Sinapic Acid-Conjugated Gadolinium Complexes as Anti-Inflammatory Theranostic Agents That Target Transforming Growth Factor β-Activated Kinase 1 (TAK1)

Recent <i>in vitro</i> studies have reported that sinapic acid (SPA) binds to transforming growth factor-β-activated kinase 1 (TAK1), a key regulator of inflammatory pathways. However, the hydrophobic nature of SPA limits its solubility in aqueous environments, posing challenges for <i>in vivo</i> biomedical applications. Thus, we synthesized Gd-DO3A-SPA by conjugating SPA with a gadolinium-based magnetic resonance imaging (MRI) contrast agent to improve its solubility. Gd-DO3A-SPA was then evaluated as a theranostic agent capable of both diagnosing inflammatory lesions via MRI and modulating inflammation by directly targeting TAK1. The physicochemical properties of the synthesized Gd-DO3A-SPA were analyzed by using MRI. The diagnostic and therapeutic effects of Gd-DO3A-SPA on inflammation were evaluated in a mouse inflammation model. TAK1 binding was investigated using cellular thermal shift assay, drug affinity responsive target stability, and <i>in silico</i> studies. The conjugated Gd-DO3A-SPA showed superior signal enhancement in inflamed tissue compared with the extracellular MR agent, Gadobutrol. Additionally, it was found to inhibit inflammatory cytokines, such as inducible nitric oxide synthase, cyclooxygenase 2, interleukin 6, interleukin 1β, and tumor necrosis factor α, as well as the NLRP3 inflammasome, through the nuclear factor kappa-light-chain-enhancer of activated B cells and mitogen-activated protein kinase pathways. Furthermore, this study demonstrated that Gd-DO3A-SPA was internalized into cells via endocytosis and directly bound to the TAK1 protein. In conclusion, Gd-DO3A-SPA demonstrated its potential as a theranostic agent that targets TAK1 at the site of inflammation and inhibits inflammatory factors; meanwhile, inflammation can be diagnosed by using MRI.