Development of a leucine aminopeptidase-activatable co-prodrug from CDDO-Me and ligustrazine for synergistic treatment of liver injury.

Liver injury is pathological basis of various hepatic diseases, including different kinds of hepatitis and even liver cancer. Hence, we designed and synthesized a co-prodrug CHL from CDDO-Me and ligustrazine (HMP) which can be specifically activated by leucine aminopeptidase (LAP) and release >90 % two active drugs (CDDO-Me and HMP) to exert its multiple anti-inflammatory activities in liver injury models by reducing intracellular reactive oxygen species (ROS), mitochondrial damage, and apoptosis. Excitingly, CHL not only exhibited more significant anti-injury effects on liver both in vitro and in vivo of CCl4-simulated models compared to the parent drugs combination therapy, but also significantly induced the expression of Nrf2-dependent antioxidant genes (HO-1 and NQO1), increasing them by 4.2- and 5.5-fold, respectively. Furthermore, CHL reduced p-p65 expression by 5-fold, indicating its effective inhibition of NF-κB transcriptional activity and thereby alleviating inflammatory responses. Therefore, the LAP-activable co-prodrug CHL holds promising potential as a candidate for the synergistic treatment of liver injury.