Nanoparticles promote in vivo breast cancer cell intravasation and extravasation by inducing endothelial leakiness

Nature Nanotechnology volume 14, pages279–286(2019)Cite this article

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Abstract

While most cancer nanomedicine is designed to eliminate cancer, the nanomaterial per se can lead to the formation of micrometre-sized gaps in the blood vessel endothelial walls. Nanomaterials-induced endothelial leakiness (NanoEL) might favour intravasation of surviving cancer cells into the surrounding vasculature and subsequently extravasation, accelerating metastasis. Here, we show that nanoparticles induce endothelial leakiness through disruption of the VE-cadherin–VE-cadherin homophilic interactions at the adherens junction. We show that intravenously injected titanium dioxide, silica and gold nanoparticles significantly accelerate both intravasation and extravasation of breast cancer cells in animal models, increasing the extent of existing metastasis and promoting the appearance of new metastatic sites. Our results add to the understanding of the behaviour of nanoparticles in complex biological systems. The potential for NanoEL needs to be taken into consideration when designing future nanomedicines, especially nanomedicine to treat cancer.

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Fig. 1: TiO2 NPs may promote in vivo intravasation and extravasation of breast cancer cells by disrupting the blood vessel barrier.
Fig. 2: TiO2 NPs disrupted endothelial cell barrier integrity.
Fig. 3: Breast cancer cells exploited increased endothelial permeability arising from NanoEL.
Fig. 4: TiO2 NPs promote the intravasation of breast cancer cells in subcutaneous MDA-MB-231-Luc xenograft female NSG mice.
Fig. 5: TiO2 NPs facilitate the extravasation of circulating breast cancer cells in female NSG mice.
Fig. 6: TiO2 NP-induced vessel leakiness may have led to increased extravasation and subsequently higher tumour load in the liver and lungs in a TiO2 NP dose-dependent manner.

Data availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

This work was supported by Ministry of Education Academic Research Grants (R-279–000–418–112, R-279-000-498-114 and R148–000–217–112).

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Author notes

  1. These authors contributed equally: Fei Peng, Magdiel Inggrid Setyawati, Jie Kai Tee.

Affiliations

  1. Department of Chemical and Biomolecular Engineering, Faculty of Engineering, National University of Singapore, Singapore, Singapore

    Fei Peng, Magdiel Inggrid Setyawati, Jie Kai Tee, Xianguang Ding, Jinping Wang & David Tai Leong

  2. Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore

    Fei Peng, Jie Kai Tee & Han Kiat Ho

  3. NUS Graduate School for Integrative Sciences & Engineering, Singapore, Singapore

    Jie Kai Tee, Han Kiat Ho & David Tai Leong

  4. Department of Pathology, National University Hospital and National University of Singapore, Singapore, Singapore

    Min En Nga

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  1. Fei Peng
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Contributions

D.T.L. and H.K.H. conceived the hypotheses, designed the experiments, performed the analysis and interpretations, and wrote the paper. F.P., M.I.S. and J.K.T. designed and performed the experiments, analysed the results and wrote the paper. X.D. and J.P.W. performed the experiments. M.E.N. analysed the results.

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Correspondence to Han Kiat Ho or David Tai Leong.

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Peng, F., Setyawati, M.I., Tee, J.K. et al. Nanoparticles promote in vivo breast cancer cell intravasation and extravasation by inducing endothelial leakiness. Nat. Nanotechnol. 14, 279–286 (2019). https://doi.org/10.1038/s41565-018-0356-z

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