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Hepatotoxic and Neurotoxic Potential of Iron Oxide Nanoparticles in Wistar Rats: a Biochemical and Ultrastructural Study

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Abstract

Iron oxide nanoparticles (IONPs) are increasingly being employed for in vivo biomedical nanotheranostic applications. The development of novel IONPs should be accompanied by careful scrutiny of their biocompatibility. Herein, we studied the effect of administration of three formulations of IONPs, based on their starting materials along with synthesizing methods, IONPs-chloride, IONPs-lactate, and IONPs-nitrate, on biochemical and ultrastructural aspects. Different techniques were utilized to assess the effect of different starting materials on the physical, morphological, chemical, surface area, magnetic, and particle size distribution accompanied with their surface charge properties. Their nanoscale sizes were below 40 nm and demonstrated surface up to 69m2/g, and increased magnetization of 71.273 emu/g. Moreover, we investigated the effects of an oral IONP administration (100 mg/kg/day) in rat for 14 days. The liver enzymatic functions were investigated. Liver and brain tissues were analyzed for oxidative stress. Finally, a transmission electron microscope (TEM) and inductively coupled plasma optical emission spectrometer (ICP-OES) were employed to investigate the ultrastructural alterations and to estimate content of iron in the selected tissues of IONP-exposed rats. This study showed that magnetite IONPs-chloride exhibited the safest toxicological profile and thus could be regarded as a promising nanotherapeutic candidate for brain or liver disorders.

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References

  1. Aitken RJ, Creely KS, Tran CL (2004) Nanoparticles: an occupational hygiene review (41–44). HSE books, London

    Google Scholar 

  2. Kataria S, Jain M, Rastogi A, Živčák M, Brestic M, Liu S, Tripathi DK (2019) Role of nanoparticles on photosynthesis: avenues and applications. In Nanomaterials in plants, algae and microorganisms (103–127). Academic Press.

  3. Mech A, Wohlleben W, Ghanem A, Hodoroaba VD, Weigel S, Babick F et al (2020) Nano or not nano? A structured approach for identifying nanomaterials according to the European Commission’s Definition. Small 16(36):2002228

    Article  CAS  Google Scholar 

  4. Jandt KD, Watts DC (2020) Nanotechnology in dentistry: Present and future perspectives on dental nanomaterials. Dent Mater 36(11):1365–1378. https://doi.org/10.1016/j.dental.2020.08.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Manzanares D, Ceña V (2020) Endocytosis: the nanoparticle and submicron nanocompounds gateway into the cell. Pharmaceutics 12(4):371

    Article  CAS  PubMed Central  Google Scholar 

  6. Ibrahim Fouad G (2021) A proposed insight into the anti-viral potential of metallic nanoparticles against novel coronavirus disease-19 (COVID-19). Bull Natl Res Cent 45(1):1–22

    Article  Google Scholar 

  7. Vance ME, Kuiken T, Vejerano EP, McGinnis SP, HochellaJr MF, Rejeski D, Hull MS (2015) Nanotechnology in the real world: redeveloping the nanomaterial consumer products inventory. Beilstein J Nanotechnol 6(1):1769–1780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mabrouk M, Das DB, Salem ZA, Beherei HH (2021) Nanomaterials for biomedical applications: production, characterisations, recent trends and difficulties. Molecules 26(4):1077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Amanzadeh E, Esmaeili A, Abadi RE, Kazemipour N, Pahlevanneshan Z, Beheshti S (2019) Quercetin conjugated with superparamagnetic iron oxide nanoparticles improves learning and memory better than free quercetin via interacting with proteins involved in LTP. Sci Rep 3 9(1) 1–9

  10. Misra R, Kandoi S, Varadaraj Vijayalakshmi S, Nanda A, Verma RS (2020) Nanotheranostics: a tactic for cancer stem cells prognosis and management. J Drug Deliv Sci Technol 55:101457

    Article  CAS  Google Scholar 

  11. Muthu MS, Leong DT, Mei L, Feng SS (2014) Nanotheranostics˗ application and further development of nanomedicine strategies for advanced theranostics. Theranostics 4(6):660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mura S, Couvreur P (2012) Nanotheranostics for personalized medicine. Adv Drug Deliv Rev 64(13):1394–1416

    Article  CAS  PubMed  Google Scholar 

  13. Silva CO, Pinho JO, Lopes JM, Almeida AJ, Gaspar MM, Reis C (2019) Current trends in cancer nanotheranostics: metallic, polymeric, and lipid-based systems. Pharmaceutics 11(1):22

    Article  CAS  PubMed Central  Google Scholar 

  14. Misra R, Acharya S (2021) Smart nanotheranostic hydrogels for on-demand cancer management. Drug Discov Today 26(2):344–359. https://doi.org/10.1016/j.drudis.2020.11.010

    Article  CAS  PubMed  Google Scholar 

  15. Ferber S, Baabur-Cohen H, Blau R, Epshtein Y et al (2014) Polymeric nanotheranostics for real-time non-invasive optical imaging of breast cancer progression and drug release. Cancer Lett 352(1):81–89

    Article  CAS  PubMed  Google Scholar 

  16. Siafaka PI, Okur NÜ, Karantas ID, Okur ME, Gündoğdu EA (2021) Current update on nanoplatforms as therapeutic and diagnostic tools: a review for the materials used as nanotheranostics and imaging modalities. Asian J Pharm Sci 16(1):24–46

    Article  PubMed  Google Scholar 

  17. Mahmoudi M, Hofmann H, Rothen-Rutishauser B, Petri-Fink A (2012) Assessing the in vitro and in vivo toxicity of superparamagnetic iron oxide nanoparticles. Chem reviews 112(4):2323–2338

    Article  CAS  Google Scholar 

  18. Ibrahim Fouad G, Ahmed KA (2021) Neuroprotective potential of Berberine against doxorubicin-induced toxicity in rat’s brain. Neurochem Res, 1–17.

  19. Zhao Y, Fletcher NL, Liu T, Gemmell AC, Houston ZH, Blakey I, Thurecht KJ (2018) In vivo therapeutic evaluation of polymeric nanomedicines: effect of different targeting peptides on therapeutic efficacy against breast cancer. Nanotheranostics 2(4):360

    Article  PubMed  PubMed Central  Google Scholar 

  20. Gupta AS (2011) Nanomedicine approaches in vascular disease: a review. Nanomedicine 7(6):763–779

    Article  PubMed  CAS  Google Scholar 

  21. Chen Q, Du Y, Zhang K, Liang Z, Li J, Yu H et al (2018) Tau-targeted multifunctional nanocomposite for combinational therapy of Alzheimer’s disease. ACS Nano 12(2):1321–1338

    Article  CAS  PubMed  Google Scholar 

  22. Poljak-Blaži M, Jaganjac M, Žarkovi´c N (2010) Cell oxidative stress: risk of metal nanoparticles. In Handbook of nanophysics nanomedicine and nanorobotic; CRC Press: New York, NY, USA.

  23. Li S, Jiang C, Wang H, Cong S, Tan M (2018) Fluorescent nanoparticles present in Coca-Cola and Pepsi-Cola: physiochemical properties, cytotoxicity, biodistribution and digestion studies. Nanotoxicol 12(1):49–62

    Article  CAS  Google Scholar 

  24. Adeyemi OS, Adewumi I, Faniyan TO (2015) Silver nanoparticles influenced rat serum metabolites and tissue morphology. JBCPP 26(4):355–361. https://doi.org/10.1515/jbcpp-2013-0092 (PMID: 25460283)

    Article  CAS  Google Scholar 

  25. Elbialy NS, Aboushoushah SF, Alshammari WW (2019) Long-term biodistribution and toxicity of curcumin capped iron oxide nanoparticles after single-dose administration in mice. Life Sci 1(230):76–83. https://doi.org/10.1016/j.lfs.2019.05.048 (Epub 2019 May 22 PMID: 31128136)

    Article  CAS  Google Scholar 

  26. Tomankova K, Horakova J, Harvanova M, Malina L, Soukupova J, Hradilova S et al (2015) Cytotoxicity, cell uptake and microscopic analysis of titanium dioxide and silver nanoparticles in vitro. Food Chem Toxicol 82:106–115

    Article  CAS  PubMed  Google Scholar 

  27. Gan J, Sun J, Chang X, Li W, Li J, Niu S et al (2020) Biodistribution and organ oxidative damage following 28 days oral administration of nanosilver with/without coating in mice. J Appl Toxicol 40(6):815–831

    Article  CAS  PubMed  Google Scholar 

  28. Yousef MI, Abuzreda AA, Kamel MA (2019) Cardiotoxicity and lung toxicity in male rats induced by long-term exposure to iron oxide and silver nanoparticles. Exp Ther Med 18:4329–4339. https://doi.org/10.3892/etm.2019.8108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Roda E, Bottone MG, Biggiogera M, Milanesi G, Coccini T (2019) Pulmonary and hepatic effects after low dose exposure to nanosilver: early and long-lasting histological and ultrastructural alterations in rat. Toxicol rep 6:1047–1060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Saptarshi SR, Duschl A, Lopata AL (2013) Interaction of nanoparticles with proteins: relation to bio-reactivity of the nanoparticle. J Nanobiotechnol 19(11):26. https://doi.org/10.1186/1477-3155-11-26 (PMID:23870291;PMCID:PMC3720198)

    Article  CAS  Google Scholar 

  31. Tsai MF, Hsu C, Yeh CS, Hsiao YJ, Su CH, Wang LF (2018) Tuning the distance of rattle-shaped IONP@ shell-in-shell nanoparticles for magnetically-targeted photothermal therapy in the second near-infrared window. ACS Appl Mater interfaces 10(2):1508–1519

    Article  CAS  PubMed  Google Scholar 

  32. Peng X, Chen H, Huang J, Mao H and Shin D M (2011) Targeted magnetic iron oxide nanoparticles for tumor imaging and therapy Biomedical Engineering—From Theory to Applications (Rijeka: InTech)

  33. Jain TK, Reddy MK, Morales MA, Leslie-Pelecky DL, Labhasetwar V (2008) Biodistribution, clearance, and biocompatibility of iron oxide magnetic nanoparticles in rats. Mol Pharm 5(2):316–327

    Article  CAS  PubMed  Google Scholar 

  34. Nosrati H, Salehiabar M, Attari E, Davaran S, Danafar H, Manjili HK (2018) Green and one-pot surface coating of iron oxide magnetic nanoparticles with natural amino acids and biocompatibility investigation. Appl Organomet Chem 32(2):e4069

    Article  CAS  Google Scholar 

  35. Nosrati H, Tarantash M, Bochani S, Charmi J, Bagheri Z, Fridoni M et al (2019) Glutathione (GSH) peptide conjugated magnetic nanoparticles as blood–brain barrier shuttle for mri-monitored brain delivery of paclitaxel. ACS Biomater Sci Eng 5(4):1677–1685

    Article  CAS  Google Scholar 

  36. Ittrich H, Peldschus K, Raabe N, Kaul M, Adam G (2013) Superparamagnetic iron oxide nanoparticles in biomedicine: applications and developments in diagnostics and therapy. Rofo 185(12):1149–66. https://doi.org/10.1055/s-0033-1335438 (Epub 2013 Sep 5. PMID: 24008761)

    Article  CAS  PubMed  Google Scholar 

  37. Lindemann A, Lüdtke-Buzug K, Fräderich BM, Gräfe K, Pries R, Wollenberg B (2014) Biological impact of superparamagnetic iron oxide nanoparticles for magnetic particle imaging of head and neck cancer cells. Int J Nanomedicine 9:5025–40. https://doi.org/10.2147/IJN.S63873 (PMID: 25378928; PMCID: PMC4218924)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rosen JE, Chan L, Shieh DB, Gu FX (2012) Iron oxide nanoparticles for targeted cancer imaging and diagnostics. Nanomedicine: NBM 8(3):275–290

    Article  CAS  Google Scholar 

  39. Mody VV, Cox A, Shah S, Singh A, Bevins W, Parihar H (2014) Magnetic nanoparticle drug delivery systems for targeting tumor. ApplNanosci 4:385–392

    CAS  Google Scholar 

  40. Dikpati A, Madgulkar AR, Kshirsagar SJ, Bhalekar MR, Chahal AS (2012) Targeted drug delivery to CNS using nanoparticles. JAPS 2(1):179–191

    Google Scholar 

  41. Albanese A, Tang PS, Chan WC (2012) The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu Rev Biomed Eng 14:1–16

    Article  CAS  PubMed  Google Scholar 

  42. Zhu M, Diao G (2011) Synthesis of porous Fe3O4 nanospheres and its application for the catalytic degradation of xylenol orange. Am J Phys Chem C 115(39):18923–18934

    Article  CAS  Google Scholar 

  43. Hyeon T (2003) Chemical synthesis of magnetic nanoparticles. ChemComm 8:927–934

    Google Scholar 

  44. Huang C, Zhang H, Sun Z, Zhao Y, Chen S, Tao R, Liu Z (2011) Porous Fe3O4 nanoparticles: synthesis and application in catalyzing epoxidation of styrene. J Colloid Interface Sci 364(2):298–303

    Article  CAS  PubMed  Google Scholar 

  45. Alkilany AM, Murphy CJ (2010) Toxicity and cellular uptake of gold nanoparticles: what we have learned so far? J Nanopart Res 12(7):2313–2333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lei L, Ling-Ling J, Yun Z, Gang L (2013) Toxicity of superparamagnetic iron oxide nanoparticles: research strategies and implications for nanomedicine. Chin Phys B 22:1–10

    Google Scholar 

  47. Voliani V, Signore G, Nifosí R, Ricci F, Luin S, Beltram F (2012) Smart delivery and controlled drug release with gold nanoparticles: new frontiers in nanomedicine. Recent Pat Nanotechnol 2(1):34–44

    CAS  Google Scholar 

  48. Prabhakar P, Vijayaraghavan S, Philip J, Doble M (2011) Biocompatibility studies of functionalized CoFe2O4 magnetic nanoparticles. Curr Nanosci 7(3):371–376

    Article  CAS  Google Scholar 

  49. Damoiseaux R, George S, Li M, Pokhrel S, Ji Z, France B et al (2011) No time to lose—high throughput screening to assess nanomaterial safety. Nanoscale 3(4):1345–1360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jeng HA, Swanson J (2006) Toxicity of metal oxide nanoparticles in mammalian cells. J Environ Sci Health A 41(12):2699–2711

    Article  CAS  Google Scholar 

  51. Valdiglesias V, Fernández-Bertólez N, Kiliç G, Costa C, Costa S, Fraga S et al (2016) Are iron oxide nanoparticles safe? Current knowledge and future perspectives. J Trace Elem Med Biol 38:53–63

    Article  CAS  PubMed  Google Scholar 

  52. El-Boubbou K (2018) Magnetic iron oxide nanoparticles as drug carriers: clinical relevance. Nanomed 13(8):953–971. https://doi.org/10.2217/nnm-2017-0336 (Epub 2018 Jan 29 PMID: 29376469)

    Article  CAS  Google Scholar 

  53. Wu J, Ding T, Sun J (2013) Neurotoxic potential of iron oxide nanoparticles in the rat brain striatum and hippocampus. Neurotoxicol 34:243–253

    Article  CAS  Google Scholar 

  54. Glat M, Skaat H, Menkes-Caspi N, Margel S, Stern EA (2013) Age-dependent efects of microglial inhibition in vivo on Alzheimer’s disease neuropathology using bioactive-conjugated iron oxide nanoparticles. J Nanobiotechnol 11(32):1–12

    Google Scholar 

  55. Poduslo JF, Hultman KL, Curran GL, Preboske GM, Chamberlain R (2011) Targeting vascular amyloid in arterioles of Alzheimer disease transgenic mice with amyloid beta protein antibody-coated nanoparticles. Neuropathol Exp Neurol 70(653–61):4

    Google Scholar 

  56. Naumenko V, Garanina A, Nikitin A, Vodopyanov S, Vorobyeva N et al (2018) Biodistribution and tumors MRI contrast enhancement of magnetic nanocubes, nanoclusters, and nanorods in multiple mice models. CONTRAST MEDIA MOL I:2018

    Google Scholar 

  57. Paik SYR, Kim JS, Shin SJ, Ko S (2015) Characterization, quantification, and determination of the toxicity of iron oxide nanoparticles to the bone marrow cells. Int J Mol Sci 16(9):22243–22257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Mohamed MI, Mohammad MK, Abdul Razak HR, Abdul Razak K, Saad WM (2015) Nanotoxic profiling of novel iron oxide nanoparticles functionalized with perchloric acid and SiPEG as a radiographic contrast medium. Biomed Res Int 2015:183525. https://doi.org/10.1155/2015/183525 (Epub May 17. PMID: 26075217; PMCID: PMC4449877)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Xiong F, Wang H, Feng Y, Li Y, Hua X, Pang X, Zhang S, Song L, Zhang Y, Gu N (2015) Cardioprotective activity of iron oxide nanoparticles. Sci Rep 5:8579. https://doi.org/10.1038/srep08579 (PMID:25716309;PMCID:PMC4341209)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Dhakshinamoorthy V, Manickam V, Perumal E (2017) Neurobehavioural toxicity of iron oxide nanoparticles in mice. Neurotox Res 32(2):187–203. https://doi.org/10.1007/s12640-017-9721-1 (Epub 2017 Mar 20. PMID: 28321581)

    Article  CAS  PubMed  Google Scholar 

  61. Valdiglesias V, Kiliç G, Costa C, Fernández-Bertólez N, Pásaro E, Teixeira JP et al (2015) Effects of iron oxide nanoparticles: cytotoxicity, genotoxicity, developmental toxicity, and neurotoxicity. Environ Mol Mutagen 56(2):125–148

    Article  CAS  PubMed  Google Scholar 

  62. Vinzant N, Scholl JL, Wu C-M, Kindle T, Koodali R, Forster GL (2017) Iron oxide nanoparticle delivery of peptides to the brain: reversal of anxiety during drug withdrawal. Front Neurosci 11:608

    Article  PubMed  PubMed Central  Google Scholar 

  63. Shaker S, Zafarian S, Chakra CS, Rao KV (2013) Preparation and characterization of magnetite nanoparticles by Sol-Gel method for water treatment. Int J Innov Res Sci Eng Technol 2(7):2969–2973

    Google Scholar 

  64. OECD Guidelines for the testing of chemicals: acute oral toxicity—fixed dose procedure, OECD/OCDE 420. Adopted: 17th December 2001.

  65. Najafabadi RE, Kazemipour N, Esmaeili A, Beheshti S, Nazifi S (2018) Using superparamagnetic iron oxide nanoparticles to enhance bioavailability of quercetin in the intact rat brain. BMC Pharmacol Toxicol 19(1):1–12

    CAS  Google Scholar 

  66. Askri D, Ouni S, Galai S, Chovelon B, Arnaud J, Sturm N et al (2019) Nanoparticles in foods? A multiscalephysiopathological investigation of iron oxide nanoparticle effects on rats after an acute oral exposure: Trace element biodistribution and cognitive capacities. Food Chem Toxicol 127:173–181

    Article  CAS  PubMed  Google Scholar 

  67. Reitman A, Frankel SA (1957) colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am J ClinPathol 28(1):56–63. https://doi.org/10.1093/ajcp/28.1.56 (PMID: 13458125)

    Article  CAS  Google Scholar 

  68. Belfield A, Goldberg DM (1971) Revised assay for serum phenyl phosphatase activity using 4-amino-antipyrine. Enzyme 12(5):561–573. https://doi.org/10.1159/000459586 (PMID: 5169852)

    Article  CAS  PubMed  Google Scholar 

  69. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95(2):351–358

    Article  CAS  PubMed  Google Scholar 

  70. Beutler E, Duron O, Kelly BM (1963) Improved method for the determination of blood glutathione. J Lab Clin Med 61:882–888 (PMID: 13967893)

    CAS  PubMed  Google Scholar 

  71. Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126

    Article  CAS  PubMed  Google Scholar 

  72. American Public Health Association (APHA), American Water Works Association (AWWA), and Water Environment Federation (WEF) 2017. Standard Methods for the Examination of Water and Wastewater, 23rd ed. (Rice, E. W., Baird, R. B., Eaton, A. D., Clesceri, L. S. eds.) Washington DC.

  73. Gaharwar US, Meena R, Rajamani P (2017) Iron oxide nanoparticles induced cytotoxicity, oxidative stress and DNA damage in lymphocytes. J Appl Toxicol 37:1232–1244. https://doi.org/10.1002/jat.3485

    Article  CAS  PubMed  Google Scholar 

  74. Xu YY, Zhao D, Zhang XJ, Jin WT, Kashkarov P, Zhang H (2009) Synthesis and characterization of single-crystalline α-Fe2O3 nanoleaves. Physica E Low Dimens Syst Nanostruct 41(5):806–811

    Article  CAS  Google Scholar 

  75. Labani MM et al (2013) Evaluation of pore size spectrum of gas shale reservoirs using low pressure nitrogen adsorption, gas expansion and mercury porosimetry: a case study from the Perth and Canning Basins, Western Australia. J Pet Sci Eng 112:7–16

    Article  CAS  Google Scholar 

  76. Fudimura KA, Seabra AB, Santos MC, Haddad PS (2017) Synthesis and characterization of methylene blue-containing silica-coated magnetic nanoparticles for photodynamic therapy. J Nanosci Nanotechnol 17(1):133–142

    Article  CAS  PubMed  Google Scholar 

  77. Santos MC, Seabra AB, Pelegrino MT, Haddad PS (2016) Synthesis, characterization and cytotoxicity of glutathione-and PEG-glutathione-superparamagnetic iron oxide nanoparticles for nitric oxide delivery. App Surface Scie 367:26–35

    Article  CAS  Google Scholar 

  78. Molina MM, Seabra AB, de Oliveira MG, Itri R, Haddad PS (2013) Nitric oxide donor superparamagnetic iron oxide nanoparticles. Mater Sci Eng C 33(2):746–751

    Article  CAS  Google Scholar 

  79. Gonçalves LC, Seabra AB, Pelegrino MT, De Araujo DR, Bernardes JS, Haddad PS (2017) Superparamagnetic iron oxide nanoparticles dispersed in Pluronic F127 hydrogel: potential uses in topical applications. RSC Adv 7(24):14496–14503

    Article  Google Scholar 

  80. Dorniani D, Hussein MZB, Kura AU, Fakurazi S, Shaari AH, Ahmad Z (2013) Sustained release of prindopril erbumine from its chitosan-coated magnetic nanoparticles for biomedical applications. Int J Mol Sci 14(12):23639–23653

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Rufus A, Sreeju N, Philip D (2016) Synthesis of biogenic hematite (α-Fe2O3) nanoparticles for antibacterial and nanofluid applications. RSC Adv 6(96):94206–94217

    Article  CAS  Google Scholar 

  82. Li Q, Kartikowati CW, Horie S, Ogi T, Iwaki T, Okuyama K (2017) Correlation between particle size/domain structure and magnetic properties of highly crystalline Fe 3 O 4 nanoparticles. Scien rep 7(1):1–7

    CAS  Google Scholar 

  83. Bodade AB, Taiwade MA, Chaudhari GN (2017) Bioelectrode based chitosan-nanocopperoxide for application to lipase biosensor. J Appl Pharm Res 5:30–39

    CAS  Google Scholar 

  84. Kumar KN, Padma R, Ratnakaram YC, Kang M (2017) Bright green emission from f-MWCNT embedded co-doped Bi 3++Tb 3+: polyvinyl alcohol polymer nanocomposites for photonic applications. RSC Adv 7:15084–15095

    Article  CAS  Google Scholar 

  85. Sivakumar M, Gedanken A, Zhong W, Jiang YH, Du YW, Brukental I et al (2004) Sonochemical synthesis of nanocrystalline LaFeO 3. J Mater Chem 14(4):764–769

    Article  CAS  Google Scholar 

  86. Kumar P, Rawat N, Hang DR, Lee HN, Kumar R (2015) Controlling band gap and refractive index in dopant-free α-Fe 2 O 3 films. Electron Mater Lett 11(1):13–23

    Article  CAS  Google Scholar 

  87. Prozorov R, Yeshurun Y, Prozorov T, Gedanken A (1999) Magnetic irreversibility and relaxation in assembly of ferromagnetic nanoparticles. Phys Rev B 59(10):6956

    Article  CAS  Google Scholar 

  88. Ashour MM, Mabrouk M, Soliman IE, Beherei HH, Tohamy KM (2021) Mesoporous silica nanoparticles prepared by different methods for biomedical applications: Comparative study. IET Nanobiotechnol 15(3):291–300

    Article  PubMed  PubMed Central  Google Scholar 

  89. Mabrouk M, Abd El-Wahab RM, Beherei HH, Selim MM, Das DB (2020) Multifunctional magnetite nanoparticles for drug delivery: preparation, characterization, antibacterial properties and drug release kinetics. Int J Pharm 587:119658

    Article  CAS  PubMed  Google Scholar 

  90. Brohi RD, Wang L, Talpur HS, Wu D, Khan FA, Bhattarai D et al (2017) Toxicity of nanoparticles on the reproductive system in animal models: a review. Front pharmacol 8:606

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Kumar A, Pandey AK, Singh SS, Shanker R, Dhawan A (2011) Cellular uptake and mutagenic potential of metal oxide nanoparticles in bacterial cells. Chemosphere 83:1124–1132

    Article  CAS  PubMed  Google Scholar 

  92. Feng Q, Liu Y, Huang J, Chen K, Huang J, Xiao K (2018) Uptake, distribution, clearance, and toxicity of iron oxide nanoparticles with different sizes and coatings. Scien rep 8(1):1–13

    Google Scholar 

  93. Hayes AW, Kruger CL (Eds.) (2014) Hayes’ principles and methods of toxicology. Crc Press.

  94. Reddy UA, Prabhakar PV, Mahboob M (2017) Biomarkers of oxidative stress for in vivo assessment of toxicological effects of iron oxide nanoparticles. Saudi J Biol Sci 24(6):1172–1180

    Article  CAS  PubMed  Google Scholar 

  95. Bugata LSP, Pitta Venkata P, Gundu AR, Mohammed Fazlur R, Reddy UA, Kumar JM et al (2019) Acute and subacute oral toxicity of copper oxide nanoparticles in female albino Wistar rats. J Appl Toxicol 39(5):702–716

    Article  CAS  PubMed  Google Scholar 

  96. Bertrand N, Wu J, Xu X, Kamaly N, Farokhzad OC (2014) Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv Drug Deliv Rev 66:2–25

    Article  CAS  PubMed  Google Scholar 

  97. Almeida JPM, Chen AL, Foster A, Drezek R (2011) In vivo biodistribution of nanoparticles. Nanomed 6(5):815–835

    Article  CAS  Google Scholar 

  98. Van Rooy I, Cakir-Tascioglu S, Hennink WE, Storm G, Schiffelers RM, Mastrobattista E (2011) In vivo methods to study uptake of nanoparticles into the brain. Pharm res 28(3):456–471

    Article  PubMed  CAS  Google Scholar 

  99. Adeyemi OS, Sulaiman FA (2012) Biochemical and morphological changes in Trypanosomabruceibrucei-infected rats treated with homidium chloride and diminazeneaceturate. JBCPP 23(4):179–183

    Article  CAS  Google Scholar 

  100. Kumari M, Rajak S, Singh SP, Murty US, Mahboob M, Grover P, Rahman MF (2013) Biochemical alterations induced by acute oral doses of iron oxide nanoparticles in Wistar rats. Drug chem toxicol 36(3):296–305. https://doi.org/10.3109/01480545.2012.720988 (Epub 2012 Oct 1 PMID: 23025823)

    Article  CAS  PubMed  Google Scholar 

  101. Sadauskas E, Wallin H, Stoltenberg M, Vogel U, Doering P, Larsen A, Danscher G (2007) Kupffer cells are central in the removal of nanoparticles from the organism. Particle fibre toxicol 4(1):1–7

    Article  CAS  Google Scholar 

  102. Lynch ED, Gu R, Pierce C, Kil J (2005) Combined oral delivery of ebselen and allopurinol reduces multiple cisplatin toxicities in rat breast and ovarian cancer models while enhancing anti-tumor activity. Anticancer Drugs 16(5):569–579

    Article  CAS  PubMed  Google Scholar 

  103. Blanco E, Shen H, Ferrari M (2015) Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nature biotech 33(9):941–951. https://doi.org/10.1038/nbt.3330

    Article  CAS  Google Scholar 

  104. Montalbetti N, Simonin A, Kovacs G, Hediger MA (2013) Mammalian iron transporters: families SLC11 and SLC40. Mol Aspects Med 34(2–3):270–287

    Article  CAS  PubMed  Google Scholar 

  105. Easo SL, Mohanan PV (2016) Hepatotoxicity evaluation of dextran stabilized iron oxide nanoparticles in Wistar rats. Int J Pharm 509(1–2):28–34

    Article  CAS  PubMed  Google Scholar 

  106. Shirband A et al (2014) Dose-dependent effects of iron oxide nanoparticles on thyroid hormone concentrations in liver enzymes: possible tissue destruction. Global J Med Res Studies 1(1):28–31

    Google Scholar 

  107. Kaplan MM (1972) Alkaline phosphatase. N Engl J Med 286(4):200–202

    Article  CAS  PubMed  Google Scholar 

  108. Askri D, Cunin V, Ouni S, Béal D, Rachidi W, Sakly M et al (2019) Effects of iron oxide nanoparticles (γ-Fe2O3) on liver, lung and brain proteomes following sub-acute intranasal exposure: a new toxicological assessment in rat model using iTRAQ-based quantitative proteomics. Int J Mol Sci 20(20):5186

    Article  CAS  PubMed Central  Google Scholar 

  109. Giannini EG, Testa R, Savarino V (2005) Liver enzyme alteration: a guide for clinicians. CMAJ 172(3):367–379

    Article  PubMed  PubMed Central  Google Scholar 

  110. Hare D, Ayton S, Bush A, Lei P (2013) A delicate balance: iron metabolism and diseases of the brain. Front Aging Neurosci 18(5):34. https://doi.org/10.3389/fnagi.2013.00034 (PMID:23874300;PMCID:PMC3715022)

    Article  CAS  Google Scholar 

  111. Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L (2014) The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol 13(10):1045–1060. https://doi.org/10.1016/S1474-4422(14)70117-6 (PMID:25231526;PMCID:PMC5672917)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Chen P, Totten M, Zhang Z, Bucinca H, Erikson K, Santamaría A, Aschner Bowman AB, M, (2019) Iron and manganese-related CNS toxicity: mechanisms, diagnosis and treatment. Expert Rev Neurother 19(3):243–260. https://doi.org/10.1080/14737175.2019.1581608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Borai IH, Ezz MK, Rizk MZ, Aly HF, El-Sherbiny M, Matloub AA, Fouad GI (2017) Therapeutic impact of grape leaves polyphenols on certain biochemical and neurological markers in AlCl3-induced Alzheimer’s disease. Biomed Pharmacother 93:837–851. https://doi.org/10.1016/j.biopha.2017.07.038 (Epub 2017 Jul 14. PMID: 28715867)

    Article  CAS  PubMed  Google Scholar 

  114. Sripetchwandee J, Wongjaikam S, Krintratun W, Chattipakorn N, Chattipakorn SC (2016) A combination of an iron chelator with an antioxidant effectively diminishes the dendritic loss, tau-hyperphosphorylation, amyloids-β accumulation and brain mitochondrial dynamic disruption in rats with chronic iron-overload. Neuroscie 332:191–202

    Article  CAS  Google Scholar 

  115. Yarjanli Z, Ghaedi K, Esmaeili A, Rahgozar S, Zarrabi A (2017) Iron oxide nanoparticles may damage to the neural tissue through iron accumulation, oxidative stress, and protein aggregation. BMC Neurosci 18(1):51. https://doi.org/10.1186/s12868-017-0369-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Sun L, Li Y, Liu X, Jin M, Zhang L, Du Z et al (2011) Cytotoxicity and mitochondrial damage caused by silica nanoparticles. Toxicol in vitro 25(8):1619–1629

    Article  CAS  PubMed  Google Scholar 

  117. Lee HP, Zhu X, Liu G, Chen SG, Perry G, Smith MA et al (2010) Divalent metal transporter, iron, and Parkinson’s disease: a pathological relationship. Cell Res 20:397–399

    Article  CAS  PubMed  Google Scholar 

  118. Cortajarena AL, Ortega D, Ocampo SM, Gonzalez-García A, Couleaud P, Miranda, R, et al. (2014) Engineering iron oxide nanoparticles for clinical settings. Nanobiomed 1(Godište 2014), 1–2.‏

  119. Fu PP, Xia Q, Hwang HM, Ray PC, Yu H (2014) Mechanisms of nanotoxicity: generation of reactive oxygen species. J Food Drug Anal 22(1):64–75

  120. Liu Y, Li J, Xu K et al (2018) Characterization of superparamagnetic iron oxide nanoparticle-induced apoptosis in PC12 cells and mouse hippocampus and striatum. Toxicol Lett 292:151–161

    Article  CAS  PubMed  Google Scholar 

  121. Barbusinski K (2009) Fenton reaction-controversy concerning the chemistry. Bioorg Chem 16:347–358

    CAS  Google Scholar 

  122. Mantzaris MD, Bellou S, Skiada V, Kitsati N, Fotsis T, Galaris D (2016) Intracellular labile iron determines H2O2-induced apoptotic signaling via sustained activation of ASK1/JNK-p38 axis. Free Radic Biol Med 97:454–465

    Article  CAS  PubMed  Google Scholar 

  123. Núñez MT, Urrutia P, Mena N, Aguirre P, Tapia V, Salazar J (2012) Iron toxicity in neurodegeneration. Biometals 25:761–776

    Article  PubMed  CAS  Google Scholar 

  124. Farshbaf MJ, Ghaedi K (2016) Does any drug to treat cancer target mTOR and iron hemostasis in neurodegenerative disorders? Biometals. https://doi.org/10.1007/s10534-016-9981-x

    Article  Google Scholar 

  125. Yu M, Huang S, Yu KJ, Clyne AM (2012) Dextran and polymer polyethylene glycol (PEG) coating reduce both 5 and 30 nm iron oxide nanoparticle cytotoxicity in 2D and 3D cell culture. Int J Mol Sci 13(5):5554–5570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Zhu L, Zhou Z, Mao H, Yang L (2017) Magnetic nanoparticles for precision oncology: theranostic magnetic iron oxide nanoparticles for image-guided and targeted cancer therapy. Nanomed 12(1):73–87

    Article  CAS  Google Scholar 

  127. Imam SZ, Lantz-McPeak SM, Cuevas E, Rosas-Hernandez H, Liachenko S, Zhang Y et al (2015) Iron oxide nanoparticles induce dopaminergic damage: in vitro pathways and in vivo imaging reveals mechanism of neuronal damage. Mol Neurobiol 52:913–926

    Article  CAS  PubMed  Google Scholar 

  128. Rajan B, Sathish S, Balakumar S, Devaki T (2015) Synthesis and dose interval dependent hepatotoxicity evaluation of intravenously administered polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticle on Wistar rats. Environ Toxicol Pharmacol 39(2):727–735

    Article  CAS  PubMed  Google Scholar 

  129. Skalska J, Dąbrowska-Bouta B, Frontczak-Baniewicz M et al (2020) A low dose of nanoparticulate silver induces mitochondrial dysfunction and autophagy in adult rat brain. Neurotox Res 38:650–664. https://doi.org/10.1007/s12640-020-00239-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Gomes LC, Di Benedetto G, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13:589–598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Patil US, Adireddy S, Jaiswal A, Mandava S, Chrisey LBR, DB, (2015) In vitro/in vivo toxicity evaluation and quantification of iron oxide nanoparticles. Int J Mol Sci 16(10):24417–24450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Yang L, Kuang H, Zhang W, Aguilar ZP, Xiong Y, Lai W, Xu H, Wei H (2015) Size dependent biodistribution and toxicokinetics of iron oxide magnetic nanoparticles in mice. Nanoscale 7(2):625–636. https://doi.org/10.1039/c4nr05061d (PMID: 25423473)

    Article  CAS  PubMed  Google Scholar 

  133. Wang J, Chen Y, Chen B, Ding J, Xia G, Gao C et al (2010) Pharmacokinetic parameters and tissue distribution of magnetic Fe3O4 nanoparticles in mice. Int J nanomed 5:861

    CAS  Google Scholar 

  134. Su L, Zhang B, Huang Y, Zhang H, Xu Q, Tan J (2017) Superparamagnetic iron oxide nanoparticles modified with dimyristoylphosphatidylcholine and their distribution in the brain after injection in the rat substantianigra. Mater Sci Eng C 81:400–406

    Article  CAS  Google Scholar 

  135. Yokel R, Grulke E, MacPhail R (2013) Metal-based nanoparticle interactions with the nervous system: the challenge of brain entry and the risk of retention in the organism. Wiley Interdiscip Rev Nanomed Nanobiotechnol WIRES NANOMED NANOBI 5(4):346–373

    Article  CAS  Google Scholar 

  136. Kwon JT, Hwang SK, Jin H, Kim DS et al (2008) Body distribution of inhaled fluorescent magnetic nanoparticles in the mice. J Occup Health 50(1):1–6

    Article  PubMed  Google Scholar 

  137. Descamps L, Dehouck MP, Torpier G, Cecchelli R (1996) Receptor-mediated transcytosis of transferrin through blood-brain barrier endothelial cells. Am J Physiol-Heart C 270(4):H1149–H1158

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Funding

This work was supported by the National Research Centre (NRC), Egypt (Project no.: 12060106, 2019–2021); P.I.: Dr. Ghadha Ibrahim Fouad).

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Authors and Affiliations

  1. Refractories, Ceramics and Building Materials Department, National Research Centre, 33 El Bohouth St, PO Box 12622, Dokki, Cairo, Egypt

    Mostafa Mabrouk, Sara A. M. El-Sayed & Hanan H. Beherei

  2. Department of Therapeutic Chemistry, National Research Centre, 33 El-Bohouth St, 12622, Dokki, Cairo, Egypt

    Ghadha Ibrahim Fouad & Maha Z. Rizk

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  1. Mostafa Mabrouk
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  2. Ghadha Ibrahim Fouad
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  3. Sara A. M. El-Sayed
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  4. Maha Z. Rizk
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  5. Hanan H. Beherei
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Contributions

Dr. Ghadha Ibrahim Fouad and Dr. Mostafa Mabrouk: equally contributed to conceptualization, methodology, investigation, formal analysis, writing-original draft, and preparation. Dr. Sara A.M. El-Sayed: methodology, investigation, formal analysis. Prof. Dr. Maha Z. Rizk and Prof. Dr. Hanan H. Beherei: review and editing of the paper.

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Correspondence to Ghadha Ibrahim Fouad.

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The animal protocol was adopted in accordance with the National Research Council’s Guide for the Care and Use of Laboratory Animals (NIH Publications No. 8023, revised 1978), and experimental procedures were approved by the Ethical Committee, National Research Centre (NRC), Egypt (Approval no. 19–313).

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Mostafa Mabrouk and Ghadha Ibrahim Fouad are contributed equally to this work

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Mabrouk, M., Ibrahim Fouad, G., El-Sayed, S.A. et al. Hepatotoxic and Neurotoxic Potential of Iron Oxide Nanoparticles in Wistar Rats: a Biochemical and Ultrastructural Study. Biol Trace Elem Res 200, 3638–3665 (2022). https://doi.org/10.1007/s12011-021-02943-4

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