体内
生物正交化学
癌症干细胞
癌细胞
细胞内
癌症研究
癌症
化学
CD44细胞
点击化学
生物化学
生物
细胞
遗传学
生物技术
组合化学
作者
Bo Yang,Jingyi Zhou,Kaimin Cai,Ying Wang,Yang Feng,Wenming Li,Yunjiang Jiang,Shanny Hsuan Kuo,Jarron Roy,Chelsea Anorma,Sarah H. Gardner,Long M. Luu,Gee W. Lau,Yan Bao,Jefferson Chan,Hua Wang,Jianjun Cheng
标识
DOI:10.1073/pnas.2302342120
摘要
Inhibition of overexpressed enzymes is among the most promising approaches for targeted cancer treatment. However, many cancer-expressed enzymes are “nonlethal,” in that the inhibition of the enzymes’ activity is insufficient to kill cancer cells. Conventional antibody-based therapeutics can mediate efficient treatment by targeting extracellular nonlethal targets but can hardly target intracellular enzymes. Herein, we report a cancer targeting and treatment strategy to utilize intracellular nonlethal enzymes through a combination of selective cancer stem-like cell (CSC) labeling and Click chemistry-mediated drug delivery. A de novo designed compound, AAMCHO [N-(3,4,6-triacetyl- N-azidoacetylmannosamine)-cis-2-ethyl-3-formylacrylamideglycoside], selectively labeled cancer CSCs in vitro and in vivo through enzymatic oxidation by intracellular aldehyde dehydrogenase 1A1. Notably, azide labeling is more efficient in identifying tumorigenic cell populations than endogenous markers such as CD44. A dibenzocyclooctyne (DBCO)-toxin conjugate, DBCO-MMAE (Monomethylauristatin E), could next target the labeled CSCs in vivo via bioorthogonal Click reaction to achieve excellent anticancer efficacy against a series of tumor models, including orthotopic xenograft, drug-resistant tumor, and lung metastasis with low toxicity. A 5/7 complete remission was observed after single-cycle treatment of an advanced triple-negative breast cancer xenograft (~500 mm 3 ).
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