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

Author:

Sung Bokyung1,Kim Hee-Kyung2ORCID,Baek Ah-Rum3,Yang Byeong-Woo1,Kim Yeoun-Hee4ORCID,Choi Garam4ORCID,Park Hyun-Jin4ORCID,Kim Minsup5,Lee Jongmin6,Chang Yongmin67

Affiliation:

1. Department of Medical & Biological Engineering, Kyungpook National University, Jung-gu, Daegu 41944, Republic of Korea

2. Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI hub), Dong-gu, Daegu 41061, Republic of Korea

3. Institute of Biomedical Engineering Research, Kyungpook National University, Jung-gu, Daegu 41566, Republic of Korea

4. R&D Center, Etnova Therapeutics Corp., Gwonseon-gu, Suwon-si 13120, Republic of Korea

5. Department of Biotechnology and Bioinformatics, Korea University Sejong Campus, 2511 Sejong-ro, Sejong City 30019, Republic of Korea

6. Department of Radiology, Kyungpook National University Hospital, Jung-gu, Daegu 41944, Republic of Korea

7. Department of Molecular Medicine, School of Medicine, Kyungpook National University, Jung-gu, Daegu 41944, Republic of Korea

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.

Funder

National Research Foundation of Korea

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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