Redox-Sensitive Curcumin Prodrug Mediated by Glycyrrhetinic Acid for Liver Cancer Therapy

Despite the development of numerous prodrugs for tumor therapy, their clinical application remains limited due to issues such as non-targeted delivery, uncontrolled release, and excessively rapid drug release rates. In this study, we synthesized a dual-functional prodrug, glycyrrhizic acid-polyethylene glycol-disulfide curcumin (GA-PEG-SS-CUR), by conjugating glycyrrhizic acid (GA), which possesses liver-targeting capabilities, with the anticancer agent curcumin (CUR). GA-PEG-SS-CUR can self-assemble in aqueous solutions to form micelles with an approximate diameter of ∼140 nm. In vitro drug release studies demonstrated that GA-PEG-SS-CUR exhibits a sensitive glutathione (GSH) response and sustained release characteristics; after 72 hours, the drug release rate was 30.5% at low GSH concentrations and 46.7% at high GSH concentrations. Due to GA receptor-mediated targeting, the uptake of GA-PEG-SS-CUR in HepG2 cells was significantly higher than that in L02 cells, and the internalization of GA-PEG-SS-CUR in HepG2 cells was markedly greater compared to unmodified PEG-SS-CUR. Cytotoxicity assays indicated that GA-PEG-SS-CUR enhanced the cytotoxicity against tumor cells compared to free CUR, while exhibiting lower toxicity towards normal L02 cells. Pharmacokinetic studies revealed that the half-life of CUR in GA-PEG-SS-CUR was 8.3 times longer than that of free CUR, extending the in vivo circulation time, with CUR accumulation at the tumor site being 6 times greater than that of free CUR, indicating significant tumor-homing ability. Therefore, the developed GA-PEG-SS-CUR represents an ideal delivery system for curcumin in tumor therapy.