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Synergistic enhancement of ultrasound therapy for tumors using hypoxia-activated 6-diazo-5-oxo-L-norleucine (DON) prodrug nanoparticles

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Abstract

Ultrasound (US) has been applied in clinical practice for its non-invasive and high selectivity. However, it is difficult to achieve a satisfactory anti-tumor effect with US alone. Meanwhile, the use of US therapy alone can exacerbate tumor hypoxia. In this study, we prepared hypoxia-activated 6-diazo-5-oxo-L-norleucine (DON) prodrug nanoparticles (HDON-NPs) to improve US therapeutic effects. In an H22 murine liver cancer model, US therapy selectively disrupted tumor blood vessels, leading to increased tumor hypoxia and a 1.67-fold increase in the expression of nitroreductase (NTR). The combination therapy of US and HDON-NPs demonstrated a synergistic effect, resulting in a tumor suppression rate (TSR) of 90.2% ± 6.4%, which was 5.93-fold higher than that of US therapy alone. The combined treatment selectively blocked the glutamine metabolism of the tumor cells while simultaneously activating the T cells in the tumor microenvironment, thereby exerting a robust anti-tumor effect.

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Acknowledgements

This work was financially supported by the Ministry of Science and Technology of China (No. 2022YFE0110200), the Natural Science Foundation of Jilin Province (No. 20230101037JC), and the National Natural Science Foundation of China (Nos. 52203198 and 52025035).

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Authors and Affiliations

  1. Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China

    Mengfei Zheng, Zhilin Liu, Hang Xu, Daping Ye, Linjie Cui, Chenguang Yang, Lili Ma, Kun Wang & Zhaohui Tang

  2. School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China

    Mengfei Zheng, Hang Xu, Daping Ye, Linjie Cui & Zhaohui Tang

  3. Jilin Biomedical Polymers Engineering Laboratory, Changchun, 130022, China

    Mengfei Zheng, Zhilin Liu, Hang Xu, Daping Ye, Linjie Cui, Chenguang Yang, Lili Ma, Kun Wang & Zhaohui Tang

  4. Department of Chemistry and Biochemistry, The University of Kitakyushu, 1-1 Hibikino, Kitakyushu, 808-0135, Japan

    Kazuo Sakurai

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  1. Mengfei Zheng
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Correspondence to Zhilin Liu or Zhaohui Tang.

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Synergistic enhancement of ultrasound therapy for tumors using hypoxia-activated 6-diazo-5-oxo-L-norleucine (DON) prodrug nanoparticles

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Zheng, M., Liu, Z., Xu, H. et al. Synergistic enhancement of ultrasound therapy for tumors using hypoxia-activated 6-diazo-5-oxo-L-norleucine (DON) prodrug nanoparticles. Nano Res. (2024). https://doi.org/10.1007/s12274-024-6534-4

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