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Surface-structure-regulated cell-membrane penetration by monolayer-protected nanoparticles

Nature Materials volume 7, pages 588–595 (2008)Cite this article

A Corrigendum to this article was published on 20 March 2013

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Abstract

Nanoscale objects are typically internalized by cells into membrane-bounded endosomes and fail to access the cytosolic cell machinery. Whereas some biomacromolecules may penetrate or fuse with cell membranes without overt membrane disruption, no synthetic material of comparable size has shown this property yet. Cationic nano-objects pass through cell membranes by generating transient holes, a process associated with cytotoxicity. Studies aimed at generating cell-penetrating nanomaterials have focused on the effect of size, shape and composition. Here, we compare membrane penetration by two nanoparticle ‘isomers’ with similar composition (same hydrophobic content), one coated with subnanometre striations of alternating anionic and hydrophobic groups, and the other coated with the same moieties but in a random distribution. We show that the former particles penetrate the plasma membrane without bilayer disruption, whereas the latter are mostly trapped in endosomes. Our results offer a paradigm for analysing the fundamental problem of cell-membrane-penetrating bio- and macro-molecules.

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Figure 1: Nanoparticles with ordered arrangements of hydrophilic and hydrophobic surface functional groups exhibit altered patterns of subcellular localization in cells.
Figure 2: ‘Striped’ nanoparticles enter cells at 37 ∘C under conditions where active internalization processes are blocked.
Figure 3: Nanoparticles with sulphonate-only or disordered sulphonate/methyl-group surfaces are largely confined to endosomal compartments, whereas ‘striped’ sulphonate/methyl-group-bearing nanoparticles enter the cytosol.
Figure 4: ‘Striped’ particles visualized at different stages of crossing the cell membrane of dendritic cells.
Figure 5: ‘Striped’ nanoparticles penetrate cell membranes without generating transient holes, in contrast with the known behaviour of cationic nanoparticles.

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  • 28 February 2013

    In the version of this Article originally published, in the caption for Fig. 1 the following statement should have been included "Right-hand STM image in panel a reproduced with permission from ref. 30, © 2008 RSC." This error has been corrected in the PDF and HTML versions of the Article.

References

  1. Weissleder, R. Molecular imaging in cancer. Science 312, 1168–1171 (2006).

    Article  CAS  Google Scholar 

  2. Somers, R. C., Bawendi, M. G. & Nocera, D. G. CdSe nanocrystal based chem-/bio-sensors. Chem. Soc. Rev. 36, 579–591 (2007).

    Article  CAS  Google Scholar 

  3. Lewin, M. et al. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nature Biotechnol. 18, 410–414 (2000).

    Article  CAS  Google Scholar 

  4. West, J. L. & Halas, N. J. Engineered nanomaterials for biophotonics applications: Improving sensing, imaging, and therapeutics. Annu. Rev. Biomed. Eng. 5, 285–292 (2003).

    Article  CAS  Google Scholar 

  5. El-Sayed, I. H., Huang, X. H. & El-Sayed, M. A. Selective laser photo-thermal therapy of epithelial carcinoma using anti-EGFR antibody conjugated gold nanoparticles. Cancer Lett. 239, 129–135 (2006).

    Article  CAS  Google Scholar 

  6. Rosi, N. L. et al. Oligonucleotide-modified gold nanoparticles for intracellular gene regulation. Science 312, 1027–1030 (2006).

    Article  CAS  Google Scholar 

  7. Han, G. et al. Light-regulated release of DNA and its delivery to nuclei by means of photolabile gold nanoparticles. Angew. Chem. Int. Ed. 45, 3165–3169 (2006).

    Article  CAS  Google Scholar 

  8. Allen, T. M. & Cullis, P. R. Drug delivery systems: Entering the mainstream. Science 303, 1818–1822 (2004).

    Article  CAS  Google Scholar 

  9. Choleris, E. et al. Microparticle-based delivery of oxytocin receptor antisense DNA in the medial amygdala blocks social recognition in female mice. Proc. Natl Acad. Sci. USA 104, 4670–4675 (2007).

    Article  CAS  Google Scholar 

  10. Leroueil, P. R. et al. Nanoparticle interaction with biological membranes: Does nanotechnology present a janus face? Acc. Chem. Res. 40, 335–342 (2007).

    Article  CAS  Google Scholar 

  11. Zorko, M. & Langel, U. Cell-penetrating peptides: mechanism and kinetics of cargo delivery. Adv. Drug Deliv. Rev. 57, 529–545 (2005).

    Article  CAS  Google Scholar 

  12. Herbig, M. E., Assi, F., Textor, M. & Merkle, H. P. The cell penetrating peptides pVEC and W2-pVEC induce transformation of gel phase domains in phospholipid bilayers without affecting their integrity. Biochemistry 45, 3598–3609 (2006).

    Article  CAS  Google Scholar 

  13. Takeuchi, T. et al. Direct and rapid cytosolic delivery using cell-penetrating peptides mediated by pyrenebutyrate. ACS Chem. Biol. 1, 299–303 (2006).

    Article  CAS  Google Scholar 

  14. Thoren, P. E. G. et al. Uptake of analogs of penetratin, Tat(48-60) and oligoarginine in live cells. Biochem. Biophys. Res. Commun. 307, 100–107 (2003).

    Article  CAS  Google Scholar 

  15. Patel, L. N., Zaro, J. L. & Shen, W. C. Cell penetrating peptides: Intracellular pathways and pharmaceutical perspectives. Pharm. Res. 24, 1977–1992 (2007).

    Article  CAS  Google Scholar 

  16. Yu, J., Patel, S. A. & Dickson, R. M. In vitro and intracellular production of peptide-encapsulated fluorescent silver nanoclusters. Angew. Chem. Int. Ed. 46, 2028–2030 (2007).

    Article  CAS  Google Scholar 

  17. Kostarelos, K. et al. Cellular uptake of functionalized carbon nanotubes is independent of functional group and cell type. Nature Nanotechnol. 2, 108–113 (2007).

    Article  CAS  Google Scholar 

  18. Lovric, J. et al. Differences in subcellular distribution and toxicity of green and red emitting CdTe quantum dots. J. Mol. Med. 83, 377–385 (2005).

    Article  Google Scholar 

  19. Hu, Y. et al. Cytosolic delivery of membrane-impermeable molecules in dendritic cells using pH-responsive core–shell nanoparticles. Nano Lett. 7, 3056–3064 (2007).

    Article  CAS  Google Scholar 

  20. Tkachenko, A. G. et al. Multifunctional gold nanoparticle-peptide complexes for nuclear targeting. J. Am. Chem. Soc. 125, 4700–4701 (2003).

    Article  CAS  Google Scholar 

  21. Shukla, R. et al. Biocompatibility of gold nanoparticles and their endocytotic fate inside the cellular compartment: A microscopic overview. Langmuir 21, 10644–10654 (2005).

    Article  CAS  Google Scholar 

  22. Colvin, V. Correlating the physical and chemical properties of nanoparticles to their biological activity. Environ. Mol. Mutagen. 48, 533–533 (2007).

    Google Scholar 

  23. Jackson, A. M., Myerson, J. W. & Stellacci, F. Spontaneous assembly of subnanometre-ordered domains in the ligand shell of monolayer-protected nanoparticles. Nature Mater. 3, 330–336 (2004).

    Article  CAS  Google Scholar 

  24. Jackson, A. M., Hu, Y., Silva, P. J. & Stellacci, F. From homoligand- to mixed-ligand-monolayer-protected metal nanoparticles: A scanning tunneling microscopy investigation. J. Am. Chem. Soc. 128, 11135–11149 (2006).

    Article  CAS  Google Scholar 

  25. DeVries, G. A. et al. Divalent metal nanoparticles. Science 315, 358–361 (2007).

    Article  CAS  Google Scholar 

  26. Daniel, M. C. & Astruc, D. Gold nanoparticles: Assembly, supramolecular chemistry, quantum-size-related properties, and applications toward biology, catalysis, and nanotechnology. Chem. Rev. 104, 293–346 (2004).

    Article  CAS  Google Scholar 

  27. Manea, F., Houillon, F. B., Pasquato, L. & Scrimin, P. Nanozymes: Gold-nanoparticle-based transphosphorylation catalysts. Angew. Chem. Int. Ed. 43, 6165–6169 (2004).

    Article  CAS  Google Scholar 

  28. Kisailus, D., Najarian, M., Weaver, J. C. & Morse, D. E. Functionalized gold nanoparticles mimic catalytic activity of a polysiloxane-synthesizing enzyme. Adv. Mater. 17, 1234 (2005).

    Article  CAS  Google Scholar 

  29. Templeton, A. C., Wuelfing, M. P. & Murray, R. W. Monolayer protected cluster molecules. Acc. Chem. Res. 33, 27–36 (2000).

    Article  CAS  Google Scholar 

  30. Uzun, O. et al. Water-soluble amphiphilic gold nanoparticles with structured ligand shells. Chem. Commun. 196–198 (2008).

  31. Kang, S. Y. & Kim, K. Comparative study of dodecanethiol-derivatized silver nanoparticles prepared in one-phase and two-phase systems. Langmuir 14, 226–230 (1998).

    Article  CAS  Google Scholar 

  32. Tan, H., Zhan, T. & Fan, W. Y. Direct functionalization of the hydroxyl group of the 6-mercapto-1-hexanol (MCH) ligand attached to gold nanoclusters. J. Phys. Chem. B 110, 21690–21693 (2006).

    Article  CAS  Google Scholar 

  33. Shen, Z. H., Reznikoff, G., Dranoff, G. & Rock, K. L. Cloned dendritic cells can present exogenous antigens on both MHC class I and class II molecules. J. Immunol. 158, 2723–2730 (1997).

    CAS  Google Scholar 

  34. Richard, J. P. et al. Cell-penetrating peptides—A reevaluation of the mechanism of cellular uptake. J. Biol. Chem. 278, 585–590 (2003).

    Article  CAS  Google Scholar 

  35. Parak, W. J. et al. Cell motility and metastatic potential studies based on quantum dot imaging of phagokinetic tracks. Adv. Mater. 14, 882–885 (2002).

    Article  CAS  Google Scholar 

  36. Wilhelm, C., Gazeau, F., Roger, J., Pons, J. N. & Bacri, J. C. Interaction of anionic superparamagnetic nanoparticles with cells: Kinetic analyses of membrane adsorption and subsequent internalization. Langmuir 18, 8148–8155 (2002).

    Article  CAS  Google Scholar 

  37. Verma, A., Simard, J. M., Worrall, J. W. E. & Rotello, V. M. Tunable reactivation of nanoparticle-inhibited beta-galactosidase by glutathione at intracellular concentrations. J. Am. Chem. Soc. 126, 13987–13991 (2004).

    Article  CAS  Google Scholar 

  38. Meister, A. & Anderson, M. E. Glutathione. Annu. Rev. Biochem. 52, 711–760 (1983).

    Article  CAS  Google Scholar 

  39. Hong, R. et al. Glutathione-mediated delivery and release using monolayer protected nanoparticle carriers. J. Am. Chem. Soc. 128, 1078–1079 (2006).

    Article  CAS  Google Scholar 

  40. Cedervall, T. et al. Detailed identification of plasma proteins adsorbed on copolymer nanoparticles. Angew. Chem. Int. Ed. 46, 5754–5756 (2007).

    Article  CAS  Google Scholar 

  41. Hong, S. P. et al. Interaction of polycationic polymers with supported lipid bilayers and cells: Nanoscale hole formation and enhanced membrane permeability. Bioconjug. Chem. 17, 728–734 (2006).

    Article  CAS  Google Scholar 

  42. Hong, S. P. et al. Interaction of poly(amidoamine) dendrimers with supported lipid bilayers and cells: Hole formation and the relation to transport. Bioconjug. Chem. 15, 774–782 (2004).

    Article  CAS  Google Scholar 

  43. Zhang, L. J., Rozek, A. & Hancock, R. E. W. Interaction of cationic antimicrobial peptides with model membranes. J. Biol. Chem. 276, 35714–35722 (2001).

    Article  CAS  Google Scholar 

  44. Nel, A., Xia, T., Madler, L. & Li, N. Toxic potential of materials at the nanolevel. Science 311, 622–627 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Science Foundation (CAREER Award) and the NHLBI TPEN program (U01-HL080731). F.S. is grateful to the Packard Foundation for their generous award.

This paper is dedicated to A. Mayes in recognition of the mentor role she had for both corresponding authors.

Author information

Authors and Affiliations

  1. Department of Materials Science and Engineering, MIT, Massachusetts 02139, USA

    Ayush Verma, Oktay Uzun, Ying Hu, Suelin Chen, Darrell J. Irvine & Francesco Stellacci

  2. Department of Chemical Engineering, MIT, Massachusetts 02139, USA

    Yuhua Hu

  3. Department of Chemistry, MIT, Massachusetts 02139, USA

    Hee-Sun Han

  4. Department of Biology, MIT, Massachusetts 02139, USA

    Nicki Watson

  5. Department of Biological Engineering, MIT, Massachusetts 02139, USA

    Darrell J. Irvine

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  1. Ayush Verma
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Contributions

D.J.I. and F.S. conceived the research question. A.V., O.U., D.J.I. and F.S. designed the experiments and analysed all of the data. The biological experiments were carried out by A.V. and Yu.H.; TEM experiments were carried out by A.V. and N.W., STM by Yi.H. and S.C., nanoparticle synthesis and characterization by O.U. and H.S.H. The paper was written by A.V., O.U., D.J.I. and F.S.

Corresponding authors

Correspondence to Darrell J. Irvine or Francesco Stellacci.

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Supplementary Figures S1–S15 and Supplementary Table 1 (PDF 878 kb)

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Verma, A., Uzun, O., Hu, Y. et al. Surface-structure-regulated cell-membrane penetration by monolayer-protected nanoparticles. Nature Mater 7, 588–595 (2008). https://doi.org/10.1038/nmat2202

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