Time-dependent uptake, subcellular deposition and brain specific effects of Gadolinium-based MRI-contrast agents – a multidisciplinary approach

• Applicants: Professorin Dr. Julia Bornhorst; Professorin Dr. Astrid Jeibmann; Professor Dr. Uwe Karst
• Subject Area: Toxicology, Laboratory Medicine
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 549855937

Gadolinium-based contrast agents (GBCAs) have been used for the enhancement of magnetic resonance imaging (MRI) for decades. Although considered safe for use in patients with normal kidney function, the reported deposition of gadolinium (Gd) in tissues throughout the body, and particularly, accumulation in specific brain regions, has renewed concerns. Although several studies did not prove clinically important side effects of these deposits in the brain, Gd depositions in the basement membrane and in the perivascular space of a capillary in humans and animals were reported and as the exact form of deposition is still not determined, doubts remain. This necessitates clarification as to whether the agents (linear or macrocyclic GBCA-species) depose compound-specific and cause brain specific effects. To address the time-dependent uptake, cellular transfer and subcellular deposition of linear GBCAs (gadopentate, gadodiamide, gadobenate) and macrocyclic GBCAs (gadoteridol, gadobutrol, gadoterate) a multidisciplinary approach will be used. First, we will investigate the uptake mechanism of GBCA species into the brain. Using in vitro brain barrier models, we will characterize the time dependent transfer and the effects on the barrier building cells. The developed highly sensitive IC-ICP-MS method will allow not only to measure Gd transfer rates and cellular amounts, it further allows the identification of potential species transformations. Furthermore, using brain cells representative of those found in the regions of reported Gd deposits and essential for the brain barriers (astrocytes and pericytes) will enable to study systematically cellular uptake and cellular processing (subcellular) of the GBCAs. Additionally, they allow identifying in subcellular fractions the compartments in which GBCA species may accumulate. In these cells, the uptake of Gd species in individual cells by single cell (sc)-ICP-MS will also be determined. Additionally, animal studies will provide information about kinetics and identify potential toxic changes of brain tissue following GBCA application. Elemental bioimaging by LA-ICP-MS shall allow an association of the observed effects with Gd distribution and concentration in brain tissues. A multi-elemental tracking technique making use of chemical similarities of other lanthanides with Gd will be developed and shall be applied to obtain simultaneous information on both GBCAs and Gd3+. Therefore, the project shall elevate the knowledge of Gd deposition in tissues to a new level, paving the way to the future development and application of novel GBCAs with significantly reduced risk for deposition in the human body.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Partner Organisation: Schweizerischer Nationalfonds (SNF)
• Cooperation Partner: Henning Richter, Ph.D.