Towards a rational design of Gd(III) complexes as contrast agents for magnetic resonance imaging

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Dinuclear gadolinium (III) chelates

Jéröme Costa

In 2003, the Nobel Assembly at the Karolinska Institute has awarded the Nobel Prize in Medicine or Physiology to Paul Lauterbur and Peter Mansfield for their seminal discoveries concerning the development of Magnetic Resonance Imaging (MRI), a non-invasive diagnosis technique notably used in medicine to visualize the human internal organs and to distinguish between healthy and pathological cells. For this purpose, contrast agents are valuable tools that enhance this distinction which is resulting from the difference in the water content of the different tissues. These drugs are used nowadays in more than 30% of the 60 millions MRI examinations performed each year. And both numbers are still growing fast. Most of the contrast agents contain a paramagnetic ion (GdIII) that accelerates the relaxation of the water protons by providing them a new relaxation pathway. Relaxivity is a way of quantifying the contrast agent efficiency and is governed by four key parameters: hydration number of the lanthanide ion, water exchange rate, electronic relaxation rate and rotational correlation time of the system. A judicious simultaneous optimization of these parameters is predicted to result in a 20-fold increase in relaxivity compared to the currently used contrast agents. In this work, with the aim of increasing the relaxivity and better understanding the involved mechanisms, the synthesis and physico-chemical characterization of new dinuclear GdIII complexes, based on thoroughly studied monomeric equivalents, were performed. We particularly stressed the outmost importance of introducing rigidity together with the increased size of the system, for a flexible assembly will hinder the relaxivity gain brought by the higher molecular weight. This rigidity is induced by using an aromatic linker between the chelating subunits or by means of the self-assembling properties of terpyridine units around FeII or RuII. We investigated the thermodynamic stability, which in crucial for toxicological reason, the spectrophotometric properties, and the rotational and water exchange dynamics of these complexes. As a result, a remarkable increase in relaxivity is obtained for all the studied compounds with respect to the clinically used actual contrast agents. Finally, insights into a promising novel class of MRI contrast agents acting simultaneously as luminescence probes are provided.

EPFL2005

Robust Phase Unwrapping via Deep Image Prior for Quantitative Phase Imaging

Nathalie Brandenberg, Matthias Lütolf, Thanh-An Michel Pham, Michaël Unser, Fangshu Yang

Quantitative phase imaging (QPI) is an emerging label-free technique that produces images containing morphological and dynamical information without contrast agents. Unfortunately, the phase is wrapped in most imaging system. Phase unwrapping is the computational process that recovers a more informative image. It is particularly challenging with thick and complex samples such as organoids. Recent works that rely on supervised training show that deep learning is a powerful method to unwrap the phase; however, supervised approaches require large and representative datasets which are difficult to obtain for complex biological samples. Inspired by the concept of deep image priors, we propose a deep-learning-based method that does not need any training set. Our framework relies on an untrained convolutional neural network to accurately unwrap the phase while ensuring the consistency of the measurements. We experimentally demonstrate that the proposed method faithfully recovers the phase of complex samples on both real and simulated data. Our work paves the way to reliable phase imaging of thick and complex samples with QPI.

IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC2021

Performance and reproducibility of C-13 and N-15 hyperpolarization using a cryogen-free DNP polarizer

Arianna Ferrari, Hikari Ananda Infinity Yoshihara

The setup, operational procedures and performance of a cryogen-free device for producing hyperpolarized contrast agents using dissolution dynamic nuclear polarization (dDNP) in a preclinical imaging center is described. The polarization was optimized using the solid-state, DNP-enhanced NMR signal to calibrate the sample position, microwave and NMR frequency and power and flip angle. The polarization of a standard formulation to yield similar to 4 mL, 60 mM 1-C-13-pyruvic acid in an aqueous solution was quantified in five experiments to P(C-13) = (38 +/- 6) % (19 +/- 1) s after dissolution. The mono-exponential time constant of the build-up of the solid-state polarization was quantified to (1032 +/- 22) s. We achieved a duty cycle of 1.5 h that includes sample loading, monitoring the polarization build-up, dissolution and preparation for the next run. After injection of the contrast agent in vivo, pyruvate, pyruvate hydrate, lactate, and alanine were observed, by measuring metabolite maps. Based on this work sequence, hyperpolarized N-15 urea was obtained (P(N-15) = (5.6 +/- 0.8) % (30 +/- 3) s after dissolution).

NATURE PORTFOLIO2022

Dinuclear gadolinium (III) chelates

Jéröme Costa

EPFL2005