前药
化学
脱氧核糖
癌症免疫疗法
免疫疗法
干扰素基因刺激剂
刺
药理学
兴奋剂
癌症研究
免疫系统
生物化学
核酸
免疫学
先天免疫系统
受体
航空航天工程
工程类
生物
医学
作者
Zhiqiang Xie,Liqing Lu,Zhenghua Wang,Qinhong Luo,Yuchen Yang,Tian Fang,Ziyi Chen,Dejun Ma,Junmin Quan,Zhen Xi
标识
DOI:10.1016/j.ejmech.2022.114796
摘要
Cancer immunotherapy is a powerful weapon in the fight against cancers. Cyclic dinucleotides (CDNs) have demonstrated the great potential by evoking the immune system to fight cancers. There are still a lot of unmet needs for highly active CDNs in clinical applications due to low cell permeation and serum stability. Here we reported S-acylthioalkyl ester (SATE)-based prodrugs of deoxyribose cyclic dinucleotides (dCDNs) with three different types of internucleotide linkages (3',3':11a; 2',3':11b; 2',2':11c). The parent dCDNs could be efficiently released from SATE-dCDNs by cellular esterases. Compared to 2',3'-cGAMP and ADU-S100, 11a exhibited much higher potency of activating STING pathway and higher serum stability. In a CT26-Luc tumor-bearing animal model, 11a showed the efficient antitumor activity in eliminating the established tumor and induced significant increase of mRNA expression of IFN-β and other related inflammatory cytokines. Hence, SATE-dCDN prodrugs demonstrated their benefits in promoting cell penetration, improving serum stability, and thus enhancing bioactivity, suggesting their potential application as immunotherapy in a variety of malignancies.
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