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])
ISSN0022-2623
EISSN1520-4804
卷号68期号:4页码:4382-4396
发表状态已发表
DOI10.1021/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.

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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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