Nuclear spin singlet states in self-assembling nanostructures as contrast agents for magnetic resonance imaging.

• Applicant: Dr. Stefan Glöggler
• Subject Area: Physical Chemistry of Molecules, Liquids and Interfaces, Biophysical Chemistry
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450146057

• Final Report Year: 2025

Final Report Abstract

Magnetic resonance is a phenomenon that is used in a variety of applications, such as chemical analysis or biomedical imaging. A key aspect of improving imaging is the use of contrast agents, which help to make diseases better visible. Typically, transition metal complexes, some of which have been found to be neurotoxic in recent years, are injected into a patient. The aim of this project was to investigate new contrast agent mechanisms that do not require the use of metals. In particular, the phenomenon of nuclear singlet states was investigated in order to find out whether such states can be used in self-organizing nanostructures to generate contrast. Nuclear singlet states can only be observed indirectly by NMR. The special feature of these states is that equilibration times for the transitions from a populated singlet state to the observable triplet state can be orders of magnitude longer than longitudinal relaxation times. This property opens up new possibilities to study dynamics and to generate potential contrast agents. Over the course of the project, peptides were synthesized that transform into nanostructures due to a chemical trigger and it was attempted to populate singlet states in the obtained peptides. However, it was not possible to excite a singlet state in the tested molecules, which is why two different directions were pursued. On the one hand, the singlet state phenomenon of para-hydrogen was investigated in order to generate contrast and in the course of the project the first tumor metabolism images could be recorded using hyperpolarized pyruvate, whose signal was enhanced with para-hydrogen. Secondly, the use of singlet states in living aquatic organisms (water fleas) was successfully tested in order to filter out the signals of certain metabolites and observe metabolic changes over time. Despite the success of the experiments, it became clear that the generation of nuclear singlet states in organisms would result in a significant loss of signal-to-noise. At the end of the project, nanostructures enriched with deuterium were therefore synthesized and investigated. A first deuterated nanoparticle was developed, which was visualized using deuterium imaging. This development now opens up the new field of deuterated nano-imaging with numerous possible applications for potential diagnostics in the future.

Publications

• A Field‐Independent Method for the Rapid Generation of Hyperpolarized [1‐13C]Pyruvate in Clean Water Solutions for Biomedical Applications. Angewandte Chemie International Edition, 61(34).
  Mamone, Salvatore; Jagtap, Anil P.; Korchak, Sergey; Ding, Yonghong; Sternkopf, Sonja & Glöggler, Stefan
  
• Metabolic Tumor Imaging with Rapidly Signal‐Enhanced 1‐13C‐Pyruvate‐d3. ChemPhysChem, 24(2).
  Hune, Theresa; Mamone, Salvatore; Schroeder, Henning; Jagtap, Anil P.; Sternkopf, Sonja; Stevanato, Gabriele; Korchak, Sergey; Fokken, Claudia; Müller, Christoph A.; Schmidt, Andreas B.; Becker, Dorothea & Glöggler, Stefan
  
• Rapidly Signal‐enhanced Metabolites for Atomic Scale Monitoring of Living Cells with Magnetic Resonance. Chemistry–Methods, 2(7).
  Ding, Yonghong; Korchak, Sergey; Mamone, Salvatore; Jagtap, Anil P.; Stevanato, Gabriele; Sternkopf, Sonja; Moll, Denis; Schroeder, Henning; Becker, Stefan; Fischer, André; Gerhardt, Ellen; Outeiro, Tiago F.; Opazo, Felipe; Griesinger, Christian & Glöggler, Stefan
  
• In vivo singlet state filtered nuclear magnetic resonance: towards monitoring toxic responses inside living organisms. Chemical Science, 14(6), 1413-1418.
  Lysak, Daniel H.; Kock, Flavio V. C.; Mamone, Salvatore; Soong, Ronald; Glöggler, Stefan & Simpson, Andre J.
  
• Real-time cell metabolism assessed repeatedly on the same cells via para-hydrogen induced polarization. Chemical Science, 14(28), 7642-7647.
  Ding, Yonghong; Stevanato, Gabriele; von Bonin, Frederike; Kube, Dieter & Glöggler, Stefan
  
• Real-Time Pyruvate Chemical Conversion Monitoring Enabled by PHIP. Journal of the American Chemical Society, 145(10), 5864-5871.
  Stevanato, Gabriele; Ding, Yonghong; Mamone, Salvatore; Jagtap, Anil P.; Korchak, Sergey & Glöggler, Stefan
  
• Parahydrogen-enhanced pH measurements using [1-13C]bicarbonate derived from non-enzymatic decarboxylation of [1-13C]pyruvate-d3. The Analyst, 149(20), 5022-5033.
  Santi, Maria Daniela; Hune, Theresa Luca Katrin; Rodriguez, Gonzalo Gabriel; Fries, Lisa M.; Mei, Ruhuai; Sternkopf, Sonja; Elsaßer, Josef & Glöggler, Stefan
  
• Assessing a hyperpolarized [1-13C]-labeled alanine derivative enhanced via parahydrogen for in vivo studies. Journal of Magnetic Resonance Open, 22, 100183.
  Fries, Lisa M.; Moll, Denis; Mei, Ruhuai; Hune, Theresa L.․ K.․; Elsaßer, Josef & Glöggler, Stefan
  
• Deuterated Nanopolymers for Renal and Lymphatic Imaging via Quantitative Deuterium MRI. Nano Letters, 25(5), 1758-1764.
  Fries, Lisa M.; Montrazi, Elton T.; Allouche-Arnon, Hyla; Opazo, Felipe; Bar-Shir, Amnon; Frydman, Lucio & Glöggler, Stefan