{"doi":"10.1021/jacs.5c12615","title":"Hypochlorous Acid-Gated Hydrolysis of a Phosphinate Ester Dye in Living Cells","abstract":"High Resolution Image Download MS PowerPoint Slide Theranostic fluorescent platforms are capable of the selective delivery of small molecules to target cells with simultaneous optical monitoring. Such technologies promise to significantly reduce off-target effects compared with cytotoxic chemotherapy. However, small-molecule approaches are often hindered by relatively complex designs that are required to incorporate a fluorescent reporter, reactive linker, targeting ligand, and cargo into a single molecule. Herein, we provide the first direct evidence for the ability to gate the delivery of small-molecule cargos from phosphinate ester-containing Nebraska Red ( NR ) dyes in vitro and in living cells. This simplified system integrates the fluorescent reporter, reactive linker, and targeting ligand into one species─a phosphinate ester dye. As a proof-of-principle for delivery of drug-like molecules to cells, we developed NR-HOCl-TFMU, which responds to hypochlorous acid (HOCl), an analyte detected in acute myeloid leukemia (AML). NR-HOCl-TFMU is stable for days prior to reaction with HOCl, leading to phosphinate ester hydrolysis and production of a NIR (near-infrared, NR dye) and blue (cargo) fluorescence signal. NR dye fluorescence is directly proportional to cargo release, and NR-HOCl-TFMU is capable of selectively delivering its drug-like, small-molecule cargo to AML cells in vitro and in a localized tumor model in an HOCl-gated manner. In the long term, we envision the potential use of this technology to afford HOCl-gated delivery systems with selectivity toward HOCl-positive AML cells. More broadly, this approach provides a potentially generalizable strategy for the development of simplified theranostic agents targeted toward small-molecule analytes and enzymatic activities associated with disease.","journal":"Journal of the American Chemical Society","year":2025,"id":547872,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9455,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":397696,"name":"Xinqi Zhou","orcid":"0000-0002-6276-6947","position":1,"is_corresponding":false},{"id":1293641,"name":"Julia L. McAfee","orcid":null,"position":2,"is_corresponding":false},{"id":1298283,"name":"Benjamin M. Faulkner","orcid":null,"position":3,"is_corresponding":false},{"id":397695,"name":"Lauren Lesiak","orcid":"0000-0001-6254-7085","position":4,"is_corresponding":false},{"id":230911,"name":"Yuchen He","orcid":"0000-0002-3985-7779","position":5,"is_corresponding":false},{"id":1091217,"name":"Frederik Brøndsted","orcid":"0000-0001-8402-2562","position":6,"is_corresponding":false},{"id":999809,"name":"Hao Fan","orcid":"0000-0002-9281-8760","position":7,"is_corresponding":false},{"id":292921,"name":"Eric D. Donarski","orcid":"0000-0002-9530-7026","position":8,"is_corresponding":false},{"id":1007004,"name":"Xiaoyan Hu","orcid":"0000-0001-8550-0896","position":9,"is_corresponding":false},{"id":302315,"name":"B. Jill Venton","orcid":"0000-0002-5096-9309","position":10,"is_corresponding":false},{"id":736161,"name":"Steven Grant","orcid":"0000-0003-4452-9320","position":11,"is_corresponding":false},{"id":294642,"name":"Francine E. Garrett-Bakelman","orcid":"0000-0002-4771-628X","position":12,"is_corresponding":false},{"id":397700,"name":"Cliff I. Stains","orcid":"0000-0002-3165-4539","position":13,"is_corresponding":false},{"id":397697,"name":"Fang Yuan","orcid":"0000-0003-1987-0885","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T02:53:53.962932Z","pmid":"41123088","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}