Review
19F MRI for quantitative in vivo cell tracking

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Cellular therapy, including stem cell transplants and dendritic cell vaccines, is typically monitored for dosage optimization, accurate delivery, and localization using noninvasive imaging, of which magnetic resonance imaging (MRI) is a key modality. 19F MRI retains the advantages of MRI as an imaging modality, and also allows direct detection of labeled cells for unambiguous identification and quantification, unlike typical metal-based contrast agents. Recent developments in 19F MRI-based in vivo cell quantification, the existing clinical use of 19F compounds and current explosive interest in cellular therapeutics have brought 19F imaging technology closer to clinical application. We review the application of 19F MRI to cell tracking, discussing intracellular 19F labels, cell labeling and in vivo quantification, as well as the potential clinical uses of 19F MRI.

Introduction

Cellular therapeutics is the transfer of cells to a patient to treat a disease or condition; for example, dendritic cells (DCs) can be used to stimulate the immune system against tumors, or stem cell transfers can restore function to damaged tissues. It is a growing field that includes islet grafts, DC vaccines, and regulatory T cell and stem cell transplants. Although these treatments are promising, the technology is still in its infancy. For successful cellular therapy, it is essential that transferred cells are monitored post-transplant noninvasively, longitudinally and quantitatively using in vivo imaging techniques.

In vivo imaging techniques that are applicable to humans can broadly be classified based on whether or not they use radioactive nuclides. Those that use radioactive nuclides include scintigraphy, positron emission tomography (PET), and single photon emission computed tomography (SPECT), whereas computed tomography (CT) relies on the use of ionizing radiation. The major advantages and disadvantages of each imaging modality are described elsewhere [1]. Briefly, magnetic resonance imaging (MRI) and ultrasound are the main imaging modalities that do not use radionuclides or ionizing radiation. Ultrasound imaging provides excellent real-time images, but the resolution is generally too low for cell tracking, in addition to other limitations, such as a restricted field-of-view and relatively poor tissue contrast. MRI is capable of high resolution imaging with excellent inherent soft tissue contrast, and is well-suited for longitudinal, noninvasive imaging because it does not rely on probes with short half-lives.

The utility of MRI for cell tracking in DC vaccines was demonstrated in melanoma patients [2]. This study found that the DCs were often mis-injected, being delivered outside the targeted lymph node, even with ultrasound-guided injections. This was a crucial finding because it showed that data from studies requiring targeted, localized delivery might not be reliable. Recent reviews cover the use of MR-based cell tracking in both clinical [3] and preclinical settings [4]. In this review, we will focus on MRI for quantitative cell tracking through the use of fluorinated (19F) labels.

Section snippets

1H MRI

Contrast agents (Box 1) function by modifying the 1H signals from the huge amount of mobile water in tissues (∼50 M). Contrast can also be generated through the modulation of intracellular metalloprotein levels through gene therapy [5]. The minimum detectable concentration of a contrast agent is dependent on the extent to which the agent modifies local nuclear magnetic resonance (NMR) relaxation rates, typically micro- or millimoles per voxel. However, because these agents only modify contrast

19F MRI and perfluorocarbons

19F MRI has been demonstrated for over 20 years [10], with the first in vitro study of 19F NMR image formation or ‘zeugmatography’ in 1977 [11]; this study also suggested the use of 19F compounds as ‘tracers’ in a sample. 19F has several properties that make it suitable for use as an MRI tracer: (i) a high relative sensitivity that is 83% of 1H; (ii) 100% natural abundance; (iii) its resonance differs by only 6% from that of 1H, potentially allowing 19F MRI to be conducted on existing 1H

Cell labeling

Cells can be labeled in situ or ex vivo before transfer to the subject. In situ labeling typically involves the nonspecific uptake of intravenous tracers by phagocytes, mainly macrophages [25]. Alternatively, the agent could be targeted to specific cells using antibodies 26, 27, 28, or the label is injected directly into the tissue of interest [29]. However, ex vivo labeling is the most commonly used technique for tracking a specific group of cells because it results in reproducible and uniform

In vivo imaging

The key factor that needs to be maximized for imaging using 19F MRI is the signal-to-noise ratio per unit time (SNR/t). For 19F MRI, this translates to the use of fast imaging sequences, sensitive hardware and high magnetic field strength. Generally, it is sufficient to detect the presence or absence of 19F signal in an ROI, and therefore high-resolution is typically not required.

Signal strength in NMR is affected by several factors, including hardware (e.g. coil design and its filling factor),

Cell number quantification

Cell number quantification in vivo requires accurate knowledge of the amount of label per cell (Lc) before cell transfer. Lc can be determined by measuring the total 19F content in a known number of cells [36]in vitro using a simple NMR measurement. In this measurement the spectral weight of the label in a cell pellet is compared with a known concentration of a 19F reference compound added to the sample having a different value of chemical shift 36, 37, 39, 52, 53. This technique can

Translation to the clinic

MRI is currently used extensively in humans, even in pregnant women, when conventional ultrasound scans are insufficient [55]. The risks involved arise from the strong, static magnetic field of the imaging system, which can turn common clinical tools (i.e. oxygen tanks or scissors) into deadly projectiles, and the pulsing RF 3–7 T is considered ‘high field’ for clinical MRI, although current cell tracking studies using 19F MRI in mice have typically been at higher field strengths. Nevertheless,

Concluding remarks

19F MRI for cell tracking is still in an early stage of development. The main hurdle facing this technology is sensitivity (i.e. detection of 19F tracers within a reasonable time frame to allow clinical use). However, the technology is actively being researched from multiple angles, including imaging hardware, imaging sequences, label development, and cell labeling. It is an exciting multi-disciplinary field involving chemistry, biology, medical research, physics, and engineering. The breadth

Disclosure statement

Eric T. Ahrens serves as a consultant to Celsense, Inc.

Acknowledgments

We thank Dr. F. Bonetto for a critical reading of the manuscript, and Prof. D.H. Laidlaw for the description of the in vivo quantification technique. This research was supported by investment grants NWO middelgroot 40-00506-90-0602 and NWO BIG (VISTA) to A.H.; and the EU grants ENCITE (HEALTH-F5-2008-201842) and Cancerimmunotherapy (LSHC-CT-2006- 518234), and NWO Vidi grant 917.76.363 to I.J.M.dV. E.T.A. acknowledges support from the National Institutes of Health (R01-CA134633, R01-EB003453,

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