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Development of ASGR-Mediated Hepatocyte-Targeting Cytotoxic Drug Conjugates with CTSB-Cleavable Linkers Incorporating Succinimide and Succinic Acid Monoamide | |
2025-02-07 | |
发表期刊 | JOURNAL OF MEDICINAL CHEMISTRY (IF:6.8[JCR-2023],7.1[5-Year]) |
ISSN | 0022-2623 |
EISSN | 1520-4804 |
卷号 | 68期号:4页码:4382-4396 |
发表状态 | 已发表 |
DOI | 10.1021/acs.jmedchem.4c02232 |
摘要 | The ASGR-mediated endocytosis has been successfully applied to the hepatocyte-targeted delivery of therapeutic oligonucleotides via glycoconjugates. However, few studies have explored the conjugated small molecules due to the challenge of cleaving suitable linkers for the release of active small molecules, which is especially different from GalNAc-ONs cleaved by the deoxyribonuclease II in the lysosome. In this study, GalNAc-MMAE conjugates linked by CTSB-cleavable linkers were designed and synthesized. A comprehensive approach revealed that the conjugates were endocytosed by ASGR and subsequently hydrolyzed by CTSB, releasing MMAE. The optimized conjugate with a succinic acid monoamide as the fragment of the linker demonstrated favorable plasma stability, excellent biodistribution, and significant antitumor activities in vivo with weight gain at the effective dose in an orthotopic hepatocellular carcinoma mouse model. This research provides a strategy for developing anti-HCC therapeutic agents using GalNAc drug conjugates with CTSB-cleavable linkers to release active small molecules. |
URL | 查看原文 |
收录类别 | SCI |
语种 | 英语 |
资助项目 | Science and Technology Commission of Shanghai Municipality[ |
WOS研究方向 | Pharmacology & Pharmacy |
WOS类目 | Chemistry, Medicinal |
WOS记录号 | WOS:001416522800001 |
出版者 | AMER CHEMICAL SOC |
文献类型 | 期刊论文 |
条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/487116 |
专题 | 生命科学与技术学院 生命科学与技术学院_特聘教授组_丁健组 生命科学与技术学院_博士生 |
通讯作者 | Liu, Jia; Chen, Yi; Hu, Youhong |
作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China 5.Nanjing Univ Chinese Med, Coll Pharm, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 7.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China 8.Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Urumqi 830011, Xinjiang, Peoples R China |
推荐引用方式 GB/T 7714 | Jiang, Jingsheng,Jian, Sigang,Lin, Feifei,et al. Development of ASGR-Mediated Hepatocyte-Targeting Cytotoxic Drug Conjugates with CTSB-Cleavable Linkers Incorporating Succinimide and Succinic Acid Monoamide[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(4):4382-4396. |
APA | Jiang, Jingsheng.,Jian, Sigang.,Lin, Feifei.,Zhang, Zhuo.,Shen, Qianqian.,...&Hu, Youhong.(2025).Development of ASGR-Mediated Hepatocyte-Targeting Cytotoxic Drug Conjugates with CTSB-Cleavable Linkers Incorporating Succinimide and Succinic Acid Monoamide.JOURNAL OF MEDICINAL CHEMISTRY,68(4),4382-4396. |
MLA | Jiang, Jingsheng,et al."Development of ASGR-Mediated Hepatocyte-Targeting Cytotoxic Drug Conjugates with CTSB-Cleavable Linkers Incorporating Succinimide and Succinic Acid Monoamide".JOURNAL OF MEDICINAL CHEMISTRY 68.4(2025):4382-4396. |
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