Luteolin and glycyrrhetinic exert cooperative effect on liver cancer by selfassembling into carrier-free nanostructures

Liver cancer is the fourth cause of cancer-related deaths and the primary cause of death in patients with compensated cirrhosis. In recent years, the role of traditional Chinese medicine in the treatment of liver cancer has attracted more and more attention and recognition. Luteolin (LUT) and glycyrrhetinic (GA) are natural compounds extracted from Chinese herbal medicine. LUT exhibits various biological activity including anti-inflammatory, antibacterial, antiviral, anti-tumor, and neuroprotective effects. GA significantly inhibits the growth and metastasis of cancer cells. However, the low water solubility of both compounds hinders their clinical applications. In this study, rod-shaped nanoparticles (NPs) self-assembled from LUT and GA were designed to enhance drug solubility and tumor-targeting capability. We verified that the assembly mechanism of the NPs was π-π stacking. These NPs significantly inhibited the proliferation of liver cancer cells while had no significant effect on normal liver cells. In a mouse model of liver cancer, these NPs demonstrated superior tumor-targeting ability due to the enhanced permeability and retention effect, and the affinity of GA for liver cancer cells, resulting in better therapeutic efficacy with lower systemic toxicity. Results of network pharmacology analysis showed that LUT and GA respectively targeted estrogen receptor 1 (ESR1) protein and cyclin-dependent kinase 1 (CDK1) protein to corporately induce tumor cell cycle arrest, which induced the inhibition of tumor cell proliferation. In conclusion, this study provides a novel reference for the treatment of liver cancer.