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Delivery of nitric oxide with a nanocarrier promotes tumour vessel normalization and potentiates anti-cancer therapies

Nature Nanotechnology volume 14, pages 1160–1169 (2019)Cite this article

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Abstract

Abnormal tumour vasculature has a significant impact on tumour progression and response to therapy. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis and, thus, can be delivered to normalize tumour vasculature. However, a NO-delivery system with a prolonged half-life and a sustained release mechanism is currently lacking. Here we report the development of NanoNO, a nanoscale carrier that enables sustained NO release to efficiently deliver NO into hepatocellular carcinoma. Low-dose NanoNO normalizes tumour vessels and improves the delivery and effectiveness of chemotherapeutics and tumour necrosis factor-related, apoptosis-inducing, ligand-based therapy in both primary tumours and metastases. Furthermore, low-dose NanoNO reprogrammes the immunosuppressive tumour microenvironment toward an immunostimulatory phenotype, thereby improving the efficacy of cancer vaccine immunotherapy. Our findings demonstrate the ability of nanoscale NO delivery to efficiently reprogramme tumour vasculature and immune microenvironments to overcome resistance to cancer therapy, resulting in a therapeutic benefit.

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Fig. 1: Schematic showing the mechanism by which NanoNO suppresses HCC progression in mice.
Fig. 2: NanoNO accumulates in tumours, releases NO and mediates anti-tumour effects.
Fig. 3: Low-dose NanoNO normalizes tumour vasculature in HCC.
Fig. 4: Low-dose NanoNO improves drug delivery efficiency and enhances anti-cancer efficacy.
Fig. 5: Low-dose NanoNO reprogrammes immunosuppressive TAMs towards an immunostimulatory phenotype, increases tumour-infiltrating T cells and achieves synergistic anti-cancer effects when combined with a vaccine in orthotopic HCC models.
Fig. 6: Low-dose NanoNO modulates TME in metastatic lesions and suppresses metastatic progression of HCC.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information. All relevant data are available from the authors upon reasonable request.

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Acknowledgements

This study was supported by the Ministry of Science and Technology (nos. 104-2628-B-007-001-MY3, 105-2628-E-007-007-MY3, 108-2321-B-009-004 and 108-2221-E-007-104-MY5 to Y.C. and 103-2632-M-033-001-MY3, 104-2113-M-033-005-MY2, 106-2113-M-007-028-MY2 and 106-2113-M-033-009-MY2 to T.-T.L.); by the Chang Gung Memorial Hospital-National Tsinghua University Joint Research Grant (no. 108Q2508E1); by the National Health Research Institutes (no. NHRI-EX108-10609BC); by the ‘Frontier Research Center on Fundamental and Applied Sciences of Matters’ from the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (no. 108QR001I5); and by the Ministry of Science and Technology (no. 108-3017-F-007-003). We are also grateful to H.-Y. Tang at College of Biomedical Science and Engineering Center, NTHU for assistance with flow cytometry and confocal laser microscopy and to C.-Y.S. Lai for assistance with pharmacokinetics analysis. We thank the National Laboratory Animal Center, NARLabs, Taiwan for technical support with measurement of blood pressure in mice. We acknowledge Prof. C.-H. Hung, W.-M. Ching, and K.-J. Hsing at the Institute of Chemistry, Academia Sinica and Instrumentation Center, National Taiwan Normal University for EPR measurements.

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Authors and Affiliations

  1. Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan

    Yun-Chieh Sung, Pei-Ru Jin, Chih-Chun Chang, Dong-Yu Gao, John Jun-Sheng Ko, Tsai-Te Lu & Yunching Chen

  2. Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan

    Yun-Chieh Sung & Jane Wang

  3. Brain Research Center, National Tsing Hua University, Hsinchu, Taiwan

    Li-An Chu & Ann-Shyn Chiang

  4. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    Fu-Fei Hsu

  5. Department of Chemistry, Chung Yuan Christian University, Taoyuan, Taiwan

    Mei-Ren Wang & Tsai-Te Lu

  6. Department of Applied Chemistry, National Chiayi University, Chiayi, Taiwan

    Show-Jen Chiou

  7. School of Medicine, Chang Gung University, Taoyuan, Taiwan

    Jiantai Timothy Qiu

  8. Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Jiantai Timothy Qiu

  9. Department of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, Taiwan

    Jiantai Timothy Qiu, Chu-Chi Lin & Yu-Sing Chen

  10. Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan

    Yi-Chiung Hsu

  11. Department of Biomedical Engineering and Environmental Sciences, ​National Tsing Hua University, Hsinchu, Taiwan

    Fu-Nien Wang & Pei-Lun Yu

  12. Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan

    Ann-Shyn Chiang

  13. Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan

    Ann-Shyn Chiang

  14. Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan

    Ann-Shyn Chiang

  15. Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, Taiwan

    Anthony Yan-Tang Wu, John Jun-Sheng Ko & Charles Pin-Kuang Lai

  16. Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan

    Anthony Yan-Tang Wu & Charles Pin-Kuang Lai

  17. Department and Graduate Institute of Pharmacology, National Taiwan University, Taipei, Taiwan

    Anthony Yan-Tang Wu

  18. Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan

    Charles Pin-Kuang Lai

Authors
  1. Yun-Chieh Sung
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Contributions

Y.-C.S. and Y.C. conceived and designed the experiments and analysed the data. Y.-C.S., P.-R.J., F.-F.H., L.-A.C., C.-C.C., D.-Y.G., J.T.Q., C.-C.L., Y.-S.C., Y.-C.H., J.W., F.-N.W., P.-L.Y., T.-T.L. and Y.C. performed the experiments. F.-F.H., M.-R.W., S.-J.C., J.T.Q., C.-C.L., Y.-S.C., A.-S.C., A.Y-.T.W., J.J.-S.K., C.P.-K.L. and T.-T.L. contributed materials and analysis tools. Y.-C.S., T.-T.L. and Y.C. co-wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Tsai-Te Lu or Yunching Chen.

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Sung, YC., Jin, PR., Chu, LA. et al. Delivery of nitric oxide with a nanocarrier promotes tumour vessel normalization and potentiates anti-cancer therapies. Nat. Nanotechnol. 14, 1160–1169 (2019). https://doi.org/10.1038/s41565-019-0570-3

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