide a sensitive means to diagnose disease and detect response to treatment (2-4). However, these measurements generally give a static picture of cellular metabolism.In contrast, 13 C-MRS measurements of cellular metabolism in systems incubated with 13 C-labeled cell substrates give a dynamic, and therefore potentially more useful, measurement of tissue metabolism (6-8). For example, dynamic measurements of 13 C-labeled glucose incorporation into muscle glycogen have been used to dissect the relative importance of glucose transport and hexokinase and glycogen synthase activity in controlling muscle glycogen synthesis (9). However, the problem of low sensitivity is even more acute in the case of 13 C-MRS. Dynamic nuclear polarization (DNP or hyperpolarization) of 13 C-labeled cell substrates enhances their sensitivity to detection by >10 4 -fold (10,11). Subsequent spectroscopic imaging of their metabolism following intravenous injection offers a solution to the problem of low sensitivity and has the potential to make dynamic metabolic imaging using MRS a routine clinical application.There have been a number of recent review articles and book chapters on this subject (12-17), and therefore, the purpose of this brief review is to: highlight those DNP substrates that have shown the greatest promise for oncological applications in vivo; summarize the biochemical mechanisms responsible for label transfer from pyruvate to other metabolites in tumors; and finally provide an overview of the main challenges in label detection and imaging and how these may be addressed. PROMISING SUBSTRATES FOR HYPERPOLA...

Influence of Dy3+ and Tb3+ doping on 13C dynamic nuclear polarization

“…41 While a variety of Ln(iii) complexes have numerous biomedical applications, particularly in contrast-enhanced MRI, 45 only Gd 3+ and Ho 3+ have been studied extensively as beneficial doping agents in 13 C dissolution DNP. [35][36][37][38] This in part takes precedent from a previous preliminary study which has shown that only Gd 3+ and Ho 3+ ions have beneficial effects on 13 C DNP, while the other Ln(iii) ions appear to have no apparent effect on 13 C DNP enhancements for trityldoped samples. 37 We would like to note that the measurements in the aforementioned previous DNP study on using lanthanide ions 37 were not really extensively optimized in terms of concentration dependence and the fact that the optimum DNP microwave frequency could shift with lanthanide doping.…”

“…1 As a result of relatively low gyromagnetic ratio γ of nuclear spins, the spin population difference between Zeeman energy states, quantified by the polarization, can be quite miniscule. This is particularly prominent in the case for low-γ nuclei such as 13 C or 15 N. Consequently, NMR under these conditions often requires a large number of scans in order to achieve adequate signal-to-noise. While NMR is relatively insensitive, electron paramagnetic resonance (EPR), a similar technology, does not suffer from this problem.…”

“…9 In dissolution DNP, nuclear spins are polarized in the solid state and subsequently dissolved rapidly, resulting in a "hyperpolarized" room-temperature liquid yielding liquid-state signal enhancements of typically more than 10 000-fold. 9,10 Using this technology, samples containing low-γ nuclei such as 13 C may be both highly polarized and physiologically compatible, allowing for biomedical applications such as 13 C metabolic imaging in real-time. [11][12][13][14][15] The efficiency of DNP is highly dependent on the sample composition and physical conditions under which it takes place.…”

“…9,10 Using this technology, samples containing low-γ nuclei such as 13 C may be both highly polarized and physiologically compatible, allowing for biomedical applications such as 13 C metabolic imaging in real-time. [11][12][13][14][15] The efficiency of DNP is highly dependent on the sample composition and physical conditions under which it takes place. Most commonly, high magnetic fields (typically >3 T) and low temperatures (close to 1 K) are used in order to ensure nearly complete electron polarization.…”

“…Thus, in this work, we have revisited the question on whether Gd 3+ and Ho 3+ really stand alone among the lanthanides as beneficial additives in 13 C dissolution DNP samples. Due to the high cost of trityl OX063 free radical and DNP instrumental operation, we have selected only two lanthanides, Tb 3+ and Dy 3+ , for extensive 13 C DNP optimization studies.…”