Glycyrrhetinic acid functionalized polyamidoamine dendrimers for targeted gene delivery in liver cancer

Gene therapy holds significant promise for the treatment of liver cancer. However, the development of safe and efficient gene delivery systems remains a critical challenge. Cationic polymers are widely utilized as gene carriers due to their high transfection efficiency, yet their application is often hindered by cytotoxicity and lack of target specificity. In this study, we present a one-step strategy to conjugate glycyrrhetinic acid (GA) to cationic polymers, aiming to reduce cytotoxicity and enhance liver-specific targeting. A series of GA-modified polyamidoamine (PPI) dendrimers were synthesized by varying the degree of GA substitution and were comprehensively characterized. The resulting GA-PPI dendrimers exhibited strong plasmid DNA (pDNA) binding and protection capabilities, forming stable GA-PPI/pDNA polyplexes. Notably, GA-PPI dendrimers with 5.10% GA substitution achieved a 5.1-fold enhancement in hepatocyte transfection efficiency (22.7% vs. 4.45% for unmodified PPI), while maintaining high cell viability (97.8% vs. 76.4%). In vivo, GA-PPI-3/pDNA polyplexes demonstrated superior antitumor efficacy in HepG2 xenograft models. These results underscore the potential of GA-functionalized PPI dendrimers as an effective and safe platform for targeted gene therapy in hepatocellular carcinoma.