Gd-Complex of a Rosmarinic Acid Conjugate as an Anti-Inflammatory Theranostic Agent via Reactive Oxygen Species Scavenging

Abstract

Rosmarinic acid (RosA), an important polyphenol, is known for its antioxidant and anti-inflammatory activities. However, its application in theranostics has been rarely reported. Therefore, a new single-molecule anti-inflammatory theranostic compound containing RosA would be of great interest. A gadolinium (Gd) complex of 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid (DO3A) and RosA (Gd(DO3A-RosA)(H2O)) was synthesized and examined for use as a single-molecule theranostic agent. Its kinetic stability is comparable to that of clinically used macrocyclic magnetic resonance imaging contrast agents. In addition, its relaxivity is higher than that of structurally analogous Gd-BT-DO3A. This agent was evaluated for inflammatory targeting magnetic resonance contrast and showed strong and prolonged enhancement of imaging in inflamed tissues of mice. The theranostic agent also possesses antioxidant and anti-inflammatory activities, as evidenced by reactive oxygen species scavenging, superoxide dismutase activity, and inflammatory factors. The novel RosA-conjugated Gd complex is a promising theranostic agent for the imaging of inflamed tissues, as well as for the treatment of inflammation and oxidative stress.

Flavonoid-Conjugated Gadolinium Complexes as Anti-Inflammatory Theranostic Agents

“…DO3A-flavonoid is designed to maintain active sites for antioxidant effects and increase synthesis efficiency ( Figure 1 ). The ester and ether bonds have a lower binding strength compared to the widely used amide bonds [ 16 , 34 ], and ester bonds can be decomposed into enzymes such as esterase [ 53 ]. Based on the ester bond, the DO3A and flavonoid portions are protected in decomposition because they have a large structure that is difficult to act on esterase [ 54 ], and the stability of DO3A-flavonoid was verified in experiments compared with used contrast agents ( Figure 2 ).…”

“…Samples used for relaxivity determinations were prepared at five concentrations (0.0625, 0.125, 0.25, 0.5, and 1 mM) in deionized water, phosphate-buffered saline (PBS), or 0.67 mM human serum albumin (HSA) solution [ 16 ]. The three synthesized Gd complexes and various commercial contrast agents Gd-BT-DO3A (Gadovist ® ), Gd-DTPA-EOB (Primovist ® ), Gd-DTPA-BOPTA (MultiHance ® ), Gd-DTPA (Magnevist ® ), and Gd-DOTA (Dotarem ® )) were measured together using a Signa Architect 3.0 T system (128 MHz, GE Healthcare, Milwaukee, WI, USA).…”

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

“…For the analysis of protein expression changes, C2C12 cells (5 × 10 3 cells/dish) were inoculated into a 60-mm culture dish. After inducing differentiation for 3 days, palmitate acid or/and drugs were added to the growth medium and incubated for 24 h. Cells were harvested, and protein extraction and Western blotting were performed as described in a previous study [ 54 ]. Membranes were incubated with the following diluted primary antibodies: COX-2 (1:2000, Cell Signaling Technologies, Beverly, MA, USA, Catalog No.…”

Biomedical features and therapeutic potential of rosmarinic acid

“…Studies have found that RA exhibits strong anti-oxidant capacity in biological systems by scavenging free radical and reactive oxygen species (Ghorbani et al 2019 ; Kim et al 2020a ). Recently, Sadeghi et al ( 2020 ) investigated the impact of RA on lipopolysaccharide-induced oxidative damage and inflammation in peripheral blood mononuclear cells.…”