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。

IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL
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*, 
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引用次数: 0

摘要

喜树碱(CPT)及其衍生物是有效的抗癌药物,但其水溶性差、缺乏靶向特异性和严重的全身毒性限制了其临床应用。在这项研究中,我们合成了一种糖缀合前药(GalNAc)3-CPT,通过将CPT偶联到三触链n -乙酰半乳糖胺(GalNAc)配体上,靶向肝细胞上过表达的asial糖蛋白受体(ASGR)。该前药在磷酸盐缓冲盐水(pH 7.4)中的溶解度比CPT高2289倍。体外研究表明,(GalNAc)3-CPT可被肝细胞癌(HCC)细胞有效吸收,显著降低细胞活力,诱导细胞凋亡。在体内,与CPT相比,(GalNAc)3-CPT表现出更强的肿瘤靶向性和更强的抗肿瘤活性,并且没有可检测到的全身毒性。激活cGAS-STING通路,促进CD8+ T细胞向肿瘤浸润。总之,galnac介导的CPT递送是一种很有前景的靶向HCC治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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

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.

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来源期刊
Journal of Medicinal Chemistry
Journal of Medicinal Chemistry 医学-医药化学
CiteScore
4.00
自引率
11.00%
发文量
804
审稿时长
1.9 months
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.
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