Nonsteroidal Anti-Inflammatory Drug Conjugated with Gadolinium (III) Complex as an Anti-Inflammatory MRI Agent

Abstract

Studies have been actively conducted to ensure that gadolinium-based contrast agents for magnetic resonance imaging (MRI) are accompanied by various biological functions. A new example is the anti-inflammatory theragnostic MRI agent to target inflammatory mediators for imaging diagnosis and to treat inflammatory diseases simultaneously. We designed, synthesized, and characterized a Gd complex of 1,4,7-tris(carboxymethylaza) cyclododecane-10-azaacetylamide (DO3A) conjugated with a nonsteroidal anti-inflammatory drug (NSAID) that exerts the innate therapeutic effect of NSAIDs and is also applicable in MRI diagnostics. Gd-DO3A-fen (0.1 mmol/kg) was intravenously injected into the turpentine oil-induced mouse model, with Gd-DO3A-BT as a control group. In the in vivo MRI experiment, the contrast-to-noise ratio (CNR) was higher and persisted longer than that with Gd-DO3A-BT; specifically, the CNR difference was almost five times at 2 h after injection. Gd-DO3A-fen had a binding affinity (Ka) of 6.68 × 106 M−1 for the COX-2 enzyme, which was 2.1-fold higher than that of fenbufen, the original NSAID. In vivo evaluation of anti-inflammatory activity was performed in two animal models. In the turpentine oil-induced model, the mRNA expression levels of inflammatory parameters such as COX-2, TNF-α, IL-1β, and IL-6 were reduced, and in the carrageenan-induced edema model, swelling was suppressed by 72% and there was a 2.88-fold inhibition compared with the saline group. Correlation analysis between in vitro, in silico, and in vivo studies revealed that Gd-DO3A-fen acts as an anti-inflammatory theragnostic agent by directly binding to COX-2.

Synthesis, Luminescence and Relaxometric Properties of Macrocyclic Lanthanide Complexes Appended with an Imidazothiadiazole, a Heterocyclic Bioactive Scaffold

“…GdDOTA monoamide complexes have been covalently linked to anticancer drugs such as colchicine, [11] chlorambucil, [12] benzothiazole, [13] camptothecin, [14] or anti-inflammatory conjugates. [15] Despite the fact that many drugs have a heterocyclic scaffold, very few examples have been described and none of them focus on the potential beneficial properties of the heterocyclic scaffold for diagnosis. Indeed, if the heterocycle is close to Gd 3 + , the rotation of the whole complex will be slowed down, and/or the heteroatoms could potentially play a role in retaining water molecules by hydrogen bonding close to Gd 3 + , all of which being beneficial to relaxation properties of the complex.…”