Rational Design of Mono-Substituted Gd-DOTA as Highly Stable and Efficient MRI Contrast Agents for Hepatobiliary and Inflammation Imaging
Yinghui Ding, Xinzhong Ruan, Kun Shu, Weiyuan Xu, Y. Liu, Gengshen Mo, Jiao Xu, Yong Jian, Jilai Zhang, Lingfeng Zhang, Keren Wang, Ji-Ting Hou, Jianliang Shen, Zhihan Yan, Fangfu Ye, Jiang Zhu, Lixiong Dai
Abstract
Hepatobiliary-specific magnetic resonance imaging contrast agents (MRI CAs) play a crucial role in the early diagnosis of hepatocellular carcinoma (HCC). However, only two acyclic CAs, Gd-BOPTA and Gd-EOB-DTPA, exhibit unfavorable kinetic inertness. Our study focused on the development of superior stable innovative macrocyclic CAs. By introducing a lipophilic benzyloxy group (OBn) into the H 4 DOTA ring ( Gd-L 1 ), we achieved significant enhancement in kinetic inertness. In vivo experiments in mice demonstrated that 40% of the dosage was distributed to the liver at 5 min, providing sustained hepatic enhancement for over 35 min. We also developed an MPO-responsive MRI CA ( Gd-L 3 ), which can participate in the “peroxidase cycle” as the substrate, generating oligomers with a 3.8-fold increase in relaxivity, and selectively enhance the lesion in an acute gout mouse model. Overall, our work represents a significant advancement in the field of hepatic and inflammatory MRI, offering promising avenues for early diagnosis and improved imaging outcomes.