Glycyrrhetinic Acid-Biguanide Conjugate-Based Nanoparticles as a Multi-Functional Drug Delivery System: Paclitaxel Encapsulation and Targeted Therapy

Paclitaxel (PTX) is a widely used chemotherapeutic agent, but its clinical utility is limited by poor solubility, systemic toxicity, and inadequate tumor targeting. To address these challenges, we developed a novel glycyrrhetinic acid-biguanide conjugate (GABG) capable of forming self-assembling, carrier-free nanoparticles. GABG's amphiphilic and self-emulsifying properties enable efficient PTX encapsulation and targeted delivery. PTX-loaded GABG nanoparticles (PTX@GABG NPs) significantly enhanced cytotoxicity against multiple tumor cell lines, improving cellular uptake and selective tumor accumulation. Molecular dynamics simulations confirmed stable PTX-GABG interactions, supporting the structural integrity of the nanocomplex. In vivo biodistribution studies revealed strong liver tropism following intraperitoneal administration, with tumor-targeting efficiency comparable to intravenous delivery. The cellular uptake of GABG nanoparticles in H22 cells was shown to be governed by GA receptor-mediated endocytosis, with both caveolae- and clathrin-dependent pathways contributing to their efficient internalization. Therapeutic evaluations demonstrated that PTX@GABG NPs induced superior tumor inhibition compared to free PTX, driven by enhanced apoptosis and ROS-mediated cytotoxicity. Notably, the antitumor efficacy of intraperitoneal administration was comparable to that of intravenous injection, highlighting its potential as a less invasive yet effective delivery route. Given its dual functionality in drug encapsulation and liver targeting, GABG presents a promising platform for hepatic tumor therapy. Its cationic biguanide groups may further enable encapsulation of biopharmaceuticals such as RNA, underscoring its versatility in precision nanomedicine.