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Nanoparticle-mediated local depletion of tumour-associated platelets disrupts vascular barriers and augments drug accumulation in tumours

An Author Correction to this article was published on 02 August 2017

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Abstract

Limited intratumoural perfusion and nanoparticle retention remain major bottlenecks for the delivery of nanoparticle therapeutics into tumours. Here, we show that polymer–lipid–peptide nanoparticles delivering the antiplatelet antibody R300 and the chemotherapeutic agent doxorubicin can locally deplete tumour-associated platelets, thereby enhancing vascular permeability and augmenting the accumulation of the nanoparticles in tumours. R300 is specifically released in the tumour on cleavage of the lipid–peptide shell of the nanoparticles by matrix metalloprotease 2, which is commonly overexpressed in tumour vascular endothelia and stroma, thus facilitating vascular breaches that enhance tumour permeability. We also show that this strategy leads to substantial tumour regression and metastasis inhibition in mice.

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Fig. 1: Design features and proposed mechanism of action of PLP–D–R in tumour blood vessels in vivo.
Fig. 2: Characterization of nanoparticles.
Fig. 3: PLP–D–R responsiveness to MMP2 in vitro.
Fig. 4: In vivo tumour targeting and pharmacokinetics of PLP–D–R.
Fig. 5: PLP–D–R administration enhances tumour vascular permeability by depleting intratumoural platelets.
Fig. 6: PLP–D–R administration induces disruptions of the tumour vascular endothelium.
Fig. 7: Antitumour activity of PLP–D–R nanoparticles.

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Change history

  • 02 August 2017

    In the version of the Supplementary Information originally published, in Supplementary Fig. 8a, in the bottom row, the left-most image (‘Control’) was not the correct image; this has now been replaced.

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Acknowledgements

The authors thank the cyclotron teams from the Department of Nuclear Medicine, Peking University Cancer Hospital and Institute for the 64Cu production. This work was supported by grants from the National Basic Research Plan of China (2016YFA0201600 and 2013CB932701), National Distinguished Young Scientist Program (31325010), Innovation Group of the National Natural Science Foundation of China (11621505), National Natural Science Foundation of China (31200752, 31661130152, 31470969, 21373067 and 51673051), Frontier Research Program of the Chinese Academy of Sciences (QYZDJ-SSW-SLH022), Beijing Municipal Science and Technology Commission (Z161100000116035), Beijing Nova Program (Z171100001117010), Beijing Natural Science Foundation (7172164) and Youth Innovation Promotion Association of the Chinese Academy of Sciences (2017056).

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S.Li, Y.Zhang and G.N. conceived and designed the experiments. J.Wang, S.Li, Y.Zhang, Y.Zhao, T.J., F.L., Xiao Zhao, X.Y., S.Liu and J.L. performed the experiments. S.Li, Y.Zhang, J.Wang, Y.Zhao, Y.D., Xiaozheng Zhao, R.Z. and G.N. collected and analysed the data. A.K.W., G.J.A., J.Wei and Z.L. provided suggestions and technical support on the project and revised the manuscript. G.N. supervised the project. S.Li, J.Wang, Y.Zhang, Y.Zhao and G.N. wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Guangjun Nie.

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Corrected online: Author correction 2 August 2017

A correction to this article is available online at https://doi.org/10.1038/s41551-017-0125-6.

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Li, S., Zhang, Y., Wang, J. et al. Nanoparticle-mediated local depletion of tumour-associated platelets disrupts vascular barriers and augments drug accumulation in tumours. Nat Biomed Eng 1, 667–679 (2017). https://doi.org/10.1038/s41551-017-0115-8

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