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

Fluorine-19 magnetic resonance imaging (F-19 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 F-19 spin-lattice relaxation time (T-1) enables rapid imaging and an improved signal-to-noise ratio, thereby improving cell detection sensitivity. We synthesized metal-binding beta-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-beta-diketonate ('FETRIS') nanoemulsions with PFPE have low cytotoxicity (<20%) and superior MRI properties. Moreover, the F-19 T-1 can readily be reduced by an order of magnitude and tuned by stoichiometric modulation of the iron concentration. The resulting F-19 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.