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Paramagnetic MRI contrast agents

Eliana Gianolio - PI

Eliana Gianolio
Biographical sketch

Associate Professor of Inorganic Chemistry at the Dep. Of Molecular Biotechnologies and Health Science of the University of Torino

Main group members
Main group members
  • Lorenzo Palagi: assegnista di ricerca
  • Serena Rizzuti: dottoranda
  • Ferdeze Hasallari: borsista di ricerca
  • Alice Santangelo: dottoranda

Research activity

Our research activity is in the field of design and testing of imaging agents for in vitro and in vivo applications, with a special focus on the characterization and application of paramagnetic contrast agents as contrast agents (CA) in Magnetic Resonance Imaging (MRI). This class of substances is mainly represented by Gadolinium(III)- based contrast agents (GBCAs).

Along the years, our research work has dealt with the elucidation of the relationships between solution structure/ dynamics of GBCAs and the determinants of their proton relaxation enhancement with the aim of generating imaging reporters endowed with high sensitivity and specificity. To this scope, our research is always active, at the preclinical level, in the synthesis, characterization and validation of new Gd complexes endowed with high relaxivity (high efficiency), while maintaining a high thermodynamic and kinetic stability. In Figure 1, some examples are reported of new Gd-complexes studied by our group whose relaxometric efficiency is far higher thanthat of GBCAs used today in the clinical settings.

Another interesting field of action is related to the obtainment of a number of MRI CAs whose relaxation enhancement properties are responsive to a specific parameter of the biological microenvironment where they distribute, i.e. pH, temperature, enzymatic activity, metabolites' concentration, oxygenation.

In recent years some concerns raised on the use of GBCAs because it has been acknowledged that a portion of the injected gadolinium can remain in the body for extended periods even in subjects with normal renal functions. In this context, our research has been focused on the comprehension, on preclinical animal models, of the mechanisms behind Gd(III) retention and the identification of the organs where the accumulation mostly occurs. Efforts were also put into the elucidation of the chemical form (free or chelated) of retained Gd (Figure 2).

On the other hand, these discoveries have sparked renewed interest in seeking alternatives to gadolinium (III) for MR contrast imaging. From our side, we are interested in the study of Fe(III) complexes bearing ligands that are represented by clinically approved iron sequestering agents with the expectation of a facilitated clinical translation as MRI CAs.

For some applications, with the aim of increasing both the efficacy (in terms of signal enhancement) and the vehicolation efficiency, our Gd- and Fe-based imaging probes are embedded into nano-sized carriers (from endogenous systems to liposomes, micelles, hydrogels, nanogels,etc.) for diagnostic and “theranostic” applications.

Currently, we are interested in the study of multicomponent peptide-based hydrogels and nanogels matrices for the incorporation/conjugation of Fe(III) complexes as a novel generation of MRI CAs characterized by lower toxicity and enhanced sensitivity.

In another project, we aim to develop a novel hydrogel based MRI device for the measure of temperature in vivo. The system consists of a device based on a peptide hydrogel containing a Gadolinium complex capable of providing absolute in vivo temperature measurements in T1-weighted Magnetic Resonance Imaging. 

Different hydrogel formulations will be analyzed to define the relationships between composition, rheological characteristics, and functional response (in vitro and in vivo on animal models) to identify the “lead” for the development of the measurement device. In addition to applications in which the hydrogel is used as-is, specific engineering solutions will be developed, such as encapsulation in alginates.

A further line of research that is just started and will be developed in the next years, involves the development and validation of in vitro experimental models (spheroids, organoids, CAM) alternative to animal models for preclinical imaging studies.

  •  Progetto di Ateneo –Research for the Territory- finaced by “Compagnia di San Paolo” entitled “ Gd-retention in the brain after Contrast Enhanced MRI” 2016-2019
  •  Regional Project (Piemonte), F.E.S.R. 2014/2020 entitled "Sviluppo preclinico e clinico di Gadoplus, un mezzo di contrasto per risonanza magnetica dotato di elevata relassività" 2017-2020
  • Progetto Fondazione CRT (Risonanza Magnetica Eco-Friendly: Esplorando nuovi Agenti di Contrasto a base di Ferro per una Diagnostica più sostenibile), 2024-2026 
  •  Regional (Piemonte) Project, Bando: AZIONE I.1i.1 "Sostegno alle attività di RSI e alla valorizzazione economica dell'innovazione F.E.S.R. 2021/2027 entitled “Sonde a base di FErro per Radiologia Avanzata-SFERA”, 2024-2026
  • Progetto Bando Trapezio – Linea 1 Sostenere la ricerca competitiva finaced by “Compagnia di San Paolo” entitled “Biodegradable chitosan hydrogels for the optimal delivery of antibody drug conjugates”, 2024-2026
  • Hasallari, F ; Carrera, C; Cavallari, E; Gianolio, E * ; Aime, S, A novel albumin-binding macrocyclic Gd-HPDO3A complex bearing a deoxycholic acid residue: the role of the hydration state, water exchange and local dynamics in the observed relaxivity, INORGANIC CHEMISTRY FRONTIERS, 2024, 11, 6511-6526.
  • Stefania R, Palagi L, Di Gregorio E, Ferrauto G, Dinatale V, Aime S, Gianolio E*. Seeking for Innovation with Magnetic Resonance Imaging Paramagnetic Contrast Agents: Relaxation Enhancement via Weak and Dynamic Electrostatic Interactions with Positively Charged Groups on Endogenous Macromolecules. J Am Chem Soc. 2024, 10;146(1):134-144. 
  • Gréa T, Jacquot G, Durand A, Mathieu C, Gasser A, Zhu C, Banerjee M, Hucteau E, Mallard J, Lopez Navarro P, Popescu BV, Thomas E, Kryza D, Sidi-Boumedine J, Ferrauto G, Gianolio E, Fleith G, Combet J, Brun S, Erb S, Cianferani S, Charbonnière LJ, Fellmann L, Mirjolet C, David L, Tillement O, Lux F, Harlepp S, Pivot X, Detappe A. Subcutaneous Administration of a Zwitterionic Chitosan-Based Hydrogel for Controlled Spatiotemporal Release of Monoclonal Antibodies. Adv Mater., 2024, 36, 2308738
  • Furlan, C., Montarolo, F., Di Gregorio, E., Parolisi, R., Atlante, S., Buffo, A., Bertolotto, A., Aime, S., Gianolio, E.*Analysis of the Gadolinium retention in the Experimental Autoimmune Encephalomyelitis (EAE) murine model of Multiple Sclerosis (2021) Journal of Trace Elements in Medicine and Biology, 68, art. no. 126831 DOI: 10.1016/j.jtemb.2021.126831
  • Palagi, L., Di Gregorio, E., Costanzo, D., Stefania, R., Cavallotti, C., Capozza, M., Aime, S., Gianolio, E.* Fe(deferasirox)2: An Iron(III)-Based Magnetic Resonance Imaging T1Contrast Agent Endowed with Remarkable Molecular and Functional Characteristics (2021) Journal of the American Chemical Society, 143 (35), pp. 14178-14188. DOI: 10.1021/jacs.1c04963
  • Tear, L.R., Carrera, C., Dhakan, C.B., Cavallari, E., Travagin, F., Calcagno, C., Aime, S., Gianolio, E.*  An albumin-binding Gd-HPDO3A contrast agent for improved intravascular retention (2021) Inorganic Chemistry Frontiers, 8 (17), pp. 4014-4025. DOI: 10.1039/d1qi00128k
  • Di Gregorio, E., Lattuada, L., Maiocchi, A., Aime, S., Ferrauto, G., Gianolio, E.* Supramolecular adducts between macrocyclic Gd(iii) complexes and polyaromatic systems: a route to enhance the relaxivity through the formation of hydrophobic interactions (2021) Chemical Science, 12 (4), pp. 1368-1377. DOI: 10.1039/d0sc03504a
  • Di Gregorio, E., Furlan, C., Atlante, S., Stefania, R., Gianolio, E.*, Aime, S. Gadolinium retention in erythrocytes and leukocytes from human and murine blood upon treatment with gadolinium-based contrast agents for magnetic resonance imaging (2020) Investigative Radiology, 55 (1), pp. 30-37. DOI: 10.1097/RLI.0000000000000608
  • Di Gregorio, E., Ferrauto, G., Furlan, C., Lanzardo, S., Nuzzi, R., Gianolio, E.*, Aime, S. The Issue of Gadolinium Retained in Tissues: Insights on the Role of Metal Complex Stability by Comparing Metal Uptake in Murine Tissues Upon the Concomitant Administration of Lanthanum-A nd Gadolinium-Diethylentriamminopentaacetate (2018) Investigative Radiology, 53 (3), pp. 167-172. DOI: 10.1097/RLI.0000000000000423
  • Gianolio, E., Bardini, P., Arena, F., Stefania, R., Gregorio, E.D., Iani, R., Aime, S. Gadolinium retention in the rat brain: Assessment of the amounts of insoluble gadolinium-containing species and intact gadolinium complexes after repeated administration of gadolinium-based contrast agents (2017) Radiology, 285 (3), pp. 839-849. DOI: 10.1148/radiol.2017162857


Link Scopus: https://www.scopus.com/authid/detail.uri?authorId =6603359686

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