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

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.

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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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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