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Paramagnetic fluorinated nanoemulsions for sensitive cellular fluorine-19 magnetic resonance imaging

Abstract

Fluorine-19 magnetic resonance imaging (19F MRI) probes enable quantitative in vivo detection of cell therapies and inflammatory cells. Here, we describe the formulation of perfluorocarbon-based nanoemulsions with improved sensitivity for cellular MRI. Reduction of the 19F spin–lattice relaxation time (T1) enables rapid imaging and an improved signal-to-noise ratio, thereby improving cell detection sensitivity. We synthesized metal-binding β-diketones conjugated to linear perfluoropolyether (PFPE), formulated these fluorinated ligands as aqueous nanoemulsions, and then metallated them with various transition and lanthanide ions in the fluorous phase. Iron(III) tris-β-diketonate (‘FETRIS’) nanoemulsions with PFPE have low cytotoxicity (<20%) and superior MRI properties. Moreover, the 19F T1 can readily be reduced by an order of magnitude and tuned by stoichiometric modulation of the iron concentration. The resulting 19F MRI detection sensitivity is enhanced by three- to fivefold over previously used tracers at 11.7 T, and is predicted to increase by at least eightfold at the clinical field strength of 3 T.

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Figure 1: Comparison of iron and gadolinium diketonates (H-fod) as 19F relaxation agents for PFPE.
Figure 2: Preparation and characterization of metal-binding nanoemulsions for 19F MRI.
Figure 3: Fluorine-19 relaxometry of metallated PFPE emulsions.
Figure 4: Relaxometry stability of FETRIS nanoemulsions in the presence of competing aqueous ligand.
Figure 5: Cell labelling with FETRIS nanoemulsion.
Figure 6: MRI of FETRIS nanoemulsion.

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Acknowledgements

This work was financially supported by National Institutes of Health grants T32-CA121938 (UCSD Cancer Therapeutics Training Program, A.A.K.), R01-CA158448 (R.Y.T.) and R01-EB017271 (E.T.A.), Radiological Society of North America grant RR1452 (K.H.N), and California Institute for Regenerative Medicine grant LA1-C12-06919 (E.T.A.). We thank T. C. Nguyen, M. J. Patrick, A. Waggoner, A. Mrse, T. Didenko, P. McConville and K. Wuthrich for technical assistance, and V. Kislukhin for helpful discussions.

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Contributions

A.A.K. designed synthesis schemes, performed chemical synthesis of the molecules and emulsions, characterized synthesis products, and wrote the first draft of the manuscript. H.X. performed tissue culture experiments. S.R.A. helped design experiments, performed chemical synthesis, and helped edit the manuscript. K.H.N. assisted with the in vivo animal experiments and MRI renderings and helped edit the manuscript. R.Y.T. helped design experiments and edit the manuscript. E.T.A. helped design experiments, acquired MRI data in phantoms and in mice, edited the final version of the manuscript.

Corresponding authors

Correspondence to Roger Y. Tsien or Eric T. Ahrens.

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The authors declare no competing financial interests.

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Kislukhin, A., Xu, H., Adams, S. et al. Paramagnetic fluorinated nanoemulsions for sensitive cellular fluorine-19 magnetic resonance imaging. Nature Mater 15, 662–668 (2016). https://doi.org/10.1038/nmat4585

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