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Protein adsorption is required for stealth effect of poly(ethylene glycol)- and poly(phosphoester)-coated nanocarriers

Nature Nanotechnology volume 11, pages 372–377 (2016)Cite this article

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Abstract

The current gold standard to reduce non-specific cellular uptake of drug delivery vehicles is by covalent attachment of poly(ethylene glycol) (PEG). It is thought that PEG can reduce protein adsorption and thereby confer a stealth effect. Here, we show that polystyrene nanocarriers that have been modified with PEG or poly(ethyl ethylene phosphate) (PEEP) and exposed to plasma proteins exhibit a low cellular uptake, whereas those not exposed to plasma proteins show high non-specific uptake. Mass spectrometric analysis revealed that exposed nanocarriers formed a protein corona that contains an abundance of clusterin proteins (also known as apolipoprotein J). When the polymer-modified nanocarriers were incubated with clusterin, non-specific cellular uptake could be reduced. Our results show that in addition to reducing protein adsorption, PEG, and now PEEPs, can affect the composition of the protein corona that forms around nanocarriers, and the presence of distinct proteins is necessary to prevent non-specific cellular uptake.

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Figure 1: Characteristics of nanocarriers.
Figure 2: Cellular uptake of PEEP and PEG nanocarriers.
Figure 3: Proteomic analysis of protein corona on the surface of nanocarriers.
Figure 4: Clusterin reduces non-specific cellular uptake.

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Acknowledgements

T.S. and F.R.W. acknowledge support from the Max Planck Graduate Center (MPGC). G.B. and T.S. acknowledge support from the Graduate School of Excellence ‘MAINZ’ (Materials Science in Mainz). This work was supported by the DFG/SFB1066 (‘Nanodimensionale polymere Therapeutika für die Tumortherapie’, Q1 and Q2). F.R.W. thanks the DFG WU 750/6-1 for funding.

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Author notes

  1. Volker Mailänder and Frederik R. Wurm: These authors jointly supervised this work

Authors and Affiliations

  1. Max Planck Institute for Polymer Research, Ackermannweg 10, Mainz, 55128, Germany

    Susanne Schöttler, Greta Becker, Svenja Winzen, Tobias Steinbach, Kristin Mohr, Katharina Landfester, Volker Mailänder & Frederik R. Wurm

  2. Department of Dermatology, Johannes Gutenberg University Mainz, University Medical Center, Langenbeckstr. 1, Mainz, 55131, Germany

    Susanne Schöttler & Volker Mailänder

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Contributions

F.R.W., V.M. and K.L. supervised the project. F.R.W., V.M., S.S. and G.B. conceived and designed the experiments. G.B. and T.S. synthesized the polymers and nanoparticles. S.S. performed the cell experiments and proteomic analysis. S.W. and K.M. performed the isothermal titration calorimetry measurements. F.R.W. and S.S. wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Volker Mailänder or Frederik R. Wurm.

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Schöttler, S., Becker, G., Winzen, S. et al. Protein adsorption is required for stealth effect of poly(ethylene glycol)- and poly(phosphoester)-coated nanocarriers. Nature Nanotech 11, 372–377 (2016). https://doi.org/10.1038/nnano.2015.330

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