A macrocyclic gadolinium contrast agent bearing an assembly-dissociable feature with albumin for enhanced magnetic resonance imaging and in vivo profiles

Abstract

Gd-based contrast agents (GBCAs) with high relaxivity and favorable in vivo profiles are greatly desired yet present formidable challenges, especially on the molecular side. Here, we report a macrocyclic GBCA (namely Gd-IN-DO3A) characterized by the presence of an isonicotinate group (IN) tethered asymmetrically to the macrocyclic DO3A scaffold with the pyridine-N coordinated to the Gd³⁺ center. Our studies reveal that it shows an assembly-dissociable feature with human serum albumin (HSA) by moderate non-covalent interactions at Sudlow site II, showing a binding fraction of ∼50%, a binding constant (K_a) of 316 M⁻¹ and a dissociation constant (K_D) of 5.24 µM. This dynamic GBCA-HSA adduct ensures a high r₁ relaxivity of ∼23.75 mM⁻¹ s⁻¹ in 4.5% HSA (∼8.29 mM⁻¹ s⁻¹ in water) and enables favorable pharmacokinetic properties, with a blood half-life (t_1/2) of ∼3.2 h, desirable biodistribution and excretion, and superior lesion imaging performance. These results suggest that developing novel GBCAs bearing an assembly-dissociable feature with albumin via moderate non-covalent interactions could serve as a compensation approach for enhanced magnetic resonance imaging and in vivo profiles.