Leveraging intracellular ALDH1A1 activity for selective cancer stem-like cell labeling and targeted treatment via in vivo click reaction

Yang Bo, Jingyi Zhou, Kaimin Cai, Ying Wang, Yujun 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

Research output: Contribution to journalArticlepeer-review


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 mm3).

Original languageEnglish (US)
Article numbere2302342120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number36
StatePublished - Sep 5 2023


  • cancer stem cell
  • cancer targeting
  • click chemistry
  • enzymes
  • metabolic glycoengineering

ASJC Scopus subject areas

  • General


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