A Macrocyclic Gadolinium Contrast Agent Bearing Assemblydissociable 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 presents formidable challenges exclusively at the molecular side. Here, we report a macrocyclic GBCA (namely Gd-IN-DO3A) characterized by the presence of isonicotinate group (IN) tethered asymmetrically on the macrocyclic DO3A scaffold with the pyridine-N coordinate to Gd 3+ center. Our studies reveal that it undergoes an assembly-dissociable feature with human serum albumin (HSA) by moderate non-covalent interactions at Sudlow site II, showing a binding fraction of ~50%, binding constant (K a ) of 316 M -1 and dissociation constant (K D ) of 5.24 μM. This dynamic GBCA-HSA adduct ensures the high r 1 relaxivity of ~23.75 mM -1 s -1 in 4.5% HSA (~8.29 mM -1 s -1 in water), enables a favorable pharmacokinetic property with the blood half-life (t₁/₂) of ~3.2 h, desirable biodistribution and excretion as well as superior lesion imaging performance. These results suggest that developing novel GBCAs bearing the assembly-dissociable feature with albumin by moderate noncovalent interactions could serve as a compensation approach for enhanced magnetic resonance imaging and in-vivo profiles.