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Combination of tumour-infarction therapy and chemotherapy via the co-delivery of doxorubicin and thrombin encapsulated in tumour-targeted nanoparticles

Nature Biomedical Engineering volume 4, pages 732–742 (2020)Cite this article

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Abstract

Drugs that induce thrombosis in the tumour vasculature have not resulted in long-term tumour eradication owing to tumour regrowth from tissue in the surviving rim of the tumour, where tumour cells can derive nutrients from adjacent non-tumoral blood vessels and tissues. Here, we report the performance of a combination of tumour-infarction therapy and chemotherapy, delivered via chitosan-based nanoparticles decorated with a tumour-homing peptide targeting fibrin–fibronectin complexes overexpressed on tumour-vessel walls and in tumour stroma, and encapsulating the coagulation-inducing protease thrombin and the chemotherapeutic doxorubicin. Systemic administration of the nanoparticles into mice and rabbits bearing subcutaneous or orthotopic tumours resulted in higher tumour growth suppression and decreased tumour recurrence than nanoparticles delivering only thrombin or doxorubicin, with histological and haematological analyses indicating an absence of detectable toxicity. The co-administration of a cytotoxic payload and a protease to elicit vascular infarction in tumours with biodegradable tumour-targeted nanoparticles represents a promising strategy for improving the therapeutic index of coagulation-based tumour therapy.

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Fig. 1: Design and characterization of NPs containing thrombin and Dox.
Fig. 2: In vivo tumour targeting and biodistribution.
Fig. 3: Plasma pharmacokinetics and tissue biodistribution.
Fig. 4: Th-Dox-NPs-induced thrombosis and tumour-cell apoptosis.
Fig. 5: Antitumour activity of Th-NPs and Th-Dox-NPs, and improvement of therapeutic effect with the addition of Dox to Th-NPs.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared but are available for research purposes from the corresponding authors on reasonable request.

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Acknowledgements

This work was supported by grants from the National Key R&D Program of China (grant nos. 2018YFA0208900 and 2018YFE0205300), the Strategic Priority Research Program of Chinese Academy of Sciences (grant no. XDB36000000), National Natural Science Foundation of China (grant nos. 31730032, 31820103004, 31728007, 81871489 and 91859118), K.C. Wong Education Foundation (grant no. GJTD-2018-03) and the National Postdoctoral Program for Innovative Talents (grant no. BX20180083).

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Author notes

  1. These authors contributed equally: Suping Li, Yinlong Zhang.

Authors and Affiliations

  1. CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China

    Suping Li, Yinlong Zhang, Bozhao Li, Meifang Wang, Xiongwei Deng, Na Yang, Guangna Liu, Zefang Lu, Junchao Xu, Quanwei Shi, Yan Wu, Yuliang Zhao & Guangjun Nie

  2. Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, China

    Suping Li, Yinlong Zhang, Zefang Lu, Junchao Xu, Quanwei Shi, Yan Wu, Yuliang Zhao & Guangjun Nie

  3. State Key Laboratory of Urban Water Resource and Environment, School of Environment, Harbin Institute of Technology, Harbin, China

    Shih-Hsin Ho

  4. Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China

    Jing-Yan Han

  5. Academy of Medical Science, Zhengzhou University, Zhengzhou, China

    Lirong Zhang

  6. GBA Research Innovation Institute for Nanotechnology, Guangdong, China

    Yuliang Zhao & Guangjun Nie

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  1. Suping Li
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Contributions

S.L., Y.W., Y.Zhao and G.N. conceived and designed the experiments. S.L., Y.Zhang, B.L., M.W., X.D., N.Y., G.L., Z.L. and J.X. performed the experiments. S.L., Y.Zhang, Y.W., Y.Zhao and G.N. analysed the data and supervised the project. S.L., Y.W., Y.Zhao and G.N. wrote the manuscript and all authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Yan Wu, Yuliang Zhao or Guangjun Nie.

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Li, S., Zhang, Y., Ho, SH. et al. Combination of tumour-infarction therapy and chemotherapy via the co-delivery of doxorubicin and thrombin encapsulated in tumour-targeted nanoparticles. Nat Biomed Eng 4, 732–742 (2020). https://doi.org/10.1038/s41551-020-0573-2

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