Fluorine MR technologies to study cellular therapies in vivo

Final Report Abstract

Fluorine (19F) MRI is an exceptional tool to detect, quantify and study the distribution of fluorinated compounds with absolute specificity. Typically, 19F MRI is used to study inflammation and cell migration in experimental models. Nanoparticles rich in perfluorocarbons are administered systemically into animal models to label inflammatory cells in vivo. Apart from perfluorocarbons, other organofluorine compounds could be present in pharmaceutical and household products. Currently there are no routine methods that non-invasively quantify levels of compounds or therapies after their introduction into humans. A non-invasive method utilizing 19F MRI to study 19F levels in vivo would be invaluable to study the distribution of fluorinated therapies as well as unwanted contaminants. However, 19F MRI is challenged by low signal-to-noise ratio (SNR). The project strategy was to overcome this limitation by developing upon novel magnetic resonance strategies that boost 19F signal detection in vivo and to proceed in monitoring low levels of levels of fluorinated compounds in vivo. Our approach involved implementation of signal-efficient MR pulse sequences, MR protocols tailored to the relaxation constants of each 19F product and application of novel acceleration techniques, compressed sensing. A novel aspect was the implementation of a first ultra-low-noise (cryogenically-cooled) 19F MR mouse head quadrature RF coil. This MR-based RF coil technology physically increased signal sensitivity and thereby lowers the detection limit in 19F MR experiments. Outlook: While we have uncovered new insights in the 19F MR method to detect 19F signals in vivo, the next challenge will be to transfer this knowledge into the clinical scenario. For this, we will make use of machine learning approaches to build upon the methods that we have developed in this project for acquisition, reconstruction, and quantification of the data in humans.

Publications

• (2016) ERK1 as a Therapeutic Target for Dendritic Cell Vaccination against High-Grade Gliomas. Mol Cancer Ther.,15:19 65
  Ku MC, Edes I, Bendix I, Pohlmann A, Waiczies H, Prozorovski T, Günther M, Martin C, Pagès G, Wolf SA, Kettenmann H, Uckert W, Niendorf T, Waiczies S
  
• (2017) Enhanced Fluorine-19 MRI Sensitivity using a Cryogenic Radiofrequency Probe: Technical Developments and Ex Vivo Demonstration in a Mouse Model of Neuroinflammation. Scientific reports 7:9808
  Waiczies S, Millward JM, Starke L, Delgado PR, Huelnhagen T, Prinz C, Marek D, Wecker D, Wissmann R, Koch SP, Boehm-Sturm P, Waiczies H, Niendorf T, Pohlmann A
  
• (2018) Fluorine-19 MRI at 21.1 Tesla: Enhanced Spin-Lattice Relaxation of Perfluoro-15- Crown-5-Ether and Sensitivity as Demonstrated in Ex Vivo Murine Neuroinflammation. Magnetic Resonance Materials in Physics, Biology and Medicine (MAGMA) (as part of the 2019 fluorine special issue)
  Waiczies S, Rosenberg JT, Kuehne A, Starke L, Ramos Delgado P, Millward JM, Prinz C, Dos Santos Periquito J, Pohlmann A, Waiczies H, Niendorf T
  
• (2019) Toward 19F Magnetic Resonance Thermometry: Spin-Lattice and Spin-Spin- Relaxation Times and Temperature Dependence of Fluorinated Drugs at 9.4 T. Magnetic Resonance Materials in Physics, Biology and Medicine (MAGMA) (as part of the 2019 fluorine special issue)
  Prinz C, Eigentler TW, Ramos Delgado P, Millward JM, Starke L, Niendorf T, Waiczies S
  
• (2020) B1 inhomogeneity correction of RARE MRI with transceive surface radiofrequency probes. Magnetic Resonance in Medicine 84(5): p. 2684-2701
  Delgado PR, Kuehne A, Periquito JS, Millward JM, Pohlmann A, Waiczies S, Niendorf T
  
• (2020) Performance of Compressed Sensing for Fluorine-19 Magnetic Resonance Imaging at low Signal-to- Noise Ratio Conditions. Magnetic Resonance in Medicine 84(2):592-608
  Starke L, Pohlmann A, Prinz C, Niendorf T, Waiczies S
  
• (2021) B1 Inhomogeneity Correction of RARE MRI at Low SNR: Quantitative In Vivo 19F MRI of Mouse Neuroinflammation with a Cryogenically-cooled Transceive Surface Radiofrequency Probe. Magnetic Resonance in Medicine
  Delgado PR, Kuehne A, Aravina M, Millward JM, Vázquez A, Starke L, Waiczies H, Pohlmann A, Niendorf T, Waiczies S
  
• (2021) In vivo detection of teriflunomide-derived fluorine signal during neuroinflammation using fluorine MR spectroscopy. Theranostics 11(6): p. 2490-2504
  Prinz C, Starke L, Millward JM, Fillmer A, Delgado PR, Waiczies H, Pohlmann A, Rothe M, Nazare M, Paul F, Niendorf T, Waiczies S
  
• (2021) Pentafluorosulfanyl (SF5) as a Superior 19F Magnetic Resonance Reporter Group: Signal Detection and Biological Activity of Teriflunomide Derivatives. ACS Sensors
  Prinz C, Starke L, Ramspoth T-F, Kerkering J, Martos Riaño V, Paul J, Neuenschwander M, Oder A, Radetzki S, Adelhoefer S, Ramos Delgado P, Aravina M, Millward JM, Fillmer A, Paul F, Siffrin V, von Kries J-P, Niendorf T, Nazaré M, Waiczies S