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

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 metalated 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 3-to-5 fold over previously used tracers at 11.7 T, and is predicted to increase by at least 8-fold at clinical field strength of 3 T.

[1]  K. Nicolay,et al.  Relaxometric studies of gadolinium-functionalized perfluorocarbon nanoparticles for MR imaging. , 2014, Contrast media & molecular imaging.

[2]  D. Laidlaw,et al.  In vivo cytometry of antigen‐specific t cells using 19F MRI , 2009, Magnetic resonance in medicine.

[3]  S. W. Hanson,et al.  Paramagnetic shift reagents. Nature of the interactions , 1972 .

[4]  Nicolaas Bloembergen,et al.  Proton Relaxation Times in Paramagnetic Solutions. Effects of Electron Spin Relaxation , 1961 .

[5]  A. Haase,et al.  Rapid NMR Imaging Using Low Flip-Angle Pulses , 2004 .

[6]  Mangala Srinivas,et al.  Fluorine‐19 MRI for visualization and quantification of cell migration in a diabetes model , 2007, Magnetic resonance in medicine.

[7]  Klaas Nicolay,et al.  Quantitative (1)H MRI, (19)F MRI, and (19)F MRS of cell-internalized perfluorocarbon paramagnetic nanoparticles. , 2011, Contrast media & molecular imaging.

[8]  C. Vigouroux,et al.  Nuclear and electronic relaxation in lanthanide solutions: (CH3)4N+/Gd3+ repulsive ion pair in D2O , 1998 .

[9]  I. Solomon.  Relaxation Processes in a System of Two Spins , 1955 .

[10]  R. L. Lintvedt,et al.  Ligand field information from charge-transfer spectra of substituted tris(1,3-diketonato)iron(III) chelates. Spectrochemical series for 1,3-diketones , 1970 .

[11]  E. Ahrens,et al.  Fluorine-containing nanoemulsions for MRI cell tracking. , 2009, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[12]  A. Baram,et al.  Electronic and nuclear relaxation in solutions of transition metal ions with spin S=3/2 and 5/2 , 1971 .

[13]  R. Lagow,et al.  Synthesis of the perfluoropoly(ethylene glycol) ethers by direct fluorination , 1978 .

[14]  R. Levine,et al.  The Synthesis of Certain Ketones and α-Substituted β-Diketones Containing Perfluoroalkyl Groups , 1953 .

[15]  P. Baran,et al.  Functionalized olefin cross-coupling to construct carbon–carbon bonds , 2014, Nature.

[16]  Mangala Srinivas,et al.  Self-delivering nanoemulsions for dual fluorine-19 MRI and fluorescence detection. , 2008, Journal of the American Chemical Society.

[17]  Enzo Terreno,et al.  Relaxometric evaluation of novel manganese(II) complexes for application as contrast agents in magnetic resonance imaging , 2001, JBIC Journal of Biological Inorganic Chemistry.

[18]  P. Bühlmann,et al.  Cation-Coordinating Properties of Perfluoro-15-Crown-5. , 2010, Journal of fluorine chemistry.

[19]  R. Bryant,et al.  NUCLEAR- AND ELECTRON-SPIN RELAXATION RATES IN SYMMETRICAL IRON, MANGANESE, AND GADOLINIUM IONS , 1995 .

[20]  J. Bulte,et al.  Tracking immune cells in vivo using magnetic resonance imaging , 2013, Nature Reviews Immunology.

[21]  V. Pecharsky,et al.  Handbook on the physics and chemistry of rare earths , 1979 .

[22]  A. Haase,et al.  FLASH imaging: rapid NMR imaging using low flip-angle pulses. 1986. , 1986, Journal of magnetic resonance.

[23]  M. Guéron,et al.  Nuclear relaxation in macromolecules by paramagnetic ions: a novel mechanism , 1975 .

[24]  I. Kuprov,et al.  Lanthanide Complexes as Paramagnetic Probes for 19F Magnetic Resonance , 2012 .

[25]  E. Ahrens,et al.  Clinical cell therapy imaging using a perfluorocarbon tracer and fluorine-19 MRI , 2014, Magnetic resonance in medicine.

[26]  R. Roy,et al.  Improved quantification from 1H-NMR spectra using reduced repetition times , 2008, Metabolomics.

[27]  Koen Binnemans,et al.  Chapter 225 – Rare-earth beta-diketonates , 2005 .

[28]  A. Kenwright,et al.  Experimental measurement and theoretical assessment of fast lanthanide electronic relaxation in solution with four series of isostructural complexes. , 2013, The journal of physical chemistry. A.

[29]  K. Nash,et al.  The kinetics of lanthanide complexation by EDTA and DTPA in lactate media. , 2012, Dalton transactions.

[30]  S. Caruthers,et al.  Gadolinium‐modulated 19F signals from perfluorocarbon nanoparticles as a new strategy for molecular imaging , 2008, Magnetic resonance in medicine.

[31]  I. Marrucho,et al.  Viscosities of Liquid Fluorocompounds , 2008 .

[32]  Eric T Ahrens,et al.  In vivo imaging platform for tracking immunotherapeutic cells , 2005, Nature Biotechnology.

[33]  Corrected equations for susceptibility-induced T2-shortening. , 1999, Journal of magnetic resonance.

[34]  E. Terreno,et al.  In vivo MRI visualization of different cell populations labeled with PARACEST agents , 2013, Magnetic resonance in medicine.

[35]  C. Bremer,et al.  Highly shifted proton MR imaging: cell tracking by using direct detection of paramagnetic compounds. , 2014, Radiology.

[36]  A. Blamire,et al.  Characterisation and evaluation of paramagnetic fluorine labelled glycol chitosan conjugates for 19F and 1H magnetic resonance imaging , 2013, JBIC Journal of Biological Inorganic Chemistry.

[37]  S. Wickline,et al.  Diffusional mechanisms augment the fluorine MR relaxation in paramagnetic perfluorocarbon nanoparticles that provides a “relaxation switch” for detecting cellular endosomal activation , 2011, Journal of magnetic resonance imaging : JMRI.

[38]  Cornelius Faber,et al.  Boosting 19F MRI—SNR efficient detection of paramagnetic contrast agents using ultrafast sequences , 2013, Magnetic resonance in medicine.