Formation of gadolinium-ferritin from clinical magnetic resonance contrast agents

Abstract

Gadolinium deposition in the brain following administration of gadolinium-based contrast agents (GBCAs) has led to health concerns. We show that some clinical GBCAs form Gd³⁺-ferritin nanoparticles at (sub)nanomolar concentrations of Gd³⁺ under physiological conditions. We describe their structure at atomic resolution and discuss potential relevance for clinical MRI.

Fig. 1. Structural formulas of GBCAs. The water molecule coordinated to the central Gd³⁺ ion is omitted for clarity.

Fig. 2. HAADF-STEM images of Gd-free ferritin (a–c) and Gd³⁺–ferritin nanoparticles (d and e). Images show the typical areas of mono-dispersed ferritin (a) and Gd³⁺–ferritin (d). Atomic resolution images of ferritin (b) and Gd³⁺–ferritin nanoparticles (e) the ferrihydrite phase with a characteristic lattice spacing of 2.59 ± 0.07 Å. Based on our electron scattering simulations, the intensity of Gd is approximately 6-fold higher than that of Fe in the cores. Selected line scans 1–4 across the atomic columns for ferritin (c) and Gd³⁺–ferritin (f) particles correspond to the green rectangles 1–4 in (b) and (e), respectively. The sites containing Gd atoms are marked with black circles.

Fig. 3. Loadings of Gd expressed as the number of Gd³⁺ ions per one ferritin nanoparticle (Gd³⁺/ferritin) formed in the presence of 1–7. “None” denotes a control ferritin sample incubated without GBCAs. The error bars represent standard deviations from three measurements. pGd values in GBCA solutions were calculated for the incubation conditions (see the ESI†). The circled numbers above the columns show the overall charge of the GBCAs at pH 7.4.