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Research Article

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

Mengfei Zheng1,2,3, Zhilin Liu1,3( ), Hang Xu1,2,3, Daping Ye1,2,3, Linjie Cui1,2,3, Chenguang Yang1,3, Lili Ma1,3, Kun Wang1,3, Kazuo Sakurai4, Zhaohui Tang1,2,3( )
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China
Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, China
Department of Chemistry and Biochemistry, The University of Kitakyushu, 1-1 Hibikino, Kitakyushu 808-0135, Japan
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Graphical Abstract

Ultrasound (US) killed tumor cells and disrupted tumor blood vessels, selectively inducing tumor hypoxia while also upregulating the expression of nitroreductase (NTR) within the tumor. Subsequently, 6-diazo-5-oxo-L-norleucine prodrug (HDON) released from HDON-NPs was reduced to DON by NTR under hypoxic conditions. DON effectively blocked the glutamine metabolism of tumor cells and stimulated the activation of CD4+ T cells and CD8+ T cells, achieving synergistic therapy.

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.

Keywords

ultrasound therapyhypoxia-activated prodrug nanoparticles6-diazo-5-oxo-L-norleucine (DON)glutamine antagoniststarvation therapy

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References

[1]

Zhang, N. S.; Wang, J.; Foiret, J.; Dai, Z. F.; Ferrara, K. W. Synergies between therapeutic ultrasound, gene therapy and immunotherapy in cancer treatment. Adv. Drug Del. Rev. 2021, 178, 113906.
Crossref Google Scholar
[2]

Zhang, D.; Wang, X. Y.; Lin, J. J.; Xiong, Y. Q.; Lu, H. X.; Huang, J. Y.; Lou, X. Multi-frequency therapeutic ultrasound: A review. Ultrason. Sonochem. 2023, 100, 106608.
Crossref Google Scholar
[3]

Deprez, J.; Lajoinie, G.; Engelen, Y.; De Smedt, S. C.; Lentacker, I. Opening doors with ultrasound and microbubbles: Beating biological barriers to promote drug delivery. Adv. Drug Del. Rev. 2021, 172, 9–36.
Crossref Google Scholar
[4]

Yue, W. W.; Chen, L.; Yu, L. D.; Zhou, B. G.; Yin, H. H.; Ren, W. W.; Liu, C.; Guo, L. H.; Zhang, Y. F.; Sun, L. P. et al. Checkpoint blockade and nanosonosensitizer-augmented noninvasive sonodynamic therapy combination reduces tumour growth and metastases in mice. Nat. Commun. 2019, 10, 2025.
Crossref Google Scholar
[5]

Wu, R. R.; Yao, Z. C.; Chen, Z. X.; Ge, X. G.; Su, L. C.; Wang, S. H.; Wu, Y.; Song, J. B. Ultrasound-activated NIR chemiluminescence for deep tissue and tumor foci imaging. Anal. Chem. 2023, 95, 11219–11226.
Crossref Google Scholar
[6]

Zhang, Z.; Li, B.; Xie, L. S.; Sang, W.; Tian, H.; Li, J.; Wang, G. H.; Dai, Y. L. Metal-phenolic network-enabled lactic acid consumption reverses immunosuppressive tumor microenvironment for sonodynamic therapy. ACS Nano 2021, 15, 16934–16945.
Crossref Google Scholar
[7]

Chaussy, C.; Thüroff, S.; Rebillard, X.; Gelet, A. Technology insight: High-intensity focused ultrasound for urologic cancers. Nat. Clin. Pract. Urol. 2005, 2, 191–198.
Crossref Google Scholar
[8]

Guzman, M. L.; Rossi, R. M.; Karnischky, L.; Li, X. J.; Peterson, D. R.; Howard, D. S.; Jordan, C. T. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 2005, 105, 4163–4169.
Crossref Google Scholar
[9]

Miller, D. L.; Smith, N. B.; Bailey, M. R.; Czarnota, G. J.; Hynynen, K.; Makin, I. R. S. Overview of therapeutic ultrasound applications and safety considerations. J. Ultrasound Med. 2012, 31, 623–634.
Crossref Google Scholar
[10]

Rapoport, N. Y.; Kennedy, A. M.; Shea, J. E.; Scaife, C. L.; Nam, K. H. Controlled and targeted tumor chemotherapy by ultrasound-activated nanoemulsions/microbubbles. J. Controlled Release 2009, 138, 268–276.
Crossref Google Scholar
[11]

Chen, Y. H.; Du, M.; Yuan, Z.; Chen, Z. Y.; Yan, F. Spatiotemporal control of engineered bacteria to express interferon-γ by focused ultrasound for tumor immunotherapy. Nat. Commun. 2022, 13, 4468.
Crossref Google Scholar
[12]

Yumita, N.; Umemura, S. Sonodynamic therapy with photofrin II on AH130 solid tumor. Cancer Chemother. Pharmacol. 2003, 51, 174–178.
Crossref Google Scholar
[13]

Wang, D. W.; Lin, L.; Li, T.; Meng, M.; Hao, K.; Guo, Z. P.; Chen, J.; Tian, H. Y.; Chen, X. S. Etching bulk covalent organic frameworks into nanoparticles of uniform and controllable size by the molecular exchange etching method for sonodynamic and immune combination antitumor therapy. Adv. Mater. 2022, 34, 2205924.
Crossref Google Scholar
[14]

Hunt, S. J.; Gade, T.; Soulen, M. C.; Pickup, S.; Sehgal, C. M. Antivascular ultrasound therapy. J. Ultrasound Med. 2015, 34, 275–287.
Crossref Google Scholar
[15]

Wood, A. K. W.; Ansaloni, S.; Ziemer, L. S.; Lee, W. M. F.; Feldman, M. D.; Sehgal, C. M. The antivascular action of physiotherapy ultrasound on murine tumors. Ultrasound Med. Biol. 2005, 31, 1403–1410.
Crossref Google Scholar
[16]

Li, C.; Yang, X. Q.; An, J.; Cheng, K.; Hou, X. L.; Zhang, X. S.; Hu, Y. G.; Liu, B.; Zhao, Y. D. Red blood cell membrane-enveloped O2 self-supplementing biomimetic nanoparticles for tumor imaging-guided enhanced sonodynamic therapy. Theranostics 2020, 10, 867–879.
Crossref Google Scholar
[17]

Vaupel, P.; Mayer, A.; Höckel, M. Tumor hypoxia and malignant progression. Methods Enzymol. 2004, 381, 335–354.
Crossref Google Scholar
[18]

Cosse, J. P.; Michiels, C. Tumour hypoxia affects the responsiveness of cancer cells to chemotherapy and promotes cancer progression. Anticancer Agents Med. Chem. 2008, 8, 790–797.
Crossref Google Scholar
[19]

Bai, R. X.; Li, Y. N.; Jian, L. Y.; Yang, Y. H.; Zhao, L.; Wei, M. J. The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: Mechanisms and clinical treatment strategies. Mol. Cancer 2022, 21, 177.
Crossref Google Scholar
[20]

Sharma, A.; Arambula, J. F.; Koo, S.; Kumar, R.; Singh, H.; Sessler, J. L.; Kim, J. S. Hypoxia-targeted drug delivery. Chem. Soc. Rev. 2019, 48, 771–813.
Crossref Google Scholar
[21]

Xu, X. X.; Chen, S. Y.; Yi, N. B.; Li, X.; Chen, S. L.; Lei, Z. X.; Cheng, D. B.; Sun, T. L. Research progress on tumor hypoxia-associative nanomedicine. J. Controlled Release 2022, 350, 829–840.
Crossref Google Scholar
[22]

Chen, Y.; Hu, L. Q. Design of anticancer prodrugs for reductive activation. Med. Res. Rev. 2008, 29, 29–64.
Google Scholar
[23]

Singleton, D. C.; Macann, A.; Wilson, W. R. Therapeutic targeting of the hypoxic tumour microenvironment. Nat. Rev. Clin. Oncol. 2021, 18, 751–772.
Crossref Google Scholar
[24]

Sun, J. L.; Liu, Z. L.; Yao, H. C.; Zhang, H. L.; Zheng, M. F.; Shen, N.; Cheng, J. J.; Tang, Z. H.; Chen, X. S. Azide-masked resiquimod activated by hypoxia for selective tumor therapy. Adv. Mater. 2023, 35, 2207733.
Crossref Google Scholar
[25]

Hay, M. P.; Gamage, S. A.; Kovacs, M. S.; Pruijn, F. B.; Anderson, R. F.; Patterson, A. V.; Wilson, W. R.; Brown, J. M.; Denny, W. A. Structure-activity relationships of 1,2,4-benzotriazine 1,4-dioxides as hypoxia-selective analogues of tirapazamine. J. Med. Chem. 2003, 46, 169–182.
Crossref Google Scholar
[26]

Li, G.; Zhang, J. B.; Zhang, S. X.; Teng, L. S.; Sun, F. Y. Multifunctional nanoadjuvant-driven microenvironment modulation for enhanced photothermal immunotherapy in breast cancer. J. Controlled Release 2023, 362, 309–324.
Crossref Google Scholar
[27]

Zheng, M. F.; Xu, H.; Huang, Y.; Sun, J. L.; Zhang, H. L.; Lv, Z.; Liu, Z. L.; Tang, Z. H.; Chen, X. S. Hypoxia-activated glutamine antagonist prodrug combined with combretastatin A4 nanoparticles for tumor-selective metabolic blockade. J. Controlled Release 2024, 365, 480–490.
Crossref Google Scholar
[28]

Wise, D. R.; Ward, P. S.; Shay, J. E. S.; Cross, J. R.; Gruber, J. J.; Sachdeva, U. M.; Platt, J. M.; DeMatteo, R. G.; Simon, M. C.; Thompson, C. B. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc. Natl. Acad. Sci. USA 2011, 108, 19611–19616.
Crossref Google Scholar
[29]

Metallo, C. M.; Gameiro, P. A.; Bell, E. L.; Mattaini, K. R.; Yang, J. J.; Hiller, K.; Jewell, C. M.; Johnson, Z. R.; Irvine, D. J.; Guarente, L. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 2012, 481, 380–384.
Crossref Google Scholar
[30]

Vander Heiden, M. G.; Cantley, L. C.; Thompson, C. B. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 2009, 324, 1029–1033.
Crossref Google Scholar
[31]

Yoo, H. C.; Yu, Y. C.; Sung, Y.; Han, J. M. Glutamine reliance in cell metabolism. Exp. Mol. Med. 2020, 52, 1496–1516.
Crossref Google Scholar
[32]

Vander Heiden, M. G. Targeting cancer metabolism: A therapeutic window opens. Nat. Rev. Drug Discov. 2011, 10, 671–684.
Crossref Google Scholar
[33]
Xiong, J.; Wang, N.; Zhong, H. J.; Cui, B. W.; Cheng, S.; Sun, R.; Chen, J. Y.; Xu, P. P.; Cai, G.; Wang, L. et al. SLC1A1 mediated glutamine addiction and contributed to natural killer T-cell lymphoma progression with immunotherapeutic potential. eBioMedicine 2021 , 72, 103614.
[34]

Stine, Z. E.; Schug, Z. T.; Salvino, J. M.; Dang, C. V. Targeting cancer metabolism in the era of precision oncology. Nat. Rev. Drug Discov. 2022, 21, 141–162.
Crossref Google Scholar
[35]

Reinfeld, B. I.; Madden, M. Z.; Wolf, M. M.; Chytil, A.; Bader, J. E.; Patterson, A. R.; Sugiura, A.; Cohen, A. S.; Ali, A.; Do, B. T. et al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature 2021, 593, 282–288.
Crossref Google Scholar
[36]

Wang, Y. Y.; Bai, C. S.; Ruan, Y. X.; Liu, M.; Chu, Q. Y.; Qiu, L.; Yang, C. Z.; Li, B. H. Coordinative metabolism of glutamine carbon and nitrogen in proliferating cancer cells under hypoxia. Nat. Commun. 2019, 10, 201.
Crossref Google Scholar
[37]

Jin, Z. J. About the evaluation of drug combination. Acta Pharmacol. Sin. 2004, 25, 146–147.
Google Scholar
[38]

Ma, Z. Y.; Zhang, Y. F.; Dai, X. X.; Zhang, W. Y.; Foda, M. F.; Zhang, J.; Zhao, Y. L.; Han, H. Y. Selective thrombosis of tumor for enhanced hypoxia-activated prodrug therapy. Adv. Mater. 2021, 33, 2104504.
Crossref Google Scholar
Nano Research
Volume 17 Issue 7,
July 2024
Pages 6323-6331
DOI: 10.1007/s12274-024-6534-4
Cite this article:
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 Research, 2024, 17(7): 6323-6331. https://doi.org/10.1007/s12274-024-6534-4
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Received: 19 December 2023
Revised: 29 January 2024
Accepted: 31 January 2024
Published: 13 March 2024
© Tsinghua University Press 2024
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