Skip to main content

Advertisement

Log in

Synthesis, physico-chemical characterization, and antioxidant effect of PEGylated cerium oxide nanoparticles

  • Original Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

Cerium oxide nanoparticles (CNPs) represent a promising class of antioxidant nanoparticles with potential therapeutic value. Due to the easily reversible oxidation states of cerium (Ce3+ and Ce4+) at the nanoscale, CNPs scavenge excessive reactive oxygen and nitrogen species in a self-regenerative manner. In this study, we have demonstrated a simple method to functionalize shape-specific CNPs (i.e., rod- and cube-shaped) with polyethylene glycol (PEG) and studied the effect of PEGylation on the physico-chemical properties, antioxidant activity, and biocompatibility of rod- and cube-shaped CNPs. The chemical conjugation of PEG onto the CNP surface was confirmed by a series of physico-chemical characterizations (1H-NMR, FTIR, and surface zeta potential). Rod-shaped CNPs demonstrated greater reactive oxygen species scavenging ability compared to cube-shaped CNPs. PEGylation of CNPs did not affect shape, cerium oxidation state, and cytocompatibility. Importantly, PEGylation significantly reduced the amount of proteins adsorbed onto the CNPs. The antioxidant effects of CNPs were maintained in PEGylated CNPs. We envision that PEGylated rod-shaped CNPs synthesized in this study have the potential to be biocompatible nanoparticles that can combat oxidative stress-related diseases.

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
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Jakupec MA, Unfried P, Keppler BK. Pharmacological properties of cerium compounds. Rev Physiol Biochem Pharmacol. 2005;153:101–11.

    Article  CAS  PubMed  Google Scholar 

  2. Ivanov VK, Shcherbakov AB, Usatenko AV. Structure-sensitive properties and biomedical applications of nanodispersed cerium dioxide. Russ Chem Rev. 2009;78:855–71.

    Article  CAS  Google Scholar 

  3. Jung H, Kittelson DB, Zachariah MR. The influence of a cerium additive on ultrafine diesel particle emissions and kinetics of oxidation. Combustion and Flame. 2005;142:276–88.

    Article  CAS  Google Scholar 

  4. Das S, Dowding JM, Klump KE, McGinnis JF, Self W, Seal S. Cerium oxide nanoparticles: applications and prospects in nanomedicine. Nanomedicine. 2013;8:1483–508.

    Article  CAS  PubMed  Google Scholar 

  5. Korsvik C, Patil S, Seal S, Self WT. Superoxide dismutase mimetic properties exhibited by vacancy engineered ceria nanoparticles. Chem Commun. 2007;1056–8. doi:10.1039/b615134e.

  6. Heckert EG, Karakoti AS, Seal S, Self WT. The role of cerium redox state in the SOD mimetic activity of nanoceria. Biomaterials. 2008;29:2705–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nelson B, Johnson M, Walker M, Riley K, Sims C. Antioxidant cerium oxide nanoparticles in biology and medicine. Antioxidants. 2016;5:15.

    Article  PubMed Central  Google Scholar 

  8. Das M, Patil S, Bhargava N, Kang J-F, Riedel LM, Seal S, et al. Auto-catalytic ceria nanoparticles offer neuroprotection to adult rat spinal cord neurons. Biomaterials. 2007;28:1918–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pourkhalili N, Hosseini A, Nili-Ahmadabadi A, Hassani S, Pakzad M, Baeeri M, et al. Biochemical and cellular evidence of the benefit of a combination of cerium oxide nanoparticles and selenium to diabetic rats. World J Diabetes. 2011;2:204–10.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Chen J, Patil S, Seal S, McGinnis JF. Rare earth nanoparticles prevent retinal degeneration induced by intracellular peroxides. Nat Nanotechnol. 2006;1:142–50.

    Article  CAS  PubMed  Google Scholar 

  11. Zhou D, Fang T, Lu L-q, Yi L. Neuroprotective potential of cerium oxide nanoparticles for focal cerebral ischemic stroke. J Huazhong Univ Sci Technolog Med Sci. 2016;36:480–6.

    Article  CAS  PubMed  Google Scholar 

  12. Qie Y, Yuan H, von Roemeling CA, Chen Y, Liu X, Shih KD, Knight JA, Tun HW, Wharen RE, Jiang W, Kim BYS. Surface modification of nanoparticles enables selective evasion of phagocytic clearance by distinct macrophage phenotypes. Scientific Reports. 2016;6.

  13. Jokerst JV, Lobovkina T, Zare RN, Gambhir SS. Nanoparticle PEGylation for imaging and therapy. Nanomedicine. 2011;6:715–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mastorakos P, Song E, Zhang C, Berry S, Park HW, Kim YE, et al. Biodegradable DNA nanoparticles that provide widespread gene delivery in the brain. Small. 2016;12:678–85.

    Article  CAS  PubMed  Google Scholar 

  15. Tang BC, Dawson M, Lai SK, Wang YY, Suk JS, Yang M, et al. Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier. Proc Natl Acad Sci. 2009;106:19268–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Owensiii D, Peppas N. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006;307:93–102.

    Article  Google Scholar 

  17. Das S, Reed McDonagh P, Selvan Sakthivel T, Barkam S, Killion K, Ortiz J, Saraf S, Kumar A, Gupta A, Zweit J, Seal S. Tissue deposition and toxicological effects of commercially significant rare earth oxide nanomaterials: material and physical properties. Environmental Toxicology. 2016;In Press.

  18. Karakoti AS, Singh S, Kumar A, Malinska M, Kuchibhatla SVNT, Wozniak K, et al. PEGylated nanoceria as radical scavenger with tunable redox chemistry. J Am Chem Soc. 2009;131:14144–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Singh R, Karakoti AS, Self W, Seal S, Singh S. Redox-sensitive cerium oxide nanoparticles protect human keratinocytes from oxidative stress induced by glutathione depletion. Langmuir. 2016;32:12202–11.

    Article  CAS  PubMed  Google Scholar 

  20. Qi L, Sehgal A, Castaing J-C, Chapel J-P, Fresnais J, Berret J-F, et al. Redispersible hybrid nanopowders: cerium oxide nanoparticle complexes with phosphonated-PEG oligomers. ACS Nano. 2008;2:879–88.

    Article  CAS  PubMed  Google Scholar 

  21. Singh D, McMillan JM, Liu X-M, Vishwasrao HM, Kabanov AV, Sokolsky-Papkov M, et al. Formulation design facilitates magnetic nanoparticle delivery to diseased cells and tissues. Nanomedicine. 2014;9:469–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cimini A, D’Angelo B, Das S, Gentile R, Benedetti E, Singh V, et al. Antibody-conjugated PEGylated cerium oxide nanoparticles for specific targeting of Aβ aggregates modulate neuronal survival pathways. Acta Biomater. 2012;8:2056–67.

    Article  CAS  PubMed  Google Scholar 

  23. Forest V, Leclerc L, Hochepied J-F, Trouvé A, Sarry G, Pourchez J. Impact of cerium oxide nanoparticles shape on their in vitro cellular toxicity. Toxicol in Vitro. 2017;38:136–41.

    Article  CAS  PubMed  Google Scholar 

  24. Sakthivel T, Das S, Kumar A, Reid DL, Gupta A, Sayle DC, et al. Morphological phase diagram of biocatalytically active ceria nanostructures as a function of processing variables and their properties. ChemPlusChem. 2013;78:1446–55.

    Article  CAS  Google Scholar 

  25. Mai H-X, Sun L-D, Zhang Y-W, Si R, Feng W, Zhang H-P, et al. Shape-selective synthesis and oxygen storage behavior of ceria nanopolyhedra, nanorods, and nanocubes. J Phys Chem B. 2005;109:24380–5.

    Article  CAS  PubMed  Google Scholar 

  26. Longmire M, Choyke PL, Kobayashi H. Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats. Nanomedicine. 2008;3:703–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ting SRS, Whitelock JM, Tomic R, Gunawan C, Teoh WY, Amal R, et al. Cellular uptake and activity of heparin functionalised cerium oxide nanoparticles in monocytes. Biomaterials. 2013;34:4377–86.

    Article  CAS  PubMed  Google Scholar 

  28. Tataurova Y, Sealy MJ, Larsen RG, Larsen SC. Surface-selective solution NMR studies of functionalized zeolite nanoparticles. The Journal of Physical Chemistry Letters. 2012;425–9.

  29. Xue Y, Patel A, Sant V, Sant S. Semiquantitative FTIR analysis of the crosslinking density of poly(ester amide)-based thermoset elastomers. Macromol Mater Eng. 2016;301:296–305.

    Article  CAS  Google Scholar 

  30. Xue Y, Patel A, Sant V, Sant S. PEGylated poly(ester amide) elastomers with tunable physico-chemical, mechanical and degradation properties. Eur Polym J. 2015;72:163–79.

    Article  CAS  Google Scholar 

  31. Zhang D, Fu H, Shi L, Pan C, Li Q, Chu Y, et al. Synthesis of CeO2 nanorods via ultrasonication assisted by polyethylene glycol. Inorg Chem. 2007;46:2446–51.

    Article  CAS  PubMed  Google Scholar 

  32. Pulido-Reyes G, Rodea-Palomares I, Das S, Sakthivel TS, Leganes F, Rosal R, et al. Untangling the biological effects of cerium oxide nanoparticles: the role of surface valence states. Scientific Reports. 2015;5:15613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang X-D, Wu Shen, Liu Sun, Zhang Fan. Size-dependent in vivo toxicity of PEG-coated gold nanoparticles. Int J Nanomedicine. 2011;6:2071–81. doi:10.2147/IJN.S21657.

  34. Walkey C, Das S, Seal S, Erlichman J, Heckman K, Ghibelli L, et al. Catalytic properties and biomedical applications of cerium oxide nanoparticles. Environ Sci: Nano. 2015;2:33–53.

    CAS  Google Scholar 

  35. Xu C, Qu X. Cerium oxide nanoparticle: a remarkably versatile rare earth nanomaterial for biological applications. NPG Asia Materials. 2014;6:e90.

    Article  CAS  Google Scholar 

  36. Rzigalinski BA, Carfagna CS, Ehrich M. Cerium oxide nanoparticles in neuroprotection and considerations for efficacy and safety. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology. 2016;In press.

  37. Larson TA, Joshi PP, Sokolov K. Preventing protein adsorption and macrophage uptake of gold nanoparticles via hydrophobic shield. ACS Nano. 2012;6:9182–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Alexis F, Pridgen E, Molnar LK, Farokhzad OC. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol Pharm. 2008;5:505–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Anselmo AC, Mitragotri S. Nanoparticles in the clinic. Bioeng Transl Med. 2016;1:10–29.

    PubMed  PubMed Central  Google Scholar 

  40. Krumova K, Cosa G. Chapter 1: overview of reactive oxygen species, in singlet oxygen: applications in biosciences and nanosciences. 2016;1:1–21. doi:10.1039/9781782622208-00001.

  41. Pyrzynska K, Pękal A. Application of free radical diphenylpicrylhydrazyl (DPPH) to estimate the antioxidant capacity of food samples. Anal Methods. 2013;5:4288.

    Article  CAS  Google Scholar 

  42. Gough DR, Cotter TG. Hydrogen peroxide: a Jekyll and Hyde signalling molecule. Cell Death Dis. 2011;2:e213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yang Z-Y, Luo S-L, Li H, Dong S-W, He J, Jiang H, et al. Alendronate as a robust anchor for ceria nanoparticle surface coating: facile binding and improved biological properties. RSC Adv. 2014;4:59965–9.

    Article  CAS  Google Scholar 

  44. Dekali S, Gamez C, Kortulewski T, Blazy K, Rat P, Lacroix G. Assessment of an in vitro model of pulmonary barrier to study the translocation of nanoparticles. Toxicol Rep. 2014;1:157–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Oberdörster G, Oberdörster E, Oberdörster J. Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect. 2005;113:823–39.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Popov AL, Popova NR, Selezneva II, Akkizov AY, Ivanov VK. Cerium oxide nanoparticles stimulate proliferation of primary mouse embryonic fibroblasts in vitro. Mater Sci Eng C. 2016;68:406–13.

    Article  CAS  Google Scholar 

  47. Franchi LP, Manshian BB, de Souza TAJ, Soenen SJ, Matsubara EY, Rosolen JM, et al. Cyto- and genotoxic effects of metallic nanoparticles in untransformed human fibroblast. Toxicol in Vitro. 2015;29:1319–31.

    Article  CAS  PubMed  Google Scholar 

  48. Fisichella M, Berenguer F, Steinmetz G, Auffan M, Rose J, Prat O. Toxicity evaluation of manufactured CeO2 nanoparticles before and after alteration: combined physicochemical and whole-genome expression analysis in Caco-2 cells. BMC Genomics. 2014;15:700.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Zhou X, Wang B, Chen Y, Mao Z, Gao C. Uptake of cerium oxide nanoparticles and their influences on functions of A549 cells. J Nanosci Nanotechnol. 2013;13:204–15.

    Article  CAS  PubMed  Google Scholar 

  50. Urner M, Schlicker A, Z’graggen BR, Stepuk A, Booy C, Buehler KP, et al. Inflammatory response of lung macrophages and epithelial cells after exposure to redox active nanoparticles: effect of solubility and antioxidant treatment. Environ Sci Technol. 2014;48:13960–8.

    Article  CAS  PubMed  Google Scholar 

  51. Mittal S, Pandey AK. Cerium oxide nanoparticles induced toxicity in human lung cells: role of ROS mediated DNA damage and apoptosis. Biomed Res Int. 2014;2014:1–14.

    Article  Google Scholar 

  52. Lin W, Y-W H, Zhou X-D, Ma Y. Toxicity of cerium oxide nanoparticles in human lung cancer cells. Int J Toxicol. 2006;25:451–7.

    Article  CAS  PubMed  Google Scholar 

  53. Grulke E, Reed K, Beck M, Huang X, Cormack A, Seal S. Nanoceria: factors affecting its pro- and anti-oxidant properties. Environ Sci Nano. 2014;1:429–44.

    Article  CAS  Google Scholar 

  54. Hirst SM, Karakoti AS, Tyler RD, Sriranganathan N, Seal S, Reilly CM. Anti-inflammatory properties of cerium oxide nanoparticles. Small. 2009;5:2848–56.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge funding support from the School of Pharmacy, University of Pittsburgh (SS). YX and AP acknowledge the Graduate Student Research Scholarship from the School of Pharmacy, University of Pittsburgh. We thank Dr. Donna Stolz, Center for Biologic Imaging, University of Pittsburgh, for access to the TEM facility. We thank Dr. Paul Johnston, School of Pharmacy, University of Pittsburgh, for access to the spectrophotometer. We thank Piyusha Sane and Michael Washington, University of Pittsburgh, for critical reading of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shilpa Sant.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xue, Y., Balmuri, S.R., Patel, A. et al. Synthesis, physico-chemical characterization, and antioxidant effect of PEGylated cerium oxide nanoparticles. Drug Deliv. and Transl. Res. 8, 357–367 (2018). https://doi.org/10.1007/s13346-017-0396-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-017-0396-1

Keywords

Navigation