{"title":"可溶性三触角n -乙酰半乳糖胺喜树碱前药用于肝细胞癌靶向治疗。","authors":"Yinqi Li, Yeteng Zheng, Taiqing Liu, Jinhua Zhao, Lingyan Zhou, Xiaodong Yang, Ziying Yao, Xiaoyu Wang, Yunhai Fu, Jingwen Wang, Kefei Yuan and Zhiyao He*, ","doi":"10.1021/acs.jmedchem.5c00466","DOIUrl":null,"url":null,"abstract":"<p >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)<sub>3</sub>-CPT, by conjugating CPT to a triantennary <i>N</i>-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)<sub>3</sub>-CPT was effectively taken up by hepatocellular carcinoma (HCC) cells, significantly reducing cell viability and inducing apoptosis. In vivo, (GalNAc)<sub>3</sub>-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<sup>+</sup> T cells into the tumor. In summary, GalNAc-mediated CPT delivery represents a promising strategy for targeted HCC therapy.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 15","pages":"15563–15578"},"PeriodicalIF":6.8000,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A Soluble Triantennary N-Acetylgalactosamine Camptothecin Prodrug for Hepatocellular Carcinoma-Targeted Therapy\",\"authors\":\"Yinqi Li, Yeteng Zheng, Taiqing Liu, Jinhua Zhao, Lingyan Zhou, Xiaodong Yang, Ziying Yao, Xiaoyu Wang, Yunhai Fu, Jingwen Wang, Kefei Yuan and Zhiyao He*, \",\"doi\":\"10.1021/acs.jmedchem.5c00466\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >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)<sub>3</sub>-CPT, by conjugating CPT to a triantennary <i>N</i>-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)<sub>3</sub>-CPT was effectively taken up by hepatocellular carcinoma (HCC) cells, significantly reducing cell viability and inducing apoptosis. In vivo, (GalNAc)<sub>3</sub>-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<sup>+</sup> T cells into the tumor. In summary, GalNAc-mediated CPT delivery represents a promising strategy for targeted HCC therapy.</p>\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":\"68 15\",\"pages\":\"15563–15578\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2025-07-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c00466\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c00466","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
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.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.