Journal Home > Online First
Nano Research https://doi.org/10.1007/s12274-024-6534-4
Research Article | Online first | Published: 13 March 2024

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

Show Author's Information 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
Keywords:
starvation therapy, ultrasound therapy, hypoxia-activated prodrug nanoparticles, glutamine antagonist, 6-diazo-5-oxo-L-norleucine (DON)
Topics:
Drug delivery
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, https://doi.org/10.1007/s12274-024-6534-4
Download citation
EndNote(RIS)
BibTeX

491

Views

65

Downloads

Citations

0

Crossref

0

WoS

0

Scopus

0

CSCD

Abstract Full text Electronic supplementary material About this article

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.


menu
Abstract
Full text
Outline
Electronic supplementary material
About this article

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

Show Author's information 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

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: starvation therapy, ultrasound therapy, hypoxia-activated prodrug nanoparticles, glutamine antagonist, 6-diazo-5-oxo-L-norleucine (DON)

References(38)

[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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI Google Scholar
[12]

Yumita, N.; Umemura, S. Sonodynamic therapy with photofrin II on AH130 solid tumor. Cancer Chemother. Pharmacol. 2003, 51, 174–178.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI Google Scholar
[17]

Vaupel, P.; Mayer, A.; Höckel, M. Tumor hypoxia and malignant progression. Methods Enzymol. 2004, 381, 335–354.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI Google Scholar
[22]

Chen, Y.; Hu, L. Q. Design of anticancer prodrugs for reductive activation. Med. Res. Rev. 2008, 29, 29–64.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI Google Scholar
[32]

Vander Heiden, M. G. Targeting cancer metabolism: A therapeutic window opens. Nat. Rev. Drug Discov. 2011, 10, 671–684.
DOI 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.
DOI
[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.
DOI 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.
DOI 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.
DOI 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.
DOI Google Scholar
File
6534_ESM.pdf (2.2 MB)
Publication history
Copyright
Acknowledgements

Publication history

Received: 19 December 2023
Revised: 29 January 2024
Accepted: 31 January 2024
Published: 13 March 2024

Copyright

© Tsinghua University Press 2024

Acknowledgements

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).

Return