Ultrasound-Driven Reductive Deoxygenation of N-Oxides for Spatiotemporally Controlled Prodrug Activation.

Authors

Jingxuan Zhang, Hongyu Chu, Weidong Zhao, Chaoying Kong, Hang Xu, Haiyang Yu, Ming Yang, Na Shen, Guoqing Wang, Zhaohui Tang

Published in

Journal of the American Chemical Society. Volume 148. Issue 32. Pages 34231-34243. Aug 19, 2026.

Abstract

Spatiotemporally controlled, tumor-selective activation of N-oxide prodrugs within tumors remains a longstanding challenge in cancer therapy. Herein, we report a broadly applicable strategy driven by clinical ultrasound for the reductive deoxygenation of N-oxides, enabling externally controlled prodrug activation via a riboflavin tetrabutyrate (TBR)/NADPH redox-relay system. Under mild, clinically translatable ultrasound (1 MHz, 2.0 W/cm2, 50% duty cycle), this platform promotes efficient N-O bond cleavage through single-electron transfer and hydrogen-atom transfer. Density functional theory calculations support that all ground-state steps are thermodynamically favorable with negative Gibbs free-energy changes (ΔG), supporting the feasibility of sonochemical N-oxide reduction. This method exhibits broad substrate generality toward diverse N-oxide compounds, including the clinically investigated hypoxia-activated prodrug banoxantrone (AQ4N), quinoline N-oxide, 8-hydroxyquinoline N-oxide, clozapine N-oxide, and olanzapine N-oxide. In hypoxic tumor cells, the ultrasound/TBR system enhances intracellular AQ4 formation significantly and reduces the IC50 of AQ4N from 35.0 to 2.8 mg/L. In vivo, the combination of AQ4N, TBR, and ultrasound increased intratumoral AQ4 formation by approximately 24.1-fold and achieved a tumor inhibition rate of 113.7%, outperforming AQ4N monotherapy (82.3%). This sonochemically triggered activation platform bypasses the heterogeneity of tumor-microenvironment stimuli and offers a versatile, externally controlled framework for precision prodrug chemotherapy with deep tissue penetration and clinical translatability.

PMID:
42619108
Bibliographic data and abstract were imported from PubMed on 20 Aug 2026.

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