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

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.

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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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 or 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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