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

Hepatocellular\ncarcinoma (HCC) is a challenging cancer to treat\ndue to its high malignancy, strong invasiveness, and high risk of\nmetastasis. Inhibiting lymphatic metastasis in the early stages is\ncrucial for HCC therapy. Active targeted drug delivery systems, imbued\nwith tumor and lymphatic targeting capability via ligand–receptor\nmediation, represent a promising therapeutic strategy. Cantharidin\n(CTD), the primary effective component of poisonous traditional Chinese\nmedicine (PTCM) <i>Mylabris</i>, has unique therapeutic\neffects on HCC. However, its high toxicity limits its clinical application.\nIn this study, based on the high expression of lymphatic vessel endothelial\nhyaluronan receptor-1 (LYVE-1) in the peritumoral lymphatic vessels\nand glycyrrhetinic acid receptor (GA-R) in hepatocellular carcinoma\ncells, we developed CTD-loaded poly(d,l-lactide-<i>co</i>-glycolide) (PLGA) nanoparticles modified with glycyrrhetinic\nacid (GA)–hyaluronic acid (HA) copolymers (GA-HA-PLGA/CTD NPs)\nthrough electrostatic interactions. This nanoparticle platform could\npreferentially accumulate cargo into the tumors and peritumoral lymphatic\nvessels, increasing drug accumulation in tumors and lymph nodes while\ndecreasing drug accumulation in other organs, particularly the heart\nand kidney. As a result, it could enhance antitumor efficacy and inhibit\nlymphatic metastasis better than PLGA/CTD NPs while also reducing\nsystemic toxicity. Furthermore, the variation of HA molecular weights\nand degrees of GA substitution could regulate the distribution of\nnanoparticles within tumors and lymph nodes. Overall, GA-HA-PLGA/CTD\nNPs exhibit promising potential as a therapeutic approach for HCC\ntreatment and lymphatic metastasis inhibition, providing a potential\nstrategy for the application of PTCMs in HCC treatment.