2. Academic Validation
  3. A Soluble Triantennary N-Acetylgalactosamine Camptothecin Prodrug for Hepatocellular Carcinoma-Targeted Therapy

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

  • J Med Chem. 2025 Aug 14;68(15):15563-15578. doi: 10.1021/acs.jmedchem.5c00466.
Yinqi Li 1,  Yeteng Zheng 1,  Taiqing Liu 1,  Jinhua Zhao 1,  Lingyan Zhou 1,  Xiaodong Yang 1,  Ziying Yao 1,  Xiaoyu Wang 1,  Yunhai Fu 1,  Jingwen Wang 1,  Kefei Yuan 2,  Zhiyao He 1 3
Affiliations

Affiliations

  • 1 Department of Pharmacy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
PMID: 40693725 DOI: 10.1021/acs.jmedchem.5c00466
Abstract

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.

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