Cerium Oxide Nanoparticles: Potential for Revolutionizing Treatment of Diseases

  • Beverly A. RzigalinskiEmail author
  • Charles S. CarfagnaJr.


Cerium oxide nanoparticles are highly efficacious and regenerative free radical scavengers that have the potential for treatment of human disease. Their relevance to human disease, mechanism of action, and parameters critical to move this nanopharmaceutical from bench to bedside are addressed in this chapter.


  1. 1.
    Reed K, Cormack A, Kulkarni A, Mayton M, Savie D, Klaessiq F, Stadler B (2014) Exploring the properties and applications of nanoceria: is there still plenty of room at the bottom? Env Sci Nano 1:390–405CrossRefGoogle Scholar
  2. 2.
    Cassee FR, van Balen EC, Singh C, Gree D, Muijser H, Weinstein J, Dreher K (2011) Exposure, health and ecological effects review of engineered nanoscale cerium and cerium oxide associated with its use as a fuel additive. Crit Rev Toxicol 41:213–229CrossRefGoogle Scholar
  3. 3.
    Eguchi K, Setoguchi T, Inoue T, Arai H (1992) Electrical properties of ceria-based oxides and their applications to solid oxide fuel-cells. Solid-State Ion 52:165–172CrossRefGoogle Scholar
  4. 4.
    Tsunekawa S, Sivamohan R, Ohsuna T, Kasuya A, Takahashi H, Tohji K (1999) Ultraviolet absorption spectra of CeO2 nano-particles. Mater Sci Forum 315–317:439–445CrossRefGoogle Scholar
  5. 5.
    Izu N, Shin W, Matsubar I, Murayama N (2004) Development of resistive oxygen sensors based on cerium oxide thick film. J Electroceram 13:703–706CrossRefGoogle Scholar
  6. 6.
    Rzigalinski BA, Meehan C, Davis RM, Miles WC, Cohen CA (2006) Radical Nanomedicine. Nanomedicine 1:399–412CrossRefGoogle Scholar
  7. 7.
    Singh N, Cohen CA, Rzigalinski BA (2007) Cerium oxide nanoparticles are neuroprotective for free radical injury and enhance neuronal longevity. Proc NY Acad Sci 1122:219–230CrossRefGoogle Scholar
  8. 8.
    Rzigalinski BA, Danelisen I, Strawn E, Cohen C, Liang C (2006) Biological nanoparticles for cell engineering – a radical concept. In: Kumar C (ed) Nanotechnologies for life sciences. Wiley, New YorkGoogle Scholar
  9. 9.
    Rzigalinski BA, Meehan K, Whiting MD, Dillon CE, Hockey K, Brewer M (2011) Antioxidant nanoparticles. In: Hunter RJ, Preedy VR (eds) Antioxidant nanoparticles in nanomedicine in health and disease. CRC Press, New YorkGoogle Scholar
  10. 10.
    Rzigalinski BA (2005) Nanoparticles & cell longevity. Tech Cancer Res Treat 4:651–660CrossRefGoogle Scholar
  11. 11.
    Eitan E, Hutchinson ER, Nigel HG, Tweedie D, Celik H, Ghosh S, Fishbein KW, Spencer RG, Sasaki CY, Ghosh P et al (2015) Combination therapy with lenalidomide and nanoceria ameliorates CNS autoimmunity. Exp Neurol 273:151–160CrossRefGoogle Scholar
  12. 12.
    Estevez AY, Pritchard S, Harper K, Aston JY, Lynch A, Lucky JJ, Ludington JS, Chatani P, Mosental WP, Leiter JC et al (2011) Neuroprotective mechanisms of cerium oxide nanoparticles in a mouse hippocampal brain slice model of ischemia. Free Radic Biol Med 51:1155–1163CrossRefGoogle Scholar
  13. 13.
    Kim CK, Kim T, Choi I-Y, Soh M, Kim D, Kim Y-J, Jang H, Yang H-S, Kim JY, Park H-K et al (2012) Ceria nanoparticles that can protect against ischemic stroke. Angew Chem 51:11039–11043CrossRefGoogle Scholar
  14. 14.
    Estevez AY, Erlichman JS (2011) Cerium oxide nanoparticles for the treatment of neurological oxidative stress diseases. In: Adreescu S et al (eds) Oxidative stress: diagnostics, prevention, & therapy, ACS symposium series. Am Chem Soc, Washington, DCGoogle Scholar
  15. 15.
    Walkey C, Das S, Seal S, Erlichman J, Heckman K, Ghibelli L, Taversa E, McGinnis JF, Self WT (2015) Catalytic properties and biomedical applications of cerium oxide nanoparticles. Environ Sci Nano 2:33–53CrossRefGoogle Scholar
  16. 16.
    He L, Su Y, Lanhong J, Shi S (2015) Recent advances of cerium oxide nanoparticles in synthesis, luminescence, and biomedical studies: a review. J Rare Earths 33:791–799CrossRefGoogle Scholar
  17. 17.
    Harman D (2003) The free radical theory of aging. Antioxid Redox Signal 5:557–561CrossRefGoogle Scholar
  18. 18.
    Howes RM (2006) The free radical fantasy: a panoply of paradoxes. Ann N Y Acad Sci 1067:22–26CrossRefGoogle Scholar
  19. 19.
    Pham DQ, Plakogiannis R (2005) Vitamin E supplementation in cardiovascular disease and cancer progression. Ann Pharmacother 39:1870–1878CrossRefGoogle Scholar
  20. 20.
    Violi F, Cangemi R (2005) Antioxidants and cardiovascular disease. Curr Opin Investig Drugs 6:895–900Google Scholar
  21. 21.
    Suzuki KT, Kosacki I, Anderson HU (2001) Electrical conductivity and lattice defects in nanocrystalline cerium oxide thin films. J Am Ceram Soc 84:2001–2014Google Scholar
  22. 22.
    Aneggi E, Boaro M, de Leitenberg C, Dolcetti G, Trovarellis A (2005) Insights into the redox properties of ceria-based oxides and their implications in catalysis. J Alloys Compd 205, 406–412:1096–1102Google Scholar
  23. 23.
    Trovarelli A (2002) Catalysis by ceria and related materials. Imperial College Press, LondonCrossRefGoogle Scholar
  24. 24.
    Schubert D, Dargusch R, Raitano J, Chan S-W (2006) Cerium and yttrium oxide nanoparticles are neuroprotective. Biochem Biophys Res Commun 342:86–96CrossRefGoogle Scholar
  25. 25.
    Das M, Patil S, Bhargava N, Kang J-F, Riedel LM, Seal S, Hickman JJ (2007) Auto-catalytic ceria nanoparticles offer neuroprotection to adult rat spinal cord neurons. Biomaterials 28:1918–1925CrossRefGoogle Scholar
  26. 26.
    Bailey D, Chow L, Merchant S, Kuiry SC, Patil S, Seal S, Rzigalinski BA (2003) Cerium oxide nanoparticles extend cell longevity and act as free radical scavengers. Nat Biotechnol 14:112Google Scholar
  27. 27.
    Ciofani G, Genchi GG, Mazzolai B, Mattoli V (1840) Transcriptional profile of genes involved in oxidative stress and antioxidant defense in PC12 cells following treatment with cerium oxide nanoparticles. Biochim Biophys Acta 2014:495–506Google Scholar
  28. 28.
    Ciofani G, Genchi GG, Liakos I, Cappello V, Gemmi M, Athanassiou A, Mazzolai B, Mattoli V (2013) Effects of cerium oxide nanoparticles on PC12 neuronal-like cells: proliferation, differentiation, and dopamine secretion. Pharm Res 30:2133–2145CrossRefGoogle Scholar
  29. 29.
    Dhall A, Self W (2018) Cerium oxide nanoparticles: a brief review of their synthesis methods and biomedical applications. Antioxidants 7:97–110CrossRefGoogle Scholar
  30. 30.
    Sadowska-Bartosz I, Bartosz G (2018) Redox nanoparticles: synthesis, properties and perspectives of use for treatment of neurodegenerative disease. J Nanobiotechnol 16:87–92CrossRefGoogle Scholar
  31. 31.
    Deshpande S, Patil S, Kuchibhatla S, Seal S (2005) Size dependency variation in lattice parameter and valency states in nanocrystalline cerium oxide. Appl Phys Lett 87:133113CrossRefGoogle Scholar
  32. 32.
    Rzigalinski BA, Hockey KS, Klein LM, Sholar CA, Himler J, Billings MJ, Cook J Cerium oxide nanoparticles for the treatment and prevention of stroke and cardiovascular disease. US Patent # 9649337, May 16, 2017Google Scholar
  33. 33.
    Xue Y, Zhai Y, Zhou K, Wang L, Tan H, Luan Q, Yao X (2012) The vital role of buffer anions in the antioxidant activity of CeO2 nanoparticles. Chem Eur J 18:11115–11122CrossRefGoogle Scholar
  34. 34.
    Hardas SS, Sultana R, Warrier G, Dan M, Florence RL, Wu P, Grulke EA, Tseng MT, Unrine JM, Graham UM, Yokel RA, Butterfield DA (2012) Rat brain pro-oxidant effects of peripherally administered 5 nm ceria 30 days after exposure. Nanotoxicology 33:1147–1155Google Scholar
  35. 35.
    Nassar SZ, Hassaan PS, Abdelmonsif DA, ElAchy SN (2018) Cardioprotective effect of cerium oxide nanoparticles in a monocrotaline rat model of pulmonary hypertension: a possible implication of endothelin-1. Life Sci 15:89–101CrossRefGoogle Scholar
  36. 36.
    Sangomla S, Saifi MA, Khurane A, Godugu C (2018) Nanoceria ameliorates doxorubicin induced cardiotoxicity: possible mitigation via reduction of oxidative stress and inflammation. J Trace Elem Med Biol 47:53–62CrossRefGoogle Scholar
  37. 37.
    Shaer SS, Salaheldin TA, Saied NM, Abdelazim SM (2017) In vivo ameliorative effect of cerium oxide nanoparticles in isoproterenol-induced cardiac toxicity. Exp Toxicol Pathol 69:435–441CrossRefGoogle Scholar
  38. 38.
    Niu J, Azfer A, Rogers LM, Wang X, Kolattukudy PE (2007) Cardioprotective effects of cerium oxide nanoparticles in a transgenic murine model of cardiomyopathy. Cardiovasc Res 73:549–559CrossRefGoogle Scholar
  39. 39.
    Heckman KL, DeCoteau W, Estevez A, Reed KJ, Costanzo W, Sanford D, Letter JC, Clauss J, Knapp K, Gomez C, Mullen P, Rathbun E, Prime K, Marini J, Patchefsky J, Patchefsky AS, Hailstone RK, Erlichman JS (2013) Custom cerium oxide nanoparticles protect against a free radical mediated autoimmune degenerative disease in the brain. ACS Nano 7:10582–10596CrossRefGoogle Scholar
  40. 40.
    Sayes CM, Warheit DB (2009) Characterization of nanomaterials for toxicity assessment. Wiley Interdiscip Rev Nanomed Nanobiotechnol 1(6):660–670CrossRefGoogle Scholar
  41. 41.
    Dowding JM, Dosai T, Kumar A, Seal S, Self WT (2012) Cerium oxide nanoparticles scavenge nitric oxide radical (NO). Chem Commun 48:4896–4898CrossRefGoogle Scholar
  42. 42.
    Kwon HJ, Cha MY, Kim D, Kim DK, Soh M, Hyeon T, Mook-Jung I (2016) Mitochondria-targeting ceria nanoparticles as antioxidants for Alzheimer’s disease. ACS Nano 10:2860–2870CrossRefGoogle Scholar
  43. 43.
    Guan Y, Li M, Dong K, Gao N, Ren J, Zheng Y, Qu X (2016) Ceria/POMs hybrid nanoparticles as a mimicking metallopeptidase for treatment of neurotoxicity of amyloid-beta peptide. Biomaterials 98:92–102CrossRefGoogle Scholar
  44. 44.
    Frey A, Bates JA, Sholar CA, Kockey KS, Rzigalinski BA (2014) Cerium oxide nanoparticles as a disease-modifying therapy for Parkinson’s Disease. (#199.01) NeuroscienceGoogle Scholar
  45. 45.
    Bailey ZS, Nilson E, Bates JA, Oyalowo A, Hockey KS, Sajja VSS, Thorpe C, Rogers H, Dunn B, Frey AS, Billings MJ, Sholar CA, Hermundstad A, Kumar C, VandeVord PJ, Rzigalinski BA (2016) Cerium oxide nanoparticles improve outcome after in vitro and in vivo mild traumatic brain injury. J Neurotrauma 33:1–11CrossRefGoogle Scholar
  46. 46.
    Fiorani L, Passacantando M, Santucci S, Di Marco S, Bisti S, Maccarone R (2015) Cerium oxide nanoparticles reduced microglial activation and neurodegeneration events in light damaged retina. PLOS One 10(10):e0140387CrossRefGoogle Scholar
  47. 47.
    Cai X, Sezate SA, Seal S, McGinnins JF (2012) Sustained protection against photoreceptor degeneration in tubby mice by intravitreal injection of nanoceria. Biomaterials 33:8771–8781CrossRefGoogle Scholar
  48. 48.
    Cai X, Seal S, McGinnis JF (2014) Sustained inhibition of neovascularization in vldlr−/− mice following intravitreal injection of cerium oxide nanoparticles and the role of the ASK1-P38/JNK-NF-kB pathway. Biomaterials 35:249–258CrossRefGoogle Scholar
  49. 49.
    Zhou X, Wong LL, Karakoti AS, Seal S, McGinnis JF (2011) Nanoceria inhibit the development and promote the regression of pathologic retinal neovascularization in the Vldlr knockout mouse. PLoS One 6:e16733CrossRefGoogle Scholar
  50. 50.
    Wong LL, Pye QN, Chen L, Seal S, McGinni JF (2015) Defining the catalytic activity of nanoceria in the P23H-1 rat, a photoreceptor degeneration model. PLoS One. Scholar
  51. 51.
    Korsvik C, Patil S, Seal S, Self WT (2007) Superoxide dismutase mimetic properties exhibited by vacancy engineered ceria nanoparticles. Chem Commun 14:1056–1058CrossRefGoogle Scholar
  52. 52.
    Pirmohamed T, Dowding JM, Singh S, Wasserman B, Heckert E, Karakoti AS, King JES, Seal S, Self WT (2010) Nanoceria exhibit redox state-dependent catalase mimetic activity. Chem Commun 46:2736–2738.28CrossRefGoogle Scholar
  53. 53.
    Heckert EG, Seal S, Self WT (2008) Fenton-like reaction catalyzed by the rare earth inner transition metal cerium. Environ Sci Technol 42:5014–5019CrossRefGoogle Scholar
  54. 54.
    Jiao X, Song H, Zhao H, Bai W, Zhang L, Li Y (2012) Well-redispersed ceria nanoparticles: promising peroxidase mimetics for H2O2 and glucose detection. Anal Methods 4:3261CrossRefGoogle Scholar
  55. 55.
    Tan F, Zhang Y, Wang J, Wei J, Cai Y, Qian X (2008) An efficient method for dephosphorylation of phosphopeptides by cerium oxide. J Mass Spectrom 43:2308–2312CrossRefGoogle Scholar
  56. 56.
    Pulido-Reyes G, Rodea-Palomares I, Das S, Sakthivel TS, Leganes F, Rosal R, Seal S, Fernandez-Pinas F (2015) Untangling the biological effects of cerium oxide nanoparticles: the role of surface valence states. Sci Rep 5:15613–15620CrossRefGoogle Scholar
  57. 57.
    Peng L, He X, Zhang P, Zhang J, Ma Y, Ding Y, Wu Z, Chai Z, Zhang Z (2014) Comparative pulmonary toxicity of two ceria nanoparticles with the same primary size. Int J Mol Sci 15:6072–6085CrossRefGoogle Scholar
  58. 58.
    Skorodumova NV, Simak SI, Lundqvist BI, Abrikosov IA, Johansson B (2002) Quantum origin of the oxygen storage capability of ceria. Phys Rev Lett 89:166601CrossRefGoogle Scholar
  59. 59.
    Celardo I, De Nicola M, Mandoli C, Pedersen JZ, Traversa E, Ghibelli L (2011) Ce3+ ions determine redox-dependent anti-apoptotic effect of cerium oxide nanoparticles. ACS Nano 5:4537–4549CrossRefGoogle Scholar
  60. 60.
    Celardo I, Pedersen JZ, Traversa E, Ghibelli L (2011) Pharmacological potential of cerium oxide nanoparticles. Nanoscale 3:1411CrossRefGoogle Scholar
  61. 61.
    Fronzi M, Piccinin S, Delley B, Traversa E, Stampfl C (2009) Water adsorption on the stoichiometric and reduced CeO2(111) surface: a first principles investigation. Phys Chem Chem Phys 11:9188–9199CrossRefGoogle Scholar
  62. 62.
    Dunnic KM, Pillai R, Pisane KL, Stefaniak AB, Sabolsky EM, Leonard SS (2014) The effect of cerium oxide nanoparticle valence state on reactive oxygen species and toxicity. Biol Trace Elem Res 166:96–107CrossRefGoogle Scholar
  63. 63.
    Cafun J-D, Kvashnina KO, Casals E, Puntes VT, Glatzel P (2013) Absence of Ce3+ sites in chemically active colloidal ceria nanoparticles. ACS Nano 7:10726–10732CrossRefGoogle Scholar
  64. 64.
    Gao P, Kang Z, Fu W, Wng W, Bai X, Wang E (2010) Electrically driven redox process in cerium oxides. J Am Chem Soc 132:4197–4201CrossRefGoogle Scholar
  65. 65.
    Kuchibhatia SVNT, Karakoti AS, Baer DR, Samudral S, Engelhard MH, Amonette JE, Thevuthasan S, Seal S (2015) Influence of aging and environment on nanoparticle chemistry – implication to confinement effects in nanoceria. J Phys Chem C Nanomater Interfaces 116:14108–14114CrossRefGoogle Scholar
  66. 66.
    Minarchick VC, Stapleton PA, Fix NR, Leonard SS, Sabolsky EM, Nurkiewicz TR (2015) Intravenous and gastric cerium dioxide nanoparticle exposure disrupts microvascular smooth muscle signaling. Toxicol Sci 144:77–89CrossRefGoogle Scholar
  67. 67.
    Minarchick VC, Stapleton PA, Sabolsky EM, Nurkiewicz TR (2015) Cerium dioxide nanoparticle exposure improves microvascular dysfunction and reduces oxidative stress in spontaneously hypertensive rats. Front Physiol 6:1–12CrossRefGoogle Scholar
  68. 68.
    Huang S, Li L, Van der Biest G, Vleugels J (2005) Influence of oxygen partial pressure on the reduction of CeO2 and CeO2-ZrO2 ceramics. Solid State Sci 7:539–544CrossRefGoogle Scholar
  69. 69.
    Spulber M, Baumann P, Liu J, Palivan G (2015) Ceria loaded nanoreactors: a nontoxic superantioxidant system with high stability and efficacy. Nanoscale 7:1411–1420CrossRefGoogle Scholar
  70. 70.
    Esch F, Fabris S, Zhou L, Montini T, Africh C, Fornasiero P, Comelli G, Rosei R (2005) Electron localization determines defect formation on ceria substrates. Science 309:752–755CrossRefGoogle Scholar
  71. 71.
    Hirst SM, Karakota A, Sing S, Self W, Tyler R, Seal S, Reilly CM (2013) Bio-distribution and in vivo antioxidant effects of cerium oxide nanoparticles in mice. Environ Toxicol 28:107–118CrossRefGoogle Scholar
  72. 72.
    Rzigalinski BA, Carfagna CS, Ehrich M (2016) Cerium oxide nanoparticles in neuroprotection and considerations for efficacy and safety. WIRES Nanomed Nanobiotechnol. Scholar
  73. 73.
    Carlander U, Moto TP, Desalegn AA, Yokel RA, Johanson G (2018) Physiologically based pharmacokinetic modeling of nanoceria systemic distribution in rats suggest a dose- and route-dependent biokinetics. Int J Nanomedicine 13:2631–2646CrossRefGoogle Scholar
  74. 74.
    Yokel RA, Tseng MT, Dan M, Unrine JM, Graham UM, Wu P, Grulke EA (2013) Biodistribution and biopersistence of ceria engineered nanomaterials: size dependence. Nanomedicine 9:398–407CrossRefGoogle Scholar
  75. 75.
    Graham UM, Tseng MT, Jasinski JB, Yokel RA, Unrine JM, Davis BH, Dozier AK, Hardas SS, Sultana R, Grulke EA, Butterfield DA (2014) In vivo processing of ceria nanoparticles inside liver: impact on free-radical scavenging activity and oxidative stress. ChemPlusChem 79:1083–1088CrossRefGoogle Scholar
  76. 76.
    Tseng MT, Fu Q, Lor K, Fernandez-Botram R, Deng Z-H, Graham U, Butterfield DA, Grulke EA, Yokel RA (2014) Resistant hepatic structural alterations following nanoceria vascular infusion in the rat. Toxicol Pathol 42:984–996CrossRefGoogle Scholar
  77. 77.
    Monopoli MP, Aberg C, Salvati A, Dawson KA (2012) Biomolecular coronas provide the biological identity of nanosized materials. Nat Nanotechnol 7:779–786CrossRefGoogle Scholar
  78. 78.
    Lynch I, Cedervall T, Lundqvist M, Cabaleiro-Lago C, Linse S, Dawson KA (2007) The nanoparticle-protein complex as a biological entity: a complex fluids and surface science challenge for the 21st century. Adv Colloid Interf Sci 134–135:167–174CrossRefGoogle Scholar
  79. 79.
    Lundqvist M, Stigler J, Elia G, Lynch I, Cedervall T, Dawson KA (2008) Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc Natl Acad Sci 105:14265–14270CrossRefGoogle Scholar
  80. 80.
    Aalapati S, Ganapathy S, Manapuram S, Anumolu G, Prakya BM (2014) Toxicity and bio-accumulatin of inhaled cerium oxide nanoparticles in CD1 mice. Nanotoxicology 48:786–798Google Scholar
  81. 81.
    Geraets L, Oomen AG, Schroeder JD, Coleman VA, Cassee FR (2012) Tissue distribution of inhaled micro- and nano-sized cerium oxide particles in rats: results from a 28 day exposure study. Toxicol Sci 127:463–473CrossRefGoogle Scholar
  82. 82.
    Yokel RA, Hussain S, Garantziotis S, Demokritou P, Castranova V, Cassee FR (2014) The yin: an adverse health perspective of nanoceria: uptake distribution, accumulation, and mechanisms of toxicity. Environ Sci Nano 1:406–428CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Beverly A. Rzigalinski
    • 1
    Email author
  • Charles S. CarfagnaJr.
    • 2
  1. 1.NanoNeurolabEdward Via College of Osteopathic Medicine, Virginia CampusBlacksburgUSA
  2. 2.Advanced MaterialsLuna Innovations IncRoanokeUSA

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