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Abstract: SA-PO935

Interaction of Gadolinium-Based Contrast Agents with Endogenous Compounds: Effect on Stability

Session Information

Category: Pathology and Lab Medicine

  • 1800 Pathology and Lab Medicine

Authors

  • Henderson, Ian, Kidney Institute of New Mexico, Albuquerque, New Mexico, United States
  • Dokladny, Karol, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
  • Escobar, G. Patricia, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
  • Deaguero, Joshua, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
  • Wagner, Brent, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
Background

Gadolinium-based contrast agents (GBCAs) are widely used in contrast-enhanced magnetic resonance imaging (MRI), improving tissue discrimination by increasing proton relaxation. GBCA complications can be catastrophic, including nephrogenic systemic fibrosis (NSF) and gadolinium encephalopathy. The stability of the metal-ligand bond correlates with gadolinium retention in vivo, with stabilities generally expressed in terms of equilibrium constants and kinetic stability. Equilibrium constants do not account for a physiologic milieu and endogenous compounds. We investigated two endogenous compound-mediated mechanisms of GBCA decomposition in vivo: associative ligand exchange (direct attack) by oxalic acid (OA) and decomposition through protein-ligand interaction.

Methods

GBCAs reacting with OA were followed spectrophotometrically at 605 nm. We measured precipitation rates. We characterized the products using elemental analysis, thermogravimetric analysis (TGA), and X-ray photoelectron spectroscopy (XPS). Contrast agents were incubated with bovine serum albumin (BSA) for 4 days. We analyzed the nanoparticulate product using transmission electron microscopy and X-ray energy-dispersive spectroscopy.

Results

Linear agents (gadodiamide and gadobenate dimeglumine) reacted with OA, forming gadolinium oxlate. Macrocyclic GBCAs (gadoteridol, gadoteric acid, and gadopiclenol) underwent two-step ligand exchange upon exposure to OA with a wide range of rates, ranging from k ~ 10-2 (gadoteridol) to <<10-6 (gadopiclenol). The presence of BSA (4%) resulted in an increased rate. Incubation of GBCAs with BSA over 4 days formed nanoparticles with a similar morphology to those found in pathologic gadolinium retention.

Conclusion

Oxalic acid, a biologically endogenous compound, can directly attack GBCAs, with linear contrast agents being particularly vulnerable. Protein enhances the rate of gadolinium oxalate formation. Simple protein/ligand interactions destabilize GBCAs. We can detect gadolinium-rich nanoparticles in vitro.