Dual Targeted Nanoparticles Encapsulating Cantharidin for Treatment of Hepatocellular Carcinoma and Lymphatic Metastasis

Hepatocellular carcinoma (HCC) is a challenging cancer to treat due to its high malignancy, strong invasiveness, and high risk of metastasis. Inhibiting lymphatic metastasis in the early stages is crucial for HCC therapy. Active targeted drug delivery systems, imbued with tumor and lymphatic targeting capability via ligand–receptor mediation, represent a promising therapeutic strategy. Cantharidin (CTD), the primary effective component of poisonous traditional Chinese medicine (PTCM) Mylabris, has unique therapeutic effects on HCC. However, its high toxicity limits its clinical application. In this study, based on the high expression of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) in the peritumoral lymphatic vessels and glycyrrhetinic acid receptor (GA-R) in hepatocellular carcinoma cells, we developed CTD-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles modified with glycyrrhetinic acid (GA)–hyaluronic acid (HA) copolymers (GA-HA-PLGA/CTD NPs) through electrostatic interactions. This nanoparticle platform could preferentially accumulate cargo into the tumors and peritumoral lymphatic vessels, increasing drug accumulation in tumors and lymph nodes while decreasing drug accumulation in other organs, particularly the heart and kidney. As a result, it could enhance antitumor efficacy and inhibit lymphatic metastasis better than PLGA/CTD NPs while also reducing systemic toxicity. Furthermore, the variation of HA molecular weights and degrees of GA substitution could regulate the distribution of nanoparticles within tumors and lymph nodes. Overall, GA-HA-PLGA/CTD NPs exhibit promising potential as a therapeutic approach for HCC treatment and lymphatic metastasis inhibition, providing a potential strategy for the application of PTCMs in HCC treatment.