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Abstract
The impact of bacteria on cancer progression and treatment is becoming increasingly recognized. Cancer-associated bacteria are linked to metastases, reduced efficacy, and survival challenges. In this study, we present a sensitive hypoxia-activated prodrug, NR-NO2, which comprises an antibiotic combined with a chemotherapeutic. This prodrug demonstrates rapid and robust fluorescence enhancement and exhibits potent antibacterial activity against both Gram-positive and Gram-negative bacteria as well as tumor cells. Upon activation, NR-NO2 produces a distinct "fluorescence-on" signal, enabling real-time drug release monitoring. By leveraging elevated nitroreductase in cancer cells, NR-NO2 gives rise to heightened bacterial cytotoxicity while sparing normal cells. In A549 solid tumor-bearing mice, NR-NO2 selectively accumulated at tumor sites, displaying fluorescence signals under hypoxia superior to those of a corresponding prodrug-like control. These findings highlight the potential of NR-NO2 as a promising cancer therapy prodrug that benefits from targeted release, antibacterial impact, and imaging-based guidance.

Affiliations

Sanu Karan 1, Mi Young Cho 1, Hyunseung Lee 1, Hyun Min Kim 1, Hye Sun Park 1, Eun Hee Han 1, Jonathan L Sessler 2, Kwan Soo Hong 1 3 4
1Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Republic of Korea.
2Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712-1224, United States.
3Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon 34134, Republic of Korea.
4Department of Chemistry, Chung-Ang University, Seoul 06974, Republic of Korea.