Comparative Analysis of Neurotoxic Potential of Synthesized, Native, and Physiological Nanoparticles

  • Arsenii Borysov
  • Natalia Pozdnyakova
  • Artem Pastukhov
  • Tatiana BorisovaEmail author
Part of the Neuromethods book series (NM, volume 135)


The importance of assessing the neurotoxic potential of nanoparticles is underscored by two main factors. From one side, nanoparticles are a perspective matter for use in neurotheranostics, neurosurgery, cancer treatment, and others branches of nanomedicine. From the other side, they are a component of air pollution that is considered to be a potential trigger factor for development of neuropathologies. The novelty of nanoparticle-related research is determined by unexpected physical and chemical properties of nanomaterials that often differ from those in bulk forms. Herein, we performed a comparative analysis of the neuromodulatory effects of synthesized detonation nanodiamonds, carbon dots, nanoparticles from native volcanic ash, and physiological ferritin-based nanoparticles using similar methodological approaches.

Key words

Nanoparticles Carbon dots Nanodiamonds Ferum oxide Environmental-derivated particles Neurotoxicity Nerve terminals 



We would like to thank our colleagues Prof. Alexander Demchenko and Maria Dekaliuk for carbon dots synthesis; Dr. Olga Leshchenko from the Bakul Institute for Superhard Materials NAS of Ukraine for the preparation of nanodiamonds and its technical characterization; Dr. Klaus Slenzka from Jacobs University in Bremen for providing JSC-1a and JSC. This work was supported by Science and Technology Center in Ukraine (#6055); the grants in the frame of Programs of NAS of Ukraine” Molecular and cellular biotechnologies for medicine, industry, and agriculture”; Scientific Space Research; HORIZON 2020, ERA-PLANET. We would like to thank Dr. Sandor Vari for support; Cedars Sinai Medical Center’s International Research and Innovation Management Program, the Association for Regional Cooperation in the Fields of Health, Science and Technology (RECOOP HST Association) for their support of our organization as participating Cedars—Sinai Medical Center—RECOOP Research Centers (CRRC).


  1. 1.
    Huang P, Lin J, Wang X et al (2012) Light-triggered theranostics based on photosensitizer-conjugated carbon dots for simultaneous enhanced-fluorescence imaging and photodynamic therapy. Adv Mater 24:5104–5110CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Chen Y-C, Huang X-C, Luo Y-L et al (2013) Non-metallic nanomaterials in cancer theranostics: a review of silica- and carbon-based drug delivery systems. Sci Technol Adv Mater 14:44407CrossRefGoogle Scholar
  3. 3.
    Nayak TR, Zhang Y, Cai W (2014) Cancer theranostics with carbon-based nanoplatforms. In: Cancer theranostics. Elsevier, Amsterdam, pp 347–361CrossRefGoogle Scholar
  4. 4.
    Mochalin VN, Shenderova O, Ho D, Gogotsi Y (2012) The properties and applications of nanodiamonds. Nat Nanotechnol 7:11–23CrossRefGoogle Scholar
  5. 5.
    Man HB, Ho D (2013) Nanodiamonds as platforms for biology and medicine. J Lab Autom 18:12–18CrossRefPubMedGoogle Scholar
  6. 6.
    Perevedentseva E, Lin Y-C, Jani M, Cheng C-L (2013) Biomedical applications of nanodiamonds in imaging and therapy. Nanomedicine (Lond) 8:2041–2060CrossRefGoogle Scholar
  7. 7.
    Butler JE, Sumant AV (2008) The CVD of nanodiamond materials. Chem Vap Depos 14:145–160CrossRefGoogle Scholar
  8. 8.
    Dolmatov VY (2001) Detonation synthesis ultradispersed diamonds: properties and applications. Russ Chem Rev 70:607–626CrossRefGoogle Scholar
  9. 9.
    Orel VE, Shevchenko AD, Bogatyreva GP et al (2012) Magnetic characteristics and anticancer activity of a nanocomplex consisting of detonation nanodiamond and doxorubicin. J Superhard Mater 34:179–185CrossRefGoogle Scholar
  10. 10.
    Chen M, Pierstorff ED, Lam R et al (2009) Nanodiamond-mediated delivery of water-insoluble therapeutics. ACS Nano 3:2016–2022CrossRefPubMedGoogle Scholar
  11. 11.
    Xi G, Robinson E, Mania-Farnell B et al (2014) Convection-enhanced delivery of nanodiamond drug delivery platforms for intracranial tumor treatment. Nanomedicine 10:381–391CrossRefPubMedGoogle Scholar
  12. 12.
    Davies G, Hamer MF (1976) Optical studies of the 1.945 eV Vibronic band in diamond. Proc R Soc A Math Phys Eng Sci 348:285–298CrossRefGoogle Scholar
  13. 13.
    Davies G, INSPEC (Information service) (1994) Properties and growth of diamond. INSPEC, The Institution of Electrical Engineers, LondonGoogle Scholar
  14. 14.
    Gruber A, Dräbenstedt A, Tietz C et al (1997) Scanning confocal optical microscopy and magnetic resonance on single defect centers. Science 276:2012–2014CrossRefGoogle Scholar
  15. 15.
    Walker J (1979) Optical absorption and luminescence in diamond. Rep Prog Phys 42:1605–1659CrossRefGoogle Scholar
  16. 16.
    Yu S-J, Kang M-W, Chang H-C et al (2005) Bright fluorescent nanodiamonds: no photobleaching and low cytotoxicity. J Am Chem Soc 127:17604–17605CrossRefPubMedGoogle Scholar
  17. 17.
    Pozdnyakova N, Pastukhov A, Dudarenko M et al (2016) Neuroactivity of detonation nanodiamonds: dose-dependent changes in transporter-mediated uptake and ambient level of excitatory/inhibitory neurotransmitters in brain nerve terminals. J Nanobiotechnology 14:25CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Esteves da Silva JCG, Gonçalves HMR (2011) Analytical and bioanalytical applications of carbon dots. TrAC Trends Anal Chem 30:1327–1336CrossRefGoogle Scholar
  19. 19.
    Li H, Kang Z, Liu Y et al (2012) Carbon nanodots: synthesis, properties and applications. J Mater Chem 22:24230CrossRefGoogle Scholar
  20. 20.
    Zhai X, Zhang P, Liu C et al (2012) Highly luminescent carbon nanodots by microwave-assisted pyrolysis. Chem Commun 48:7955CrossRefGoogle Scholar
  21. 21.
    Chandra S, Pathan SH, Mitra S et al (2012) Tuning of photoluminescence on different surface functionalized carbon quantum dots. RSC Adv 2:3602CrossRefGoogle Scholar
  22. 22.
    Hsu P-C, Shih Z-Y, Lee C-H et al (2012) Synthesis and analytical applications of photoluminescent carbon nanodots. Green Chem 14:917CrossRefGoogle Scholar
  23. 23.
    Zhou J, Sheng Z, Han H et al (2012) Facile synthesis of fluorescent carbon dots using watermelon peel as a carbon source. Mater Lett 66:222–224CrossRefGoogle Scholar
  24. 24.
    Borisova T, Nazarova A, Dekaliuk M et al (2015) Neuromodulatory properties of fluorescent carbon dots: effect on exocytotic release, uptake and ambient level of glutamate and GABA in brain nerve terminals. Int J Biochem Cell Biol 59:203–215CrossRefPubMedGoogle Scholar
  25. 25.
    Baker SN, Baker GA (2010) Luminescent carbon nanodots: emergent nanolights. Angew Chem Int Ed Engl 49:6726–6744CrossRefPubMedGoogle Scholar
  26. 26.
    Dong Y, Wang R, Li H et al (2012) Polyamine-functionalized carbon quantum dots for chemical sensing. Carbon 50:2810–2815CrossRefGoogle Scholar
  27. 27.
    Bhunia SK, Saha A, Maity AR et al (2013) Carbon nanoparticle-based fluorescent bioimaging probes. Sci Rep 3:1473CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Luo PG, Sahu S, Yang S-T et al (2013) Carbon “quantum” dots for optical bioimaging. J Mater Chem B 1:2116CrossRefGoogle Scholar
  29. 29.
    Wang X, Qu K, Xu B et al (2011) Microwave assisted one-step green synthesis of cell-permeable multicolor photoluminescent carbon dots without surface passivation reagents. J Mater Chem 21:2445CrossRefGoogle Scholar
  30. 30.
    Cao L, Wang X, Meziani MJ et al (2007) Carbon dots for multiphoton bioimaging. J Am Chem Soc 129:11318–11319CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Sun Y-P, Zhou B, Lin Y et al (2006) Quantum-sized carbon dots for bright and colorful photoluminescence. J Am Chem Soc 128:7756–7757CrossRefPubMedGoogle Scholar
  32. 32.
    Dorcéna CJ, Olesik KM, Wetta OG, Winter JO (2013) Characterization and toxicity of carbon dot-poly(lactic-co-glycolic acid) nanocomposites for biomedical imaging. Nano Life 3:1340002CrossRefGoogle Scholar
  33. 33.
    Krisanova N, Kasatkina L, Sivko R et al (2013) Neurotoxic potential of lunar and Martian dust: influence on Em, proton gradient, active transport, and binding of glutamate in rat brain nerve terminals. Astrobiology 13:679–692CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Andrews SC, Arosio P, Bottke W et al (1992) Structure, function, and evolution of ferritins. J Inorg Biochem 47:161–174CrossRefPubMedGoogle Scholar
  35. 35.
    Kidane TZ, Sauble E, Linder MC (2006) Release of iron from ferritin requires lysosomal activity. Am J Physiol Cell Physiol 291:C445–C455CrossRefPubMedGoogle Scholar
  36. 36.
    Munro HN, Linder MC (1978) Ferritin: structure, biosynthesis, and role in iron metabolism. Physiol Rev 58:317–396CrossRefPubMedGoogle Scholar
  37. 37.
    Chasteen ND, Harrison PM (1999) Mineralization in ferritin: an efficient means of iron storage. J Struct Biol 126:182–194CrossRefPubMedGoogle Scholar
  38. 38.
    Langlois d’Estaintot B, Santambrogio P, Granier T et al (2004) Crystal structure and biochemical properties of the human mitochondrial ferritin and its mutant Ser144Ala. J Mol Biol 340:277–293CrossRefPubMedGoogle Scholar
  39. 39.
    Ford GC, Harrison PM, Rice DW et al (1984) Ferritin: design and formation of an iron-storage molecule. Philos Trans R Soc Lond Ser B Biol Sci 304:551–565CrossRefGoogle Scholar
  40. 40.
    Friedman A, Arosio P, Finazzi D et al (2011) Ferritin as an important player in neurodegeneration. Parkinsonism Relat Disord 17:423–430CrossRefPubMedGoogle Scholar
  41. 41.
    Linder MC, Kakavandi HR, Miller P et al (1989) Dissociation of ferritins. Arch Biochem Biophys 269:485–496CrossRefPubMedGoogle Scholar
  42. 42.
    Dubiel SM, Zablotna-Rypien B, Mackey JB (1999) Magnetic properties of human liver and brain ferritin. Eur Biophys J 28:263–267CrossRefPubMedGoogle Scholar
  43. 43.
    May CA, Grady JK, Laue TM et al (2010) The sedimentation properties of ferritins. New insights and analysis of methods of nanoparticle preparation. Biochim Biophys Acta 1800:858–870CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Meyron-Holtz EG, Moshe-Belizowski S, Cohen LA (2011) A possible role for secreted ferritin in tissue iron distribution. J Neural Transm 118:337–347CrossRefPubMedGoogle Scholar
  45. 45.
    Kalgaonkar S, Lönnerdal B (2009) Receptor-mediated uptake of ferritin-bound iron by human intestinal Caco-2 cells. J Nutr Biochem 20:304–311CrossRefPubMedGoogle Scholar
  46. 46.
    Liao QK, Kong PA, Gao J et al (2001) Expression of ferritin receptor in placental microvilli membrane in pregnant women with different iron status at mid-term gestation. Eur J Clin Nutr 55:651–656CrossRefPubMedGoogle Scholar
  47. 47.
    Krisanova N, Sivko R, Kasatkina L et al (2014) Excitotoxic potential of exogenous ferritin and apoferritin: changes in ambient level of glutamate and synaptic vesicle acidification in brain nerve terminals. Mol Cell Neurosci 58:95–104CrossRefPubMedGoogle Scholar
  48. 48.
    Burdo JR, Antonetti DA, Wolpert EB, Connor JR (2003) Mechanisms and regulation of transferrin and iron transport in a model blood-brain barrier system. Neuroscience 121:883–890CrossRefPubMedGoogle Scholar
  49. 49.
    Fisher J, Devraj K, Ingram J et al (2007) Ferritin: a novel mechanism for delivery of iron to the brain and other organs. Am J Physiol Cell Physiol 293:C641–C649CrossRefPubMedGoogle Scholar
  50. 50.
    Hulet SW, Heyliger SO, Powers S, Connor JR (2000) Oligodendrocyte progenitor cells internalize ferritin via clathrin-dependent receptor mediated endocytosis. J Neurosci Res 61:52–60CrossRefPubMedGoogle Scholar
  51. 51.
    Wang W, Knovich MA, Coffman LG et al (2010) Serum ferritin: past, present and future. Biochim Biophys Acta 1800:760–769CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Dávalos A, Castillo J, Marrugat J et al (2000) Body iron stores and early neurologic deterioration in acute cerebral infarction. Neurology 54:1568–1574CrossRefPubMedGoogle Scholar
  53. 53.
    Hann HL, Stahlhut MW, Millman I (1984) Human ferritins present in the sera of nude mice transplanted with human neuroblastoma or hepatocellular carcinoma. Cancer Res 44:3898–3901PubMedGoogle Scholar
  54. 54.
    Ruddell RG, Hoang-Le D, Barwood JM et al (2009) Ferritin functions as a proinflammatory cytokine via iron-independent protein kinase C zeta/nuclear factor kappaB-regulated signaling in rat hepatic stellate cells. Hepatology 49:887–900CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Alekseenko AV, Waseem TV, Fedorovich SV (2008) Ferritin, a protein containing iron nanoparticles, induces reactive oxygen species formation and inhibits glutamate uptake in rat brain synaptosomes. Brain Res 1241:193–200CrossRefPubMedGoogle Scholar
  56. 56.
    Yang Z, Liu ZW, Allaker RP et al (2010) A review of nanoparticle functionality and toxicity on the central nervous system. J R Soc Interface 7(Suppl 4):S411–S422CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Borysov A, Krisanova N, Chunihin O et al (2014) A comparative study of neurotoxic potential of synthesized polysaccharide-coated and native ferritin-based magnetic nanoparticles. Croat Med J 55:195–205CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Fedorovich SV, Alekseenko AV, Waseem TV (2010) Are synapses targets of nanoparticles? Biochem Soc Trans 38:536–538CrossRefPubMedGoogle Scholar
  59. 59.
    Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105CrossRefPubMedGoogle Scholar
  60. 60.
    Borisova T, Krisanova N, Sivko R, Borysov A (2010) Cholesterol depletion attenuates tonic release but increases the ambient level of glutamate in rat brain synaptosomes. Neurochem Int 56:466–478CrossRefPubMedGoogle Scholar
  61. 61.
    Borisova T, Borysov A, Pastukhov A, Krisanova N (2016) Dynamic gradient of glutamate across the membrane: glutamate/aspartate-induced changes in the ambient level of L-[(14)C]glutamate and D-[(3)H]aspartate in rat brain nerve terminals. Cell Mol Neurobiol 36:1229–1240CrossRefPubMedGoogle Scholar
  62. 62.
    Borisova T (2016) Permanent dynamic transporter-mediated turnover of glutamate across the plasma membrane of presynaptic nerve terminals: arguments in favor and against. Rev Neurosci 27:71–81PubMedGoogle Scholar
  63. 63.
    Borisova T, Borysov A (2016) Putative duality of presynaptic events. Rev Neurosci 27:377–383PubMedGoogle Scholar
  64. 64.
    Borisova TA, Krisanova NV (2008) Presynaptic transporter-mediated release of glutamate evoked by the protonophore FCCP increases under altered gravity conditions. Adv Space Res 42:1971–1979CrossRefGoogle Scholar
  65. 65.
    Borisova T (2014) The neurotoxic effects of heavy metals: alterations in acidification of synaptic vesicles and glutamate transport in brain nerve terminals. Horizons Neurosci Res 14:89–112Google Scholar
  66. 66.
    Sudhof TC (2004) The synaptic vesicle cycle. Annu Rev Neurosci 27:509–547CrossRefPubMedGoogle Scholar
  67. 67.
    Borisova T (2013) Cholesterol and presynaptic glutamate transport in the brain. Springer, New York, NY. CrossRefGoogle Scholar
  68. 68.
    Borisova T, Sivko R, Borysov A, Krisanova N (2010) Diverse presynaptic mechanisms underlying methyl-β-cyclodextrin-mediated changes in glutamate transport. Cell Mol Neurobiol 30:1013–1023CrossRefPubMedGoogle Scholar
  69. 69.
    Borisova T, Krisanova N, Himmelreich N (2004) Exposure of animals to artificial gravity conditions leads to the alteration of the glutamate release from rat cerebral hemispheres nerve terminals. Adv Space Res 33:1362–1367CrossRefPubMedGoogle Scholar
  70. 70.
    Borisova TA, Himmelreich NH (2005) Centrifuge-induced hypergravity: [3H]GABA and L-[14C]glutamate uptake, exocytosis and efflux mediated by high-affinity, sodium-dependent transporters. Adv Space Res 36:1340–1345CrossRefGoogle Scholar
  71. 71.
    Georgakilas V, Perman JA, Tucek J, Zboril R (2015) Broad family of carbon nanoallotropes: classification, chemistry, and applications of fullerenes, carbon dots, nanotubes, graphene, nanodiamonds, and combined superstructures. Chem Rev 115:4744–4822CrossRefPubMedGoogle Scholar
  72. 72.
    Block ML, Elder A, Auten RL et al (2012) The outdoor air pollution and brain health workshop. Neurotoxicology 33:972–984CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Wang J, Sahu S, Sonkar SK et al (2013) Versatility with carbon dots—from overcooked BBQ to brightly fluorescent agents and photocatalysts. RSC Adv 3:15604CrossRefGoogle Scholar
  74. 74.
    Sk MP, Jaiswal A, Paul A et al (2012) Presence of amorphous carbon nanoparticles in food caramels. Sci Rep 2:383CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Kao Y-Y, Cheng T-J, Yang D-M et al (2012) Demonstration of an olfactory bulb-brain translocation pathway for ZnO nanoparticles in rodent cells in vitro and in vivo. J Mol Neurosci 48:464–471CrossRefPubMedGoogle Scholar
  76. 76.
    Mikawa M, Kato H, Okumura M et al (2001) Paramagnetic water-soluble metallofullerenes having the highest relaxivity for MRI contrast agents. Bioconjug Chem 12:510–514CrossRefPubMedGoogle Scholar
  77. 77.
    Oberdörster G, Sharp Z, Atudorei V et al (2004) Translocation of inhaled ultrafine particles to the brain. Inhal Toxicol 16:437–445CrossRefPubMedGoogle Scholar
  78. 78.
    Qingnuan L, Yan X, Xiaodong Z et al (2002) Preparation of 99mTc-C60(OH)x and its biodistribution studies. Nucl Med Biol 29:707–710CrossRefPubMedGoogle Scholar
  79. 79.
    Wang H, Wang J, Deng X et al (2004) Biodistribution of carbon single-wall carbon nanotubes in mice. J Nanosci Nanotechnol 4:1019–1024CrossRefPubMedGoogle Scholar
  80. 80.
    Oberdörster G, Ferin J, Lehnert BE (1994) Correlation between particle size, in vivo particle persistence, and lung injury. Environ Health Perspect 102(Suppl 5):173–179CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Takeda K, Suzuki K, Ishihara A et al (2009) Nanoparticles transferred from pregnant mice to their offspring can damage the genital and cranial nerve systems. J Health Sci 55:95–102CrossRefGoogle Scholar
  82. 82.
    Kreyling WG, Semmler-Behnke M, Takenaka S, Möller W (2013) Differences in the biokinetics of inhaled nano- versus micrometer-sized particles. Acc Chem Res 46:714–722CrossRefPubMedGoogle Scholar
  83. 83.
    Bourdon JA, Saber AT, Jacobsen NR et al (2012) Carbon black nanoparticle instillation induces sustained inflammation and genotoxicity in mouse lung and liver. Part Fibre Toxicol 9:5CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Oberdörster G, Sharp Z, Atudorei V et al (2002) Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats. J Toxicol Environ Health A 65:1531–1543CrossRefPubMedGoogle Scholar
  85. 85.
    Garred Ø, Rodal SK, van Deurs B, Sandvig K (2001) Reconstitution of clathrin-independent endocytosis at the apical domain of permeabilized MDCK II cells: requirement for a Rho-family GTPase. Traffic 2:26–36CrossRefPubMedGoogle Scholar
  86. 86.
    Xia T, Kovochich M, Liong M et al (2008) Cationic polystyrene nanosphere toxicity depends on cell-specific endocytic and mitochondrial injury pathways. ACS Nano 2:85–96CrossRefPubMedGoogle Scholar
  87. 87.
    Geiser M, Rothen-Rutishauser B, Kapp N et al (2005) Ultrafine particles cross cellular membranes by nonphagocytic mechanisms in lungs and in cultured cells. Environ Health Perspect 113:1555–1560CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Tao H, Yang K, Ma Z et al (2012) In vivo NIR fluorescence imaging, biodistribution, and toxicology of photoluminescent carbon dots produced from carbon nanotubes and graphite. Small 8:281–290CrossRefPubMedGoogle Scholar
  89. 89.
    Nadjar Y, Gordon P, Corcia P et al (2012) Elevated serum ferritin is associated with reduced survival in amyotrophic lateral sclerosis. PLoS One 7:e45034CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Lossinsky AS, Shivers RR (2004) Structural pathways for macromolecular and cellular transport across the blood-brain barrier during inflammatory conditions. Review. Histol Histopathol 19:535–564PubMedGoogle Scholar
  91. 91.
    Cotman CW (1974) Isolation of synaptosomal and synaptic plasma membrane fractions. Methods Enzymol 31:445–452CrossRefPubMedGoogle Scholar
  92. 92.
    Larson E, Howlett B, Jagendorf A (1986) Artificial reductant enhancement of the Lowry method for protein determination. Anal Biochem 155:243–248CrossRefPubMedGoogle Scholar
  93. 93.
    Pozdnyakova N, Dudarenko M, Borisova T (2015) New effects of GABAB receptor allosteric modulator rac-BHFF on ambient GABA, uptake/release, Em and synaptic vesicle acidification in nerve terminals. Neuroscience 304:60–70CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2018

Authors and Affiliations

  • Arsenii Borysov
    • 1
  • Natalia Pozdnyakova
    • 1
  • Artem Pastukhov
    • 1
  • Tatiana Borisova
    • 1
    Email author
  1. 1.Department of NeurochemistryPalladin Institute of Biochemistry, National Academy of Sciences of UkraineKievUkraine

Personalised recommendations