Design and evaluation of glycyrrhetinic acid-Pt(IV) hybrids for targeted therapy of liver cancer with reduced systemic toxicity.

Multitarget natural product-platinum conjugates represent a promising strategy to overcome the limitations of Pt(IV) drugs, including severe side effects and drug resistance. In this study, a series of platinum-based hybrids incorporating glycyrrhetinic acid (GA) as axial ligands were designed, synthesized, and evaluated for their antitumor activity against various cancer cell lines. The lead complex GABP (glycyrrhetinic acid-carboplatin conjugate) demonstrated superior cytotoxicity compared to carboplatin, along with enhanced anti-liver cancer activity and low toxicity toward THLE-2 normal liver cells. Moreover, GABP significantly reversed cisplatin resistance in A549/CDDP cells. Mechanistic studies revealed that GABP induces DNA damage and ROS generation, leading to G2/M phase arrest, inhibition of migration and invasion, and apoptosis in HepG-2 cells via the Bcl-2/Bax/Caspase-3 pathway. Pharmacokinetic analysis indicated favorable plasma stability and liver tissue distribution for GABP. In a zebrafish model, GABP exhibited reduced hepatotoxicity and cardiotoxicity relative to carboplatin. In vivo, GABP achieved a tumor inhibition rate of 71.5% in HepG-2 xenograft mice, significantly outperforming carboplatin (48.3%) and the carboplatin/GA combination (55.2%), with no observable toxicity. By leveraging the hepatoselective accumulation of glycyrrhetinic acid, this study validates the GA-Pt(IV) prodrug conjugate as a "two-birds-one-stone" strategy that simultaneously enhances tissue targeting, overcomes resistance, and improves the safety profile of platinum-based anticancer agents.