Skip to main content
Log in

Short-chained oligo(ethylene oxide)-functionalized gold nanoparticles: realization of significant protein resistance

  • Research Paper
  • Published:
Analytical and Bioanalytical Chemistry Aims and scope Submit manuscript

Abstract

Protein corona formed on nanomaterial surfaces play an important role in the bioavailability and cellular uptake of nanomaterials. Modification of surfaces with oligoethylene glycols (OEG) are a common way to improve the resistivity of nanomaterials to protein adsorption. Short-chain ethylene oxide (EO) oligomers have been shown to improve the protein resistance of planar Au surfaces. We describe the application of these EO oligomers for improved protein resistance of 30 nm spherical gold nanoparticles (AuNPs). Functionalized AuNPs were characterized using UV-Vis spectroscopy, dynamic light scattering (DLS), and zeta potential measurements. Capillary electrophoresis (CE) was used for separation and quantitation of AuNPs and AuNP-protein mixtures. Specifically, nonequilibrium capillary electrophoresis of equilibrium mixtures (NECEEM) was employed for the determination of equilibrium and rate constants for binding between citrate-stabilized AuNPs and two model proteins, lysozyme and fibrinogen. Semi-quantitative CE analysis was carried out for mixtures of EO-functionalized AuNPs and proteins, and results demonstrated a 2.5-fold to 10-fold increase in protein binding resistance to lysozyme depending on the AuNP surface functionalization and a 15-fold increase in protein binding resistance to fibrinogen for both EO oligomers examined in this study.

Using capillary electrophoresis, the addition of short-chained oligo(ethylene oxide) ligands to gold nanoparticles was shown to improve protein binding resistance up to 15-fold.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Notes

  1. Certain commercial equipment, instruments, and materials are identified in this paper to specify an experimental procedure as completely as possible. In no case does the identification of particular equipment or materials imply a recommendation or endorsement by the National Institute of Standards and Technology nor does it imply that the materials, instruments, or equipment are necessarily the best available for the purpose.

References

  1. Daniel MC, Astruc D. Gold nanoparticles: assembly, supramolecular chemistry, quantum-size-related properties, and applications toward biology, catalysis, and nanotechnology. Chem Rev. 2004;104(1):293–346. https://doi.org/10.1021/cr030698+.

    Article  CAS  Google Scholar 

  2. Eustis S, el-Sayed MA. Why gold nanoparticles are more precious than pretty gold: noble metal surface plasmon resonance and its enhancement of the radiative and nonradiative properties of nanocrystals of different shapes. Chem Soc Rev. 2006;35(3):209–17. https://doi.org/10.1039/b514191e.

    Article  CAS  Google Scholar 

  3. Han G, Ghosh P, Rotello VM. Functionalized gold nanoparticles for drug delivery. Nanomedicine (Lond). 2007;2(1):113–23. https://doi.org/10.2217/17435889.2.1.113.

    Article  CAS  Google Scholar 

  4. Giljohann DA, Seferos DS, Daniel WL, Massich MD, Patel PC, Mirkin CA. Gold nanoparticles for biology and medicine. Angew Chem Int Ed Engl. 2010;49(19):3280–94. https://doi.org/10.1002/anie.200904359.

    Article  CAS  Google Scholar 

  5. Murphy CJ, Gole AM, Stone JW, Sisco PN, Alkilany AM, Goldsmith EC, et al. Gold nanoparticles in biology: beyond toxicity to cellular imaging. Acc Chem Res. 2008;41(12):1721–30. https://doi.org/10.1021/ar800035u.

    Article  CAS  Google Scholar 

  6. Jain PK, Huang X, El-Sayed IH, El-Sayed MA. Noble metals on the nanoscale: optical and photothermal properties and some applications in imaging, sensing, biology, and medicine. Acc Chem Res. 2008;41(12):1578–86. https://doi.org/10.1021/ar7002804.

    Article  CAS  Google Scholar 

  7. Dreaden EC, Alkilany AM, Huang X, Murphy CJ, El-Sayed MA. The golden age: gold nanoparticles for biomedicine. Chem Soc Rev. 2012;41(7):2740–79. https://doi.org/10.1039/C1CS15237H.

    Article  CAS  Google Scholar 

  8. Klein J. Probing the interactions of proteins and nanoparticles. Proc Natl Acad Sci U S A. 2007;104(7):2029–30. https://doi.org/10.1073/pnas.0611610104.

    Article  CAS  Google Scholar 

  9. Lundqvist M, Stigler J, Elia G, Lynch I, Cedervall T, Dawson KA. Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc Natl Acad Sci U S A. 2008;105(38):14265–70. https://doi.org/10.1073/pnas.0805135105.

    Article  CAS  Google Scholar 

  10. Lundqvist M, Stigler J, Cedervall T, Berggard T, Flanagan MB, Lynch I, et al. The evolution of the protein corona around nanoparticles: a test study. ACS Nano. 2011;5(9):7503–9. https://doi.org/10.1021/nn202458g.

    Article  CAS  Google Scholar 

  11. Lynch I, Cedervall T, Lundqvist M, Cabaleiro-Lago C, Linse S, Dawson KA. The nanoparticle-protein complex as a biological entity; a complex fluids and surface science challenge for the 21st century. Adv Colloid Interf Sci. 2007;134-135:167–74. https://doi.org/10.1016/j.cis.2007.04.021.

    Article  CAS  Google Scholar 

  12. Treuel L, Nienhaus GU. Toward a molecular understanding of nanoparticle–protein interactions. Biophys Rev. 2012;4(2):137–47. https://doi.org/10.1007/s12551-012-0072-0.

    Article  CAS  Google Scholar 

  13. Monopoli MP, Walczyk D, Campbell A, Elia G, Lynch I, Bombelli FB, et al. Physical-chemical aspects of protein corona: relevance to in vitro and in vivo biological impacts of nanoparticles. J Am Chem Soc. 2011;133(8):2525–34. https://doi.org/10.1021/ja107583h.

    Article  CAS  Google Scholar 

  14. Monopoli MP, Aberg C, Salvati A, Dawson KA. Biomolecular coronas provide the biological identity of nanosized materials. Nat Nanotechnol. 2012;7(12):779–86. https://doi.org/10.1038/nnano.2012.207.

    Article  CAS  Google Scholar 

  15. Fleischer CC, Payne CK. Nanoparticle-cell interactions: molecular structure of the protein corona and cellular outcomes. Acc Chem Res. 2014;47(8):2651–9. https://doi.org/10.1021/ar500190q.

    Article  CAS  Google Scholar 

  16. Walkey CD, Olsen JB, Song F, Liu R, Guo H, Olsen DW, et al. Protein corona fingerprinting predicts the cellular interaction of gold and silver nanoparticles. ACS Nano. 2014;8(3):2439–55. https://doi.org/10.1021/nn406018q.

    Article  CAS  Google Scholar 

  17. Treuel L, Brandholt S, Maffre P, Wiegele S, Shang L, Nienhaus GU. Impact of protein modification on the protein corona on nanoparticles and nanoparticle-cell interactions. ACS Nano. 2014;8(1):503–13. https://doi.org/10.1021/nn405019v.

    Article  CAS  Google Scholar 

  18. Arvizo RR, Giri K, Moyano D, Miranda OR, Madden B, McCormick DJ, et al. Identifying new therapeutic targets via modulation of protein corona formation by engineered nanoparticles. PLoS One. 2012;7(3):e33650. https://doi.org/10.1371/journal.pone.0033650.

    Article  CAS  Google Scholar 

  19. Zheng M, Davidson F, Huang X. Ethylene glycol monolayer protected nanoparticles for eliminating nonspecific binding with biological molecules. J Am Chem Soc. 2003;125(26):7790–1. https://doi.org/10.1021/ja0350278.

    Article  CAS  Google Scholar 

  20. Zhang F, Skoda MW, Jacobs RM, Zorn S, Martin RA, Martin CM, et al. Gold nanoparticles decorated with oligo(ethylene glycol) thiols: protein resistance and colloidal stability. J Phys Chem A. 2007;111(49):12229–37. https://doi.org/10.1021/jp074293v.

    Article  CAS  Google Scholar 

  21. Deng ZJ, Liang M, Toth I, Monteiro MJ, Minchin RF. Molecular interaction of poly(acrylic acid) gold nanoparticles with human fibrinogen. ACS Nano. 2012;6(10):8962–9. https://doi.org/10.1021/nn3029953.

    Article  CAS  Google Scholar 

  22. Larson TA, Joshi PP, Sokolov K. Preventing protein adsorption and macrophage uptake of gold nanoparticles via a hydrophobic shield. ACS Nano. 2012;6(10):9182–90. https://doi.org/10.1021/nn3035155.

    Article  CAS  Google Scholar 

  23. Boulos SP, Davis TA, Yang JA, Lohse SE, Alkilany AM, Holland LA, et al. Nanoparticle-protein interactions: a thermodynamic and kinetic study of the adsorption of bovine serum albumin to gold nanoparticle surfaces. Langmuir. 2013;29(48):14984–96. https://doi.org/10.1021/la402920f.

    Article  CAS  Google Scholar 

  24. Murthy AK, Stover RJ, Hardin WG, Schramm R, Nie GD, Gourisankar S, et al. Charged gold nanoparticles with essentially zero serum protein adsorption in undiluted fetal bovine serum. J Am Chem Soc. 2013;135(21):7799–802. https://doi.org/10.1021/ja400701c.

    Article  CAS  Google Scholar 

  25. Khan S, Gupta A, Verma NC, Nandi CK. Kinetics of protein adsorption on gold nanoparticle with variable protein structure and nanoparticle size. J Chem Phys. 2015;143(16):164709. https://doi.org/10.1063/1.4934605.

    Article  CAS  Google Scholar 

  26. Pensa E, Cortes E, Corthey G, Carro P, Vericat C, Fonticelli MH, et al. The chemistry of the sulfur-gold interface: in search of a unified model. Acc Chem Res. 2012;45(8):1183–92. https://doi.org/10.1021/ar200260p.

    Article  CAS  Google Scholar 

  27. Niidome T, Yamagata M, Okamoto Y, Akiyama Y, Takahashi H, Kawano T, et al. PEG-modified gold nanorods with a stealth character for in vivo applications. J Control Release. 2006;114(3):343–7. https://doi.org/10.1016/j.jconrel.2006.06.017.

    Article  CAS  Google Scholar 

  28. Shenoy D, Fu W, Li J, Crasto C, Jones G, DiMarzio C, et al. Surface functionalization of gold nanoparticles using hetero-bifunctional poly(ethylene glycol) spacer for intracellular tracking and delivery. Int J Nanomedicine. 2006;1(1):51–7. https://doi.org/10.2147/nano.2006.1.1.51.

    Article  CAS  Google Scholar 

  29. Pelaz B, del Pino P, Maffre P, Hartmann R, Gallego M, Rivera-Fernandez S, et al. Surface functionalization of nanoparticles with polyethylene glycol: effects on protein adsorption and cellular uptake. ACS Nano. 2015;9(7):6996–7008. https://doi.org/10.1021/acsnano.5b01326.

    Article  CAS  Google Scholar 

  30. Jokerst JV, Lobovkina T, Zare RN, Gambhir SS. Nanoparticle PEGylation for imaging and therapy. Nanomedicine (Lond). 2011;6(4):715–28. https://doi.org/10.2217/nnm.11.19.

    Article  CAS  Google Scholar 

  31. Kenausis GL, Voros J, Elbert DL, Huang NP, Hofer R, Ruiz-Taylor L, et al. Poly(L-lysine)-g-poly(ethylene glycol) layers on metal oxide surfaces: attachment mechanism and effects of polymer architecture on resistance to protein adsorption. J Phys Chem B. 2000;104(14):3298–309. https://doi.org/10.1021/jp993359m.

    Article  CAS  Google Scholar 

  32. Zheng M, Li Z, Huang X. Ethylene glycol monolayer protected nanoparticles: synthesis, characterization, and interactions with biological molecules. Langmuir. 2004;20(10):4226–35. https://doi.org/10.1021/la035981i.

    Article  CAS  Google Scholar 

  33. Zhang F, Dressen DG, Skoda MW, Jacobs RM, Zorn S, Martin RA, et al. Gold nanoparticles decorated with oligo(ethylene glycol) thiols: kinetics of colloid aggregation driven by depletion forces. Eur Biophys J. 2008;37(5):551–61. https://doi.org/10.1007/s00249-007-0255-y.

    Article  Google Scholar 

  34. Schollbach M, Zhang F, Roosen-Runge F, Skoda MW, Jacobs RM, Schreiber F. Gold nanoparticles decorated with oligo(ethylene glycol) thiols: surface charges and interactions with proteins in solution. J Colloid Interface Sci. 2014;426:31–8. https://doi.org/10.1016/j.jcis.2014.03.052.

    Article  CAS  Google Scholar 

  35. Vanderah DJ, Valincius G, Meuse CW. Self-assembled monolayers of methyl 1-thiahexa(ethylene oxide) for the inhibition of protein adsorption. Langmuir. 2002;18(12):4674–80. https://doi.org/10.1021/la025720t.

    Article  CAS  Google Scholar 

  36. Vanderah DJ, La H, Naff J, Silin V, Rubinson KA. Control of protein adsorption: molecular level structural and spatial variables. J Am Chem Soc. 2004;126(42):13639–41. https://doi.org/10.1021/ja047744n.

    Article  CAS  Google Scholar 

  37. Jeon SI, Andrade JD. Protein—surface interactions in the presence of polyethylene oxide. J Colloid Interface Sci. 1991;142(1):159–66. https://doi.org/10.1016/0021-9797(91)90044-9.

    Article  CAS  Google Scholar 

  38. Love JC, Estroff LA, Kriebel JK, Nuzzo RG, Whitesides GM. Self-assembled monolayers of thiolates on metals as a form of nanotechnology. Chem Rev. 2005;105(4):1103–69. https://doi.org/10.1021/cr0300789.

    Article  CAS  Google Scholar 

  39. Vanderah DJ, Vierling RJ, Walker ML. Oligo(ethylene oxide) self-assembled monolayers with self-limiting packing densities for the inhibition of nonspecific protein adsorption. Langmuir. 2009;25(9):5026–30. https://doi.org/10.1021/la803896a.

    Article  CAS  Google Scholar 

  40. Vaish A, Vanderah DJ, Vierling R, Crawshaw F, Gallagher DT, Walker ML. Membrane protein resistance of oligo(ethylene oxide) self-assembled monolayers. Colloids Surf B Biointerfaces. 2014;122(0):552–8. https://doi.org/10.1016/j.colsurfb.2014.07.031.

    Article  CAS  Google Scholar 

  41. Ostuni E, Grzybowski BA, Mrksich M, Roberts CS, Whitesides GM. Adsorption of proteins to hydrophobic sites on mixed self-assembled monolayers. Langmuir. 2003;19(5):1861–72. https://doi.org/10.1021/la020649c.

    Article  CAS  Google Scholar 

  42. Zheng M, Huang X. Nanoparticles comprising a mixed monolayer for specific bindings with biomolecules. J Am Chem Soc. 2004;126(38):12047–54. https://doi.org/10.1021/ja047029d.

    Article  CAS  Google Scholar 

  43. Patra A, Ding T, Engudar G, Wang Y, Dykas MM, Liedberg B, et al. Component-specific analysis of plasma protein corona formation on gold nanoparticles using multiplexed surface Plasmon resonance. Small. 2016;12(9):1174–82. https://doi.org/10.1002/smll.201501603.

    Article  CAS  Google Scholar 

  44. Cedervall T, Lynch I, Lindman S, Berggard T, Thulin E, Nilsson H, et al. Understanding the nanoparticle-protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles. Proc Natl Acad Sci U S A. 2007;104(7):2050–5. https://doi.org/10.1073/pnas.0608582104.

    Article  CAS  Google Scholar 

  45. Sasidharan A, Riviere JE, Monteiro-Riviere NA. Gold and silver nanoparticle interactions with human proteins: impact and implications in biocorona formation. J Mater Chem B. 2015;3(10):2075–82. https://doi.org/10.1039/c4tb01926a.

    Article  CAS  Google Scholar 

  46. Treuel L, Malissek M, Grass S, Diendorf J, Mahl D, Meyer-Zaika W, et al. Quantifying the influence of polymer coatings on the serum albumin corona formation around silver and gold nanoparticles. J Nanopart Res. 2012;14(9):1102. https://doi.org/10.1007/s11051-012-1102-3.

    Article  Google Scholar 

  47. Lacerda SH, Park JJ, Meuse C, Pristinski D, Becker ML, Karim A, et al. Interaction of gold nanoparticles with common human blood proteins. ACS Nano. 2010;4(1):365–79. https://doi.org/10.1021/nn9011187.

    Article  Google Scholar 

  48. Bekdemir A, Stellacci F. A centrifugation-based physicochemical characterization method for the interaction between proteins and nanoparticles. Nat Commun. 2016;7:13121. https://doi.org/10.1038/ncomms13121.

    Article  CAS  Google Scholar 

  49. Galievsky VA, Stasheuski AS, Krylov SN. Capillary electrophoresis for quantitative studies of biomolecular interactions. Anal Chem. 2015;87(1):157–71. https://doi.org/10.1021/ac504219r.

    Article  CAS  Google Scholar 

  50. Ban E, Song EJ. Recent developments and applications of capillary electrophoresis with laser-induced fluorescence detection in biological samples. J Chromatogr B Analyt Technol Biomed Life Sci. 2013;929:180–6. https://doi.org/10.1016/j.jchromb.2013.04.028.

    Article  CAS  Google Scholar 

  51. Righetti PG, Candiano G. Recent advances in electrophoretic techniques for the characterization of protein biomolecules: a poker of aces. J Chromatogr A. 2011;1218(49):8727–37. https://doi.org/10.1016/j.chroma.2011.04.011.

    Article  CAS  Google Scholar 

  52. Guihen E. Nanoparticles in modern separation science. Trends Anal Chem. 2013;46:1–14. https://doi.org/10.1016/j.trac.2013.01.011.

    Article  CAS  Google Scholar 

  53. Pyell U. Characterization of nanoparticles by capillary electromigration separation techniques. Electrophoresis. 2010;31(5):814–31. https://doi.org/10.1002/elps.200900555.

    Article  CAS  Google Scholar 

  54. Surugau N, Urban PL. Electrophoretic methods for separation of nanoparticles. J Sep Sci. 2009;32(11):1889–906. https://doi.org/10.1002/jssc.200900071.

    Article  CAS  Google Scholar 

  55. Aleksenko SS, Shmykov AY, Oszwaldowski S, Timerbaev AR. Interactions of tumour-targeting nanoparticles with proteins: potential of using capillary electrophoresis as a direct probe. Metallomics. 2012;4(11):1141–8. https://doi.org/10.1039/c2mt20141k.

    Article  CAS  Google Scholar 

  56. Li N, Zeng S, He L, Zhong W. Probing nanoparticle--protein interaction by capillary electrophoresis. Anal Chem. 2010;82(17):7460–6. https://doi.org/10.1021/ac101627p.

    Article  CAS  Google Scholar 

  57. Berezovski M, Krylov SN. Nonequilibrium capillary electrophoresis of equilibrium mixtures--a single experiment reveals equilibrium and kinetic parameters of protein-DNA interactions. J Am Chem Soc. 2002;124(46):13674–5. https://doi.org/10.1021/ja028212e.

    Article  CAS  Google Scholar 

  58. Berezovski M, Nutiu R, Li Y, Krylov SN. Affinity analysis of a protein−aptamer complex using nonequilibrium capillary electrophoresis of equilibrium mixtures. Anal Chem. 2003;75(6):1382–6. https://doi.org/10.1021/ac026214b.

    Article  CAS  Google Scholar 

  59. Krylov SN, Berezovski M. Non-equilibrium capillary electrophoresis of equilibrium mixtures - appreciation of kinetics in capillary electrophoresis. Analyst. 2003;128(6):571–5. https://doi.org/10.1039/b212913b.

    Article  CAS  Google Scholar 

  60. Okhonin V, Krylova SM, Krylov SN. Nonequilibrium capillary electrophoresis of equilibrium mixtures, mathematical model. Anal Chem. 2004;76(5):1507–12. https://doi.org/10.1021/ac035259p.

    Article  CAS  Google Scholar 

  61. Berezovski M, Drabovich A, Krylova SM, Musheev M, Okhonin V, Petrov A, et al. Nonequilibrium capillary electrophoresis of equilibrium mixtures: a universal tool for development of aptamers. J Am Chem Soc. 2005;127(9):3165–71. https://doi.org/10.1021/ja042394q.

    Article  CAS  Google Scholar 

  62. Berezovski MV, Musheev MU, Drabovich AP, Jitkova JV, Krylov SN. Non-SELEX: selection of aptamers without intermediate amplification of candidate oligonucleotides. Nat Protoc. 2006;1(3):1359–69. https://doi.org/10.1038/nprot.2006.200.

    Article  CAS  Google Scholar 

  63. Hackley VA, Clogston JD (2010) NIST - NCL Joint Assay Protocol, PCC-1 Version 1.1 Measuring the Size of Nanoparticles in Aqueous Media Using BatchMode Dynamic Light Scattering. https://ncl.cancer.gov/sites/default/files/protocols/NCL_Method_PCC-1.pdf.

  64. Light TS, Kingman B, Bevilacqua AC (1995) The Conductivity of Low Concentrations of CO2 Dissolved in Ultrapure Water from 0–100°C. Paper presented at the 209th American Chemical Society National Meeting, Anaheim.

  65. Haiss W, Thanh NT, Aveyard J, Fernig DG. Determination of size and concentration of gold nanoparticles from UV-vis spectra. Anal Chem. 2007;79(11):4215–21. https://doi.org/10.1021/ac0702084.

    Article  CAS  Google Scholar 

  66. Egerton RF, Li P, Malac M. Radiation damage in the TEM and SEM. Micron. 2004;35(6):399–409. https://doi.org/10.1016/j.micron.2004.02.003.

    Article  CAS  Google Scholar 

  67. Riley KR, Liu S, Yu G, Libby K, Cubicciotti R, Colyer CL. Using capillary electrophoresis to characterize polymeric particles. J Chromatogr A. 2016;1463:169–75. https://doi.org/10.1016/j.chroma.2016.08.017.

    Article  CAS  Google Scholar 

  68. Qu H, Mudalige TK, Linder SW. Capillary electrophoresis/inductively-coupled plasma-mass spectrometry: development and optimization of a high resolution analytical tool for the size-based characterization of nanomaterials in dietary supplements. Anal Chem. 2014;86(23):11620–7. https://doi.org/10.1021/ac5025655.

    Article  CAS  Google Scholar 

  69. Liu F-K, Wei G-T. Adding sodium dodecylsulfate to the running electrolyte enhances the separation of gold nanoparticles by capillary electrophoresis. Anal Chim Acta. 2004;510(1):77–83. https://doi.org/10.1016/j.aca.2003.12.064.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

KRR and CMS acknowledge funding and support from the National Academy of Sciences - National Research Council Postdoctoral Research Associateship Program. ITW recognizes the support of the NIST Summer Undergraduate Research Fellowship (SURF) Program.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

Authors

Contributions

M. L. Walker and D. J. Vanderah conceived the initial project; I. T. Wood and M. L. Walker performed initial studies; K.R. Riley and C.M. Sims refined the project and contributed equally to essential experimentation and composition of the completed work.

Corresponding authors

Correspondence to Kathryn R. Riley, Christopher M. Sims or Marlon L. Walker.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any research with human or animal subjects.

Electronic supplementary material

ESM 1

(PDF 9.52 mb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Riley, K.R., Sims, C.M., Wood, I.T. et al. Short-chained oligo(ethylene oxide)-functionalized gold nanoparticles: realization of significant protein resistance. Anal Bioanal Chem 410, 145–154 (2018). https://doi.org/10.1007/s00216-017-0704-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00216-017-0704-0

Keywords

Navigation