A Soluble Triantennary N-Acetylgalactosamine Camptothecin Prodrug for Hepatocellular Carcinoma-Targeted Therapy

Camptothecin (CPT) and its derivatives are potent anticancer agents, but their clinical application is limited by poor aqueous solubility, lack of targeting specificity, and severe systemic toxicity. In this study, we synthesized a glycoconjugate prodrug, (GalNAc)₃-CPT, by conjugating CPT to a triantennary N-acetylgalactosamine (GalNAc) ligand that targeted the asialoglycoprotein receptor (ASGR) overexpressed on hepatocytes. This prodrug exhibited a solubility 2289 times higher than that of CPT in phosphate-buffered saline (pH 7.4). In vitro studies indicated that (GalNAc)₃-CPT was effectively taken up by hepatocellular carcinoma (HCC) cells, significantly reducing cell viability and inducing apoptosis. In vivo, (GalNAc)₃-CPT showed enhanced tumor targeting and superior antitumor activity compared to CPT and exhibited no detectable systemic toxicity. Moreover, it activated the cGAS-STING pathway and promoted the infiltration of CD8⁺ T cells into the tumor. In summary, GalNAc-mediated CPT delivery represents a promising strategy for targeted HCC therapy.