Toxicity Assessment of Nanomaterials

  • Mariana Tasso
  • Maria Amparo Lago Huvelle
  • Ines Diaz Bessone
  • Agustin S. PiccoEmail author
Part of the Nanomedicine and Nanotoxicology book series (NANOMED)


In the last decades, nanoscience had a spectacular evolution providing new, versatile engineered nanomaterials and nanotools with a plethora of applications in very diverse fields ranging from energy storage to medicine. Among the palette of nanomaterials, magnetic nanoparticles (in particular iron oxide-based) present unique physicochemical properties that are actively being exploited in the biomedical field. Currently, they are used for induced magnetic hyperthermia cancer treatments, as contrast agents for magnetic resonance imaging, as cell tracking elements, and for drug delivery modalities. In parallel to the growth of nanoscience and the ever-increasing applications of nanomaterials, concerns regarding the safety and toxicity of nanoparticles have arisen, both during and post-administration. In this chapter, we review key concepts related to nanotoxicology and to the fate of nanomaterials in the human body. A detailed description about the most accepted and practiced in vitro and in vivo methods used to evaluate the toxicity of nanomaterials is provided, with emphasis in magnetic nanomaterials for nanomedicine applications.


Nanotoxicity Cell-nanomaterial interactions In vitro and in vivo evaluation 3D culture system Animal model 



A.S.P. and M.T. thank INIFTA, UNLP, and CONICET for their support. A.S.P and M.T. are CONICET fellows.


  1. Abakumov MA et al (2018) Toxicity of iron oxide nanoparticles: size and coating effects. J Biochem Mol Toxicol 32:e22225CrossRefGoogle Scholar
  2. Adiseshaiah PP, Hall JB, McNeil SE (2010) Nanomaterial standards for efficacy and toxicity assessment. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2:99–112CrossRefGoogle Scholar
  3. Aggarwal P, Hall JB, McLeland CB, Dobrovolskaia MA, McNeil SE (2009) Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy. Adv Drug Deliv Rev 61:428–437CrossRefGoogle Scholar
  4. Ahamed M et al (2008) DNA damage response to different surface chemistry of silver nanoparticles in mammalian cells. Toxicol Appl Pharmacol 233:404–410CrossRefGoogle Scholar
  5. Ahamed M et al (2013) Iron oxide nanoparticle-induced oxidative stress and genotoxicity in human skin epithelial and lung epithelial cell lines. Curr Pharm Des 19:6681–6690CrossRefGoogle Scholar
  6. Al Faraj A, Shaik AP, Shaik AS (2014) Effect of surface coating on the biocompatibility and in vivo MRI detection of iron oxide nanoparticles after intrapulmonary administration. Nanotoxicology 5390:1–10Google Scholar
  7. Alarifi S, Ali D, Alkahtani S, Alhader MS (2014) Iron oxide nanoparticles induce oxidative stress, DNA damage, and caspase activation in the human breast cancer cell line. Biol Trace Elem Res 159:416–424CrossRefGoogle Scholar
  8. Alberts B et al (2015) Molecular biology of the cell. Garland ScienseGoogle Scholar
  9. Ali S, Rytting E (2014) Influences of nanomaterials on the barrier function of epithelial cells. In: Advances in experimental medicine and biology, vol 811, pp 45–54Google Scholar
  10. Alivisatos AP (1996) Semiconductor clusters, nanocrystals, and quantum dots. Science (80–.) 271:933–937Google Scholar
  11. Almeida JPM, Chen AL, Foster A, Drezek R (2011) Vivo biodistribution of nanoparticles. Nanomedicine 6:815–835CrossRefGoogle Scholar
  12. Amstad E, Textor M, Reimhult E (2011) Stabilization and functionalization of iron oxide nanoparticles for biomedical applications. Nanoscale 3:2819CrossRefGoogle Scholar
  13. Arami H, Khandhar A, Liggitt D, Krishnan KM (2015) In vivo delivery, pharmacokinetics, biodistribution and toxicity of iron oxide nanoparticles. Chem Soc Rev 44:8576–8607CrossRefGoogle Scholar
  14. Aranda A et al (2013) Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay: a quantitative method for oxidative stress assessment of nanoparticle-treated cells. Toxicol Vitr 27:954–963CrossRefGoogle Scholar
  15. Arbab AS et al (2003) Characterization of biophysical and metabolic properties of cells labeled with superparamagnetic iron oxide nanoparticles and transfection agent for cellular MR imaging. Radiology 229:838–846CrossRefGoogle Scholar
  16. Auffan M et al (2006) In vitro interactions between DMSA-coated maghemite nanoparticles and human fibroblasts: a physicochemical and cyto-genotoxical study. Environ Sci Technol 40:4367–4373CrossRefGoogle Scholar
  17. Auffan M et al (2009) Towards a definition of inorganic nanoparticles from an environmental, health and safety perspective. Nat Nanotechnol 4:634–641CrossRefGoogle Scholar
  18. Azqueta A, Arbillaga L, López de Cerain A (2015) Genotoxicity of nanoparticles. In: Sutariya Y, Pathak Y (eds) Biointeractions of nanomaterials. CRC Press, pp 353–363Google Scholar
  19. Banerjee R et al (2010) Nanomedicine: magnetic nanoparticles and their biomedical applications. Curr Med Chem 17:3120–3141CrossRefGoogle Scholar
  20. Barick KC et al (2009) Novel and efficient MR active aqueous colloidal Fe3O4 nanoassemblies. J Mater Chem 19:7023CrossRefGoogle Scholar
  21. Barltrop JA, Owen TC, Cory AH, Cory JG (1991) 5-(3-carboxymethoxyphenyl)-2-(4,5-dimethylthiazolyl)-3-(4-sulfophenyl)tetrazolium, inner salt (MTS) and related analogs of 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT) reducing to purple water-soluble formazans As cell-viability indicators. Bioorg Med Chem Lett 1:611–614CrossRefGoogle Scholar
  22. Barnham KJ, Bush AI (2008) Metals in Alzheimer’s and Parkinson’s diseases. Curr Opin Chem Biol 12:222–228CrossRefGoogle Scholar
  23. Barry SE (2008) Challenges in the development of magnetic particles for therapeutic applications. Int J Hyperth 24:451–466CrossRefGoogle Scholar
  24. Beddoes CM, Case CP, Briscoe WH (2015) Understanding nanoparticle cellular entry: a physicochemical perspective. Adv Colloid Interface Sci 218:48–68CrossRefGoogle Scholar
  25. Bell G et al (2019) Functionalised iron oxide nanoparticles for multimodal optoacoustic and magnetic resonance imaging. J Mater Chem B7:2212–2219CrossRefGoogle Scholar
  26. Benigni R, Bossa C (2011) Mechanisms of chemical carcinogenicity and mutagenicity: a review with implications for predictive toxicology. Chem Rev 111:2507–2536CrossRefGoogle Scholar
  27. Bernas T, Dobrucki J (2002) Mitochondrial and nonmitochondrial reduction of MTT: interaction of MTT with TMRE, JC-1, and NAO mitochondrial fluorescent probes. Cytometry 47:236–242CrossRefGoogle Scholar
  28. Berridge MV, Tan AS, McCoy KD, Wang RUI (1996) The biochemical and cellular basis of cell proliferation assays that use tetrazolium salts. Biochemica 4:14–19Google Scholar
  29. Berridge MV, Herst PM, Tan AS (2005) Tetrazolium dyes as tools in cell biology: new insights into their cellular reduction. Biotechnol Annu Rev 11:127–152CrossRefGoogle Scholar
  30. Bhabra G et al (2009) Nanoparticles can cause DNA damage across a cellular barrier. Nat Nanotechnol 4:876–883CrossRefGoogle Scholar
  31. Bhatia SN, Ingber DE (2014) Microfluidic organs-on-chips. Nat Biotechnol. Scholar
  32. Bhattacharya K et al (2012) Comparison of micro- and nanoscale Fe+3–containing (hematite) particles for their toxicological properties in human lung cells in vitro. Toxicol Sci 126:173–182CrossRefGoogle Scholar
  33. Biehl P et al (2018) Synthesis, characterization, and applications of magnetic nanoparticles featuring polyzwitterionic coatings. Polymers 10:91Google Scholar
  34. Blanco E, Shen H, Ferrari M (2015) Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol. Scholar
  35. Bolognesi C, Fenech M (2013) Micronucleus assay in human cells: lymphocytes and buccal cells. In: Dhawan A, Bajpayee M (2013) Genotoxicity assessment: methods and protocols. Springer Science+Business Media, pp 191–208Google Scholar
  36. Bonvin D, Bastiaansen JAM, Stuber M, Hofmann H, Mionić Ebersold M (2017) Folic acid on iron oxide nanoparticles: platform with high potential for simultaneous targeting, MRI detection and hyperthermia treatment of lymph node metastases of prostate cancer. Dalton Trans 46:12692–12704Google Scholar
  37. Borenfreund E, Babich H, Martin-Alguacil N (1988) Comparisons of two in vitro cytotoxicity assays—the neutral red (NR) and tetrazolium MTT tests. Toxicol Vitr 2:1–6CrossRefGoogle Scholar
  38. Borm P et al (2006) Research strategies for safety evaluation of nanomaterials, Part V: role of dissolution in biological fate and effects of nanoscale particles. Toxicol Sci. Scholar
  39. Bouhifd M et al (2012) Automation of an in vitro cytotoxicity assay used to estimate starting doses in acute oral systemic toxicity tests. Food Chem Toxicol 50:2084–2096CrossRefGoogle Scholar
  40. Bourrinet P et al (2006) Preclinical safety and pharmacokinetic profile of ferumoxtran-10, an ultrasmall superparamagnetic iron oxide magnetic resonance contrast agent. Invest Radiol 41:313–324CrossRefGoogle Scholar
  41. Boverhof DR et al (2015) Comparative assessment of nanomaterial definitions and safety evaluation considerations. Regul Toxicol Pharmacol 73:137–150CrossRefGoogle Scholar
  42. Boyer C et al (2010) Anti-fouling magnetic nanoparticles for siRNA delivery. J Mater Chem 20:255–265CrossRefGoogle Scholar
  43. Bresgen N, Eckl P, Bresgen N, Eckl PM (2015) Oxidative stress and the homeodynamics of iron metabolism. Biomolecules 5:808–847CrossRefGoogle Scholar
  44. Briley-Saebo K et al (2004) Hepatic cellular distribution and degradation of iron oxide nanoparticles following single intravenous injection in rats: implications for magnetic resonance imaging. Cell Tissue Res 316:315–323CrossRefGoogle Scholar
  45. Buliaková B et al (2017) Surface-modified magnetite nanoparticles act as aneugen-like spindle poison. Nanomed Nanotechnol Biol Med 13:69–80\Google Scholar
  46. Busquets M et al (2015a) Magnetic nanoparticles cross the blood-brain barrier: when physics rises to a challenge. Nanomaterials 5:2231–2248CrossRefGoogle Scholar
  47. Busquets M, Espargaró A, Sabaté R, Estelrich J (2015b) Magnetic nanoparticles cross the blood-brain barrier: when physics rises to a challenge. Nanomaterials. Scholar
  48. Buzea C, Pacheco II, Robbie K (2007) Nanomaterials and nanoparticles: sources and toxicity. Biointerphases 2:MR17–MR71Google Scholar
  49. Cai H et al (2013) Facile hydrothermal synthesis and surface functionalization of polyethyleneimine-coated iron oxide nanoparticles for biomedical applications. ACS Appl Mater Interfaces 5:1722–1731CrossRefGoogle Scholar
  50. Candeias LP et al (1998) The catalysed NADH reduction of resazurin to resorufin. J Chem Soc Perkin Trans 20:2333–2334CrossRefGoogle Scholar
  51. Caro C et al (2019) Comprehensive toxicity assessment of PEGylated magnetic nanoparticles for in vivo applications. Colloids Surf B Biointerfaces. Scholar
  52. Chen J et al (2009a) Cationic nanoparticles induce nanoscale disruption in living cell plasma membranes. J Phys Chem B 113:11179–11185CrossRefGoogle Scholar
  53. Chen Y-S, Hung Y-C, Liau I, Huang GS (2009b) Assessment of the in vivo toxicity of gold nanoparticles. Nanoscale Res Lett 4:858–864CrossRefGoogle Scholar
  54. Chen BA et al (2010) The effect of magnetic nanoparticles of Fe3O4 on immune function in normal ICR mice. Int J Nanomed 5:593–599CrossRefGoogle Scholar
  55. Chertok B, Cole AJ, David AE, Yang VC (2010) Comparison of electron spin resonance spectroscopy and inductively-coupled plasma optical emission spectroscopy for biodistribution analysis of iron-oxide nanoparticles. Mol Pharm 7:375–385CrossRefGoogle Scholar
  56. Child HW et al (2011) Working together: the combined application of a magnetic field and penetratin for the delivery of magnetic nanoparticles to cells in 3D. ACS Nano. Scholar
  57. Choi HS, Frangioni JV (2010) Nanoparticles for biomedical imaging: fundamentals of clinical translation. Mol Imaging 9:291–310Google Scholar
  58. Choi HS et al (2007) Renal clearance of quantum dots. Nat Biotechnol 25:1165–1170CrossRefGoogle Scholar
  59. Choi S-J, Oh J-M, Choy J-H (2009) Toxicological effects of inorganic nanoparticles on human lung cancer A549 cells. J Inorg Biochem 103:463–471CrossRefGoogle Scholar
  60. Chonn A, Semple SC, Cullis PR (1992) Association of blood proteins with large unilamellar liposomes in vivo: relation to circulation lifetimes. J Biol ChemGoogle Scholar
  61. Chouly C, Pouliquen D, Lucet I, Jeune JJ, Jallet P (1996) Development of superparamagnetic nanoparticles for MRI: effect of particle size, charge and surface nature on biodistribution. J Microencapsul 13:245–255CrossRefGoogle Scholar
  62. Chow A, Brown BD, Merad M (2011) Studying the mononuclear phagocyte system in the molecular age. Nat Rev Immunol 11:788–798CrossRefGoogle Scholar
  63. Chu M et al (2013) Near-infrared laser light mediated cancer therapy by photothermal effect of Fe3O4 magnetic nanoparticles. Biomaterials 34:4078–4088CrossRefGoogle Scholar
  64. Contini C, Schneemilch M, Gaisford S, Quirke N (2018) Nanoparticle–membrane interactions. J Exp Nanosci 13:62–81CrossRefGoogle Scholar
  65. Corbo C et al (2016) The impact of nanoparticle protein corona on cytotoxicity, immunotoxicity and target drug delivery. Nanomedicine 11:81–100CrossRefGoogle Scholar
  66. Cory AH, Owen TC, Barltrop JA, Cory JG (1991) Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture. Cancer Commun 3:207–212CrossRefGoogle Scholar
  67. Costa C et al (2015) In vitro cytotoxicity of superparamagnetic iron oxide nanoparticles on neuronal and glial cells. Evaluation of nanoparticle interference with viability tests. J Appl Toxicol 36:361–372Google Scholar
  68. Costa EC, Gaspar VM, Marques JG, Coutinho P, Correia IJ (2013) Evaluation of nanoparticle uptake in co-culture cancer models. PLoS One 8:1–13Google Scholar
  69. Countryman PI, Heddle JA (1976) The production of micronuclei from chromosome aberrations in irradiated cultures of human lymphocytes. Mutat Res 41Google Scholar
  70. Cowie H et al (2015) Suitability of human and mammalian cells of different origin for the assessment of genotoxicity of metal and polymeric engineered nanoparticles. Nanotoxicology 9:57–65CrossRefGoogle Scholar
  71. Crisponi G et al (2017) Toxicity of nanoparticles: etiology and mechanisms. Antimicrob Nanoarchitectonics 511–546.
  72. Czekanska EM (2011) Assessment of cell proliferation with resazurin-based fluorescent dye. In: Stoddart MJ (ed) Mammalian cell viability: methods and protocols. Methods in molecular biology, vol 740. Humana Press, pp 27–32.
  73. Davies LC, Jenkins SJ, Allen JE, Taylor PR (2013) Tissue-resident macrophages. Nat Immunol 14:986–995CrossRefGoogle Scholar
  74. de Lima R et al (2013) Iron oxide nanoparticles show no toxicity in the comet assay in lymphocytes: a promising vehicle as a nitric oxide releasing nanocarrier in biomedical applications. J Phys Conf Ser 429:012021CrossRefGoogle Scholar
  75. De Matteis V (2017) Exposure to inorganic nanoparticles: routes of entry, immune response, biodistribution and in vitro/in vivo toxicity evaluation. Toxics 5Google Scholar
  76. De Simone U et al (2018) Human 3D cultures as models for evaluating magnetic nanoparticle CNS cytotoxicity after short- and repeated long-term exposure. Int J Mol Sci 19Google Scholar
  77. Debnath J, Muthuswamy SK, Brugge JS (2003) Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods. Scholar
  78. Decker T, Lohmann-Matthes M-L (1988) A quick and simple method for the quantitation of lactate dehydrogenase release in measurements of cellular cytotoxicity and tumor necrosis factor (TNF) activity. J Immunol Methods 115:61–69CrossRefGoogle Scholar
  79. Deng ZJ, Liang M, Monteiro M, Toth I, Minchin RF (2011) Nanoparticle-induced unfolding of fibrinogen promotes Mac-1 receptor activation and inflammation. Nat Nanotechnol 6:39–44CrossRefGoogle Scholar
  80. Dhawan A, Bajpayee M (eds) (2013) Genotoxicity assessment: methods and protocols. Methods in molecular biology, vol 1044. Humana PressGoogle Scholar
  81. Doak SH et al (2009) Confounding experimental considerations in nanogenotoxicology. Mutagenesis 24:285–293CrossRefGoogle Scholar
  82. Doak SH, Liu Y, Chen C (2017) Genotoxicity and cancer. In: Fadeel B, Pietroiusti A, Shvedova AA (eds) Adverse effects of engineered nanomaterials: exposure, toxicology, and impact on human health, 2nd edn. Academic Press, pp 423–445.
  83. Dobson J (2006) Magnetic micro- and nano-particle-based targeting for drug and gene delivery. Nanomedicine 1:31–37CrossRefGoogle Scholar
  84. Donaldson K, Poland CA (2013) Nanotoxicity: challenging the myth of nano-specific toxicity. Curr Opin Biotechnol 24:724–734CrossRefGoogle Scholar
  85. Douville NJ et al (2010) Fabrication of two-layered channel system with embedded electrodes to measure resistance across epithelial and endothelial barriers. Anal Chem. Scholar
  86. Eastmond DA, Pinkel D (1990) Detection of aneuploidy and aneuploidy-inducing agents in human lymphocytes using fluorescence in situ hybridization with chromosome-specific DNA probes. Mutat Res Mutagen Relat Subj 234:303–318Google Scholar
  87. Elder A et al (2006) Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ Health Perspect 114:1172–1178CrossRefGoogle Scholar
  88. Evans SJ et al (2019) In vitro detection of in vitro secondary mechanisms of genotoxicity induced by engineered nanomaterials. Part Fibre Toxicol 16:1–14CrossRefGoogle Scholar
  89. Fadeel B (2015) Handbook of safety assessment of nanomaterials: from toxicological testing to personalized medicine. Pan Standford series on biomedical nanotechnology. doi:10.1017/CBO9781107415324.004Google Scholar
  90. Fairbairn DW, Olive PL, O’Neill KL (1995) The comet assay: a comprehensive review. Mutat Res Genet Toxicol 339:37–59CrossRefGoogle Scholar
  91. Fang K et al (2016) Magnetofection based on superparamagnetic iron oxide nanoparticle-mediated low lncRNA HOTAIR expression decreases the proliferation and invasion of glioma stem cells. Int J Oncol 49:509–518CrossRefGoogle Scholar
  92. Fenech M (2000) The in vitro micronucleus technique. Mutat Res Mol Mech Mutagen 455:81–95CrossRefGoogle Scholar
  93. Fenech M, Morley AA (1985) Measurement of micronuclei in lymphocytes. Mutat Res Mutagen Relat Subj 147:29–36Google Scholar
  94. Feng Q et al (2018a) Uptake, distribution, clearance, and toxicity of iron oxide nanoparticles with different sizes and coatings. Sci Rep 8:2082CrossRefGoogle Scholar
  95. Feng Q et al (2018b) Uptake, distribution, clearance, and toxicity of iron oxide nanoparticles with different sizes and coatings. Sci Rep 8:1–13CrossRefGoogle Scholar
  96. Fernández-Bertólez N et al (2018a) Neurotoxicity assessment of oleic acid-coated iron oxide nanoparticles in SH-SY5Y cells. Toxicology 406–407:81–91CrossRefGoogle Scholar
  97. Fernández-Bertólez N et al (2018b) Assessment of oxidative damage induced by iron oxide nanoparticles on different nervous system cells. Mutat Res Toxicol Environ Mutagen. Scholar
  98. Fernández-Bertólez N et al (2018c) Toxicological assessment of silica-coated iron oxide nanoparticles in human astrocytes. Food Chem Toxicol 118:13–23CrossRefGoogle Scholar
  99. Fischer HC, Chan WC (2007) Nanotoxicity: the growing need for in vivo study. Curr Opin Biotechnol 18:565–571CrossRefGoogle Scholar
  100. Fischer D, Li Y, Ahlemeyer B, Krieglstein J, Kissel T (2003) In vitro cytotoxicity testing of polycations: influence of polymer structure on cell viability and hemolysis. Biomaterials 24:1121–1131CrossRefGoogle Scholar
  101. Fischer AH, Jacobson KA, Rose J, Zeller R (2008) Hematoxylin and eosin staining of tissueand cell sections. Cold Spring Harb Protoc 3:4986–4988Google Scholar
  102. Foroozandeh P, Aziz AA (2018) Insight into cellular uptake and intracellular trafficking of nanoparticles. Nanoscale Res Lett 13:339CrossRefGoogle Scholar
  103. Friedrich J et al (2007) A reliable tool to determine cell viability in complex 3-D culture: the acid phosphatase assay. J Biomol Screen. Scholar
  104. Friedrich J, Seidel C, Ebner R, Kunz-Schughart LA (2009) Spheroid-based drug screen: considerations and practical approach. Nat Protoc. Scholar
  105. Fu X, Wang X, Zhou S, Zhang Y (2017) IONP-doped nanoparticles for highly effective NIR-controlled drug release and combination tumor therapy. Int J Nanomed 12:3751–3766CrossRefGoogle Scholar
  106. Fubini B, Ghiazza M, Fenoglio I (2010) Physico-chemical features of engineered nanoparticles relevant to their toxicity. Nanotoxicology 4:347–363CrossRefGoogle Scholar
  107. Gaharwar US, Meena R, Rajamani P (2017) Iron oxide nanoparticles induced cytotoxicity, oxidative stress and DNA damage in lymphocytes. J Appl Toxicol 37:1232–1244CrossRefGoogle Scholar
  108. Gamboa JM, Leong KW (2013) In vitro and in vivo models for the study of oral delivery of nanoparticles. Adv Drug Deliv Rev. Scholar
  109. Gangopadhyay S et al (1992) Magnetic properties of ultrafine iron particles. Phys Rev B 45:9778–9787CrossRefGoogle Scholar
  110. Garnett MC, Kallinteri P (2006) Nanomedicines and nanotoxicology: some physiological principles. Occup Med (Chic Ill) 56:307–311Google Scholar
  111. Gilbert DF, Friedrich O (2017) Cell viability assays: methods and protocols. Methods in molecular biology, vol 1601. Humana PressGoogle Scholar
  112. Gojova A et al (2007) Induction of inflammation in vascular endothelial cells by metal oxide nanoparticles: effect of particle composition. Environ Health Perspect 115:403–409CrossRefGoogle Scholar
  113. Gonzalez RJ, Tarloff JB (2001) Evaluation of hepatic subcellular fractions for Alamar blue and MTT reductase activity. Toxicol Vitr 15:257–259CrossRefGoogle Scholar
  114. Gonzalez L, Sanderson BJS, Kirsch-Volders M (2011) Adaptations of the in vitro MN assay for the genotoxicity assessment of nanomaterials. Mutagenesis 26:185–191CrossRefGoogle Scholar
  115. Gonzalez-Moragas L et al (2017) Toxicogenomics of iron oxide nanoparticles in the nematode C. elegans. Nanotoxicology 11:647–657Google Scholar
  116. Goodman TT, Olive PL, Pun SH (2007) Increased nanoparticle penetration in collagenase-treated multicellular spheroids. Int J NanomedGoogle Scholar
  117. Goodman TT, Chee PN, Suzie HP (2008) 3-D tissue culture systems for the evaluation and optimization of nanoparticle-based drug carriers. Bioconjugate Chem. Scholar
  118. Gordon S, Martinez-Pomares L (2017) Physiological roles of macrophages. Pflugers Arch 469:365–374CrossRefGoogle Scholar
  119. Granot D, Shapiro EM (2011) Release activation of iron oxide nanoparticles: (REACTION) a novel environmentally sensitive MRI paradigm. Magn Reson Med 65:1253–1259CrossRefGoogle Scholar
  120. Gratton SEA et al (2008) The effect of particle design on cellular internalization pathways. Proc Natl Acad Sci 105:11613–11618CrossRefGoogle Scholar
  121. Graziano MJ, Jacobson-Kram D (2015) Genotoxicity and carcinogenicity testing of pharmaceuticals. Springer International PublishingGoogle Scholar
  122. Gref R et al (1994) Biodegradable long-circulating polymeric nanospheres. Science 263:1600–1603CrossRefGoogle Scholar
  123. Greish K (2010) Enhanced permeability and retention (EPR) effect for anticancer nanomedicine drug targeting. In: Methods molecular biology, vol 624, pp 25–37Google Scholar
  124. Grunwald DJ, Eisen JS (2002) Headwaters of the zebrafish—emergence of a new model vertebrate. Nat Rev Genet 3:711–717CrossRefGoogle Scholar
  125. Guarnieri D et al (2014) Transport across the cell-membrane dictates nanoparticle fate and toxicity: a new paradigm in nanotoxicology. Nanoscale 6:10264–10273CrossRefGoogle Scholar
  126. Guo S, Huang L (2011) Nanoparticles escaping RES and endosome: challenges for siRNA delivery for cancer therapy. J Nanomater 2011:1–12Google Scholar
  127. Guo C, Sun L, Chen X, Zhang D (2013) Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res 8:2003–2014Google Scholar
  128. Guo Y, Wang W, Peng L, Zhang P (2015) Transferrin-conjugated doxorubicin-loaded lipid-coated nanoparticles for the targeting and therapy of lung cancer. Oncol Lett 9:1065–1072CrossRefGoogle Scholar
  129. Gustafson HH, Holt-Casper D, Grainger DW, Ghandehari H (2015) Nanoparticle uptake: the phagocyte problem. Nano Today 10:487–510CrossRefGoogle Scholar
  130. Halamoda Kenzaoui B, Chapuis Bernasconi C, Guney-Ayra S, Juillerat-Jeanneret L (2012) Induction of oxidative stress, lysosome activation and autophagy by nanoparticles in human brain-derived endothelial cells. Biochem J 441:813–821Google Scholar
  131. Hamid R, Rotshteyn Y, Rabadi L, Parikh R, Bullock P (2004) Comparison of alamar blue and MTT assays for high through-put screening. Toxicol Vitr 18:703–710CrossRefGoogle Scholar
  132. Han D-W et al (2011) Subtle cytotoxicity and genotoxicity differences in superparamagnetic iron oxide nanoparticles coated with various functional groups. Int J Nanomed 6:3219CrossRefGoogle Scholar
  133. Hanot CC, Choi YS, Anani TB, Soundarrajan D, David AE (2015) Effects of iron-oxide nanoparticle surface chemistry on uptake kinetics and cytotoxicity in CHO-K1 cells. Int J Mol Sci 17Google Scholar
  134. Harris G et al (2015) Iron oxide nanoparticle toxicity testing using high-throughput analysis and high-content imaging. Nanotoxicology 9:87–94CrossRefGoogle Scholar
  135. Haselsberger K, Peterson DC, Thomas DG, Darling JL (1996) Assay of anticancer drugs in tissue culture: comparison of a tetrazolium-based assay and a protein binding dye assay in short-term cultures derived from human malignant glioma. Anticancer Drugs 7:331–338CrossRefGoogle Scholar
  136. Heldin CH, Rubin K, Pietras K, Östman A (2004) High interstitial fluid pressure—an obstacle in cancer therapy. Nat Rev Cancer. Scholar
  137. Helmlinger G, Netti PA, Lichtenbeld HC, Melder RJ, Jain RK (1997) Solid stress inhibits the growth of multicellular tumor spheroids. Nat Biotechnol. Scholar
  138. Hirayama D, Iida T, Nakase H (2017) The phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis. Int J Mol Sci 19Google Scholar
  139. Hirsch V et al (2013) Surface charge of polymer coated SPIONs influences the serum protein adsorption, colloidal stability and subsequent cell interaction in vitro. Nanoscale 5:3723CrossRefGoogle Scholar
  140. Hong S et al (2004) Interaction of poly(amidoamine) dendrimers with supported lipid bilayers and cells: hole formation and the relation to transport. Bioconjug Chem 15:774–782CrossRefGoogle Scholar
  141. Hong S et al (2006) Interaction of polycationic polymers with supported lipid bilayers and cells: nanoscale hole formation and enhanced membrane permeability. Bioconjug Chem 17:728–734CrossRefGoogle Scholar
  142. Horváth S (1980) Cytotoxicity of drugs and diverse chemical agents to cell cultures. Toxicology 16:59–66CrossRefGoogle Scholar
  143. Hsiao J-K et al (2008) Macrophage physiological function after superparamagnetic iron oxide labeling. NMR Biomed 21:820–829CrossRefGoogle Scholar
  144. Huang Y-W, Wu C, Aronstam RS (2010) Toxicity of transition metal oxide nanoparticles: recent insights from in vitro studies. Materials 3:4842–4859Google Scholar
  145. Huang X et al (2011a) The shape effect of mesoporous silica nanoparticles on biodistribution, clearance, and biocompatibility in vivo. ACS Nano 5:5390–5399CrossRefGoogle Scholar
  146. Huang H-C, Barua S, Sharma G, Dey SK, Rege K (2011b) Inorganic nanoparticles for cancer imaging and therapy. J Control Release 155:344–357CrossRefGoogle Scholar
  147. Huang Y, Mao K, Zhang B, Zhao Y (2017) Superparamagnetic iron oxide nanoparticles conjugated with folic acid for dual target-specific drug delivery and MRI in cancer theranostics. Mater Sci Eng C 70:763–771CrossRefGoogle Scholar
  148. Hume DA (2006) The mononuclear phagocyte system. Curr Opin Immunol 18:49–53CrossRefGoogle Scholar
  149. Hume DA, Irvine KM, Pridans C (2019) The mononuclear phagocyte system: the relationship between monocytes and macrophages. Trends Immunol 40:98–112CrossRefGoogle Scholar
  150. Huth S et al (2004) Insights into the mechanism of magnetofection using PEI-based magnetofectins for gene transfer. J Gene Med 6:923–936CrossRefGoogle Scholar
  151. Inglese J (2010) A practical guide to assay development and high-throughput screening in drug discovery. CRC PressGoogle Scholar
  152. Ishiyama M, Shiga M, Sasamoto K, Mizoguchi M, He PG (1993) A new sulfonated tetrazolium salt that produces a highly water-soluble formazan dye. Chem Pharm Bull 41:1118–1122CrossRefGoogle Scholar
  153. ISO/TS 80004-1 (2015(en)) Nanotechnologies—vocabulary—Part 1: Core terms. Available at: Accessed: 29 Mar 2019
  154. 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 5:316–327CrossRefGoogle Scholar
  155. Jain MR, Bandyopadhyay D, Sundar R (2018) Scientific and regulatory considerations in the development of in vitro techniques for toxicology. In Vitro Toxicol 165–185.
  156. Jia G et al (2018) NRP-1 targeted and cargo-loaded exosomes facilitate simultaneous imaging and therapy of glioma in vitro and in vivo. Biomaterials 178Google Scholar
  157. Jones DP (2002) Redox potential of GSH/GSSG couple: assay and biological significance. Methods Enzymol 348:93–112CrossRefGoogle Scholar
  158. Joris F et al (2016) The impact of species and cell type on the nanosafety profile of iron oxide nanoparticles in neural cells. J Nanobiotechnol 14:69CrossRefGoogle Scholar
  159. Jun Y, Seo J, Cheon J (2008) Nanoscaling laws of magnetic nanoparticles and their applicabilities in biomedical sciences. Acc Chem Res 41:179–189CrossRefGoogle Scholar
  160. Kain J, Karlsson HL, Moller L (2012) DNA damage induced by micro- and nanoparticles–interaction with FPG influences the detection of DNA oxidation in the comet assay. Mutagenesis 27:491–500CrossRefGoogle Scholar
  161. Kang H et al (2018) Theranostic nanosystems for targeted cancer therapy. Nano Today 23:59–72CrossRefGoogle Scholar
  162. Kansara K et al (2015) TiO2 nanoparticles induce DNA double strand breaks and cell cycle arrest in human alveolar cells. Environ Mol Mutagen 56:204–217CrossRefGoogle Scholar
  163. Karlsson HL, Gustafsson J, Cronholm P, Möller L (2009) Size-dependent toxicity of metal oxide particles—a comparison between nano- and micrometer size. Toxicol Lett 188:112–118CrossRefGoogle Scholar
  164. Karlsson HL et al (2013) Cell membrane damage and protein interaction induced by copper containing nanoparticles—importance of the metal release process. Toxicology 313:59–69CrossRefGoogle Scholar
  165. Kenny PA et al (2007) The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression. Mol Oncol. Scholar
  166. Khandhar AP, Ferguson RM, Simon JA, Krishnan KM (2012) Tailored magnetic nanoparticles for optimizing magnetic fluid hyperthermia. J Biomed Mater Res A 100:728–737CrossRefGoogle Scholar
  167. Khanna P, Ong C, Bay B, Baeg G (2015) Nanotoxicity: an interplay of oxidative stress. Inflamm Cell Death Nanomater 5:1163–1180Google Scholar
  168. Kharazian B et al (2018) Bare surface of gold nanoparticle induces inflammation through unfolding of plasma fibrinogen. Sci Rep 8:12557CrossRefGoogle Scholar
  169. Kievit FM et al (2009) PEI-PEG-chitosan copolymer coated iron oxide nanoparticles for safe gene delivery: synthesis, complexation, and transfection. Adv Funct Mater 19:2244–2251CrossRefGoogle Scholar
  170. Kievit FM et al (2011) Doxorubicin loaded iron oxide nanoparticles overcome multidrug resistance in cancer in vitro. J Control Release 152:76–83CrossRefGoogle Scholar
  171. Kiliç G et al (2015) In vitro toxicity evaluation of silica-coated iron oxide nanoparticles in human SHSY5Y neuronal cells. Toxicol Res 5:235–247Google Scholar
  172. Kim JS et al (2006) Toxicity and tissue distribution of magnetic nanoparticles in mice. Toxicol Sci 89:338–347CrossRefGoogle Scholar
  173. Kim T-H et al (2012) Size-dependent cellular toxicity of silver nanoparticles. J Biomed Mater Res Part A100A:1033–1043CrossRefGoogle Scholar
  174. Kim Y et al (2014) Probing nanoparticle translocation across the permeable endothelium in experimental atherosclerosis. Proc Natl Acad Sci. Scholar
  175. Kircher MF, Mahmood U, King RS, Weissleder R, Josephson L (2003) A multimodal nanoparticle for preoperative magnetic resonance imaging and intraoperative optical brain tumor delineation. Cancer Res 63:8122–8125Google Scholar
  176. Klein S, Sommer A, Distel LVR, Neuhuber W, Kryschi C (2012) Superparamagnetic iron oxide nanoparticles as radiosensitizer via enhanced reactive oxygen species formation. Biochem Biophys Res Commun 425:393–397CrossRefGoogle Scholar
  177. Koh JY, Choi DW (1987) Quantitative determination of glutamate mediated cortical neuronal injury in cell culture by lactate dehydrogenase efflux assay. J Neurosci Methods 20:83–90CrossRefGoogle Scholar
  178. Könczöl M et al (2011) Cytotoxicity and genotoxicity of size-fractionated iron oxide (magnetite) in A549 human lung epithelial cells: role of ROS, JNK, and NF-jB. Chem Res Toxicol 24:1460–1475CrossRefGoogle Scholar
  179. Kreyling WG et al (2009) Size dependence of the translocation of inhaled iridium and carbon nanoparticle aggregates from the lung of rats to the blood and secondary target organs. Inhal Toxicol 21:55–60CrossRefGoogle Scholar
  180. Kristensen BW, Noer H, Gramsbergen JB, Zimmer J, Noraberg J (2003) Colchicine induces apoptosis in organotypic hippocampal slice cultures. Brain Res. Scholar
  181. Kroll A, Pillukat MH, Hahn D, Schnekenburger J (2012) Interference of engineered nanoparticles with in vitro toxicity assays. Arch Toxicol 86:1123–1136CrossRefGoogle Scholar
  182. Kuhn SJ, Hallahan DE, Giorgio TD (2006) Characterization of superparamagnetic nanoparticle interactions with extracellular matrix in an in vitro system. Ann Biomed Eng. Scholar
  183. Kumar A, Dhawan A (2013) Genotoxic and carcinogenic potential of engineered nanoparticles: an update. Arch Toxicol 87:1883–1900CrossRefGoogle Scholar
  184. Kumar V, Sharma N, Maitra SS (2017) In vitro and in vivo toxicity assessment of nanoparticles. Int Nano Lett 7:243–256CrossRefGoogle Scholar
  185. Kumar A, Aileen Senapati V, Dhawan A (2018) Protocols for in vitro and in vivo toxicity assessment of engineered nanoparticles. In: Dhawan A, Anderson D, Shanker R (eds) Nanotoxicology: experimental and computational perspectives (issues in toxicology No. 35). Royal Society of Chemistry, pp 94–132.
  186. Kunzmann A et al (2011) Efficient internalization of silica-coated iron oxide nanoparticles of different sizes by primary human macrophages and dendritic cells. Toxicol Appl Pharmacol 253:81–93CrossRefGoogle Scholar
  187. Kupcsik L (2011) Estimation of cell number based on metabolic activity: the MTT reduction assay. In: Stoddart M (ed) Mammalian cell viability: methods and protocols. Methods in molecular biology, vol 740. Humana Press, pp 13–19.
  188. Kurtz-Chalot A et al (2014) Adsorption at cell surface and cellular uptake of silica nanoparticles with different surface chemical functionalizations: impact on cytotoxicity. J Nanoparticle Res 16:2738CrossRefGoogle Scholar
  189. Kwon Y-S, Choi K-B, Lim H, Lee S, Lee J-J (2018) Preparation and characterization of alginate based-fluorescent magnetic nanoparticles for fluorescence/magnetic resonance multimodal imaging applications. Jpn J Appl Phys 57:06HE03Google Scholar
  190. Langley G et al (2015) Lessons from toxicology: developing a 21st-century paradigm for medical research. Environ Health Perspect 123:A268–A272CrossRefGoogle Scholar
  191. Lartigue L et al (2012) Cooperative organization in iron oxide multi-core nanoparticles potentiates their efficiency as heating mediators and MRI contrast agents. ACS Nano 6:10935–10949CrossRefGoogle Scholar
  192. Lee MJE et al (2010) Rapid pharmacokinetic and biodistribution studies using cholorotoxin-conjugated iron oxide nanoparticles: a novel non-radioactive method. PLoS One 5:e9536Google Scholar
  193. Lee C-M et al (2009a) SPION-loaded chitosan–linoleic acid nanoparticles to target hepatocytes. Int J Pharm 371:163–169CrossRefGoogle Scholar
  194. Lee J, Lilly D, Doty C, Podsiadlo P, Kotov N (2009b) In vitro toxicity testing of nanoparticles in 3D cell culture. Small. Scholar
  195. Leroueil PR et al (2007) Nanoparticle interaction with biological membranes: does nanotechnology present a Janus face? Acc Chem Res 40:335–342CrossRefGoogle Scholar
  196. Levy M et al (2011) Long term in vivo biotransformation of iron oxide nanoparticles. Biomaterials 32:3988–3999CrossRefGoogle Scholar
  197. Li L et al (2015) Folic acid-conjugated superparamagnetic iron oxide nanoparticles for tumor-targeting MR imaging. Drug Deliv 1–8 (2015).
  198. Li S-D, Huang L (2009) Nanoparticles evading the reticuloendothelial system: role of the supported bilayer. Biochim Biophys Acta 1788:2259–2266CrossRefGoogle Scholar
  199. Li J et al (2013) Facile one-pot synthesis of Fe3O4@Au composite nanoparticles for dual-mode MR/CT imaging applications. ACS Appl Mater Interfaces 5:10357–10366CrossRefGoogle Scholar
  200. Lindberg HK et al (2009) Genotoxicity of nanomaterials: DNA damage and micronuclei induced by carbon nanotubes and graphite nanofibres in human bronchial epithelial cells in vitro. Toxicol Lett 186:166–173CrossRefGoogle Scholar
  201. Ling D, Hyeon T (2013) Chemical design of biocompatible iron oxide nanoparticles for medical applications. Small 9:1450–1466CrossRefGoogle Scholar
  202. Liu H-L et al (2010) Magnetic resonance monitoring of focused ultrasound/magnetic nanoparticle targeting delivery of therapeutic agents to the brain. Proc Natl Acad Sci 107:15205–15210CrossRefGoogle Scholar
  203. Liu G et al (2011) N-Alkyl-PEI-functionalized iron oxide nanoclusters for efficient siRNA delivery. Small 7:2742–2749CrossRefGoogle Scholar
  204. Liu MC et al (2013) Electrofluidic pressure sensor embedded microfluidic device: a study of endothelial cells under hydrostatic pressure and shear stress combinations. Lab Chip. Scholar
  205. Liu Z et al (2016) Magnetic-dependent protein corona of tailor-made superparamagnetic iron oxides alters their biological behaviors. Nanoscale 8:7544–7555CrossRefGoogle Scholar
  206. Longmire M, Choyke PL, Kobayashi H (2008) Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats. Nanomedicine 3:703–17Google Scholar
  207. Lu A-H, Salabas EL, Schüth F (2007) Magnetic nanoparticles: synthesis, protection, functionalization, and application. Angew Chemie Int Ed 46:1222–1244Google Scholar
  208. Lundin A, Hasenson M, Persson J, Pousette A (1986) Estimation of biomass in growing cell lines by ATP assay. Methods Enzymol 133:27–42CrossRefGoogle Scholar
  209. Lundqvist M et al (2017) The nanoparticle protein corona formed in human blood or human blood fractions. PLoS One 12:e0175871Google Scholar
  210. Lundqvist M et al (2008) Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc Natl Acad Sci. Scholar
  211. Luo C et al (2015) Superparamagnetic iron oxide nanoparticles exacerbate the risks of reactive oxygen species-mediated external stresses. Arch Toxicol 89:357–369CrossRefGoogle Scholar
  212. Ma HL, Xu YF, Qi XR, Maitani Y, Nagai T (2008) Superparamagnetic iron oxide nanoparticles stabilized by alginate: pharmacokinetics, tissue distribution, and applications in detecting liver cancers. Int J Pharm 354:217–226CrossRefGoogle Scholar
  213. Magdolenova Z et al (2014) Mechanisms of genotoxicity. A review of in vitro and in vivo studies with engineered nanoparticles. Nanotoxicology 8:233–278Google Scholar
  214. Magdolenova Z et al (2015) Coating-dependent induction of cytotoxicity and genotoxicity of iron oxide nanoparticles. Nanotoxicology 9:44–56CrossRefGoogle Scholar
  215. Mahmoudi M et al (2011) Irreversible changes in protein conformation due to interaction with superparamagnetic iron oxide nanoparticles. Nanoscale 3:1127–1138CrossRefGoogle Scholar
  216. 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 Rev 112:2323–2338CrossRefGoogle Scholar
  217. Malvindi MA et al (2014) Toxicity assessment of silica coated iron oxide nanoparticles and biocompatibility improvement by surface engineering. PLoS ONE 9:1–11CrossRefGoogle Scholar
  218. Manke A, Wang L, Rojanasakul Y (2013) Mechanisms of nanoparticle-induced oxidative stress and toxicity. Biomed Res Int 2013:1–15CrossRefGoogle Scholar
  219. Manshian BB et al (2018) Nanoparticle-induced inflammation can increase tumor malignancy. Acta Biomater 68:99–112CrossRefGoogle Scholar
  220. Marshall RR, Murphy M, Kirkland DJ, Bentley KS (1996) Fluorescence in situ hybridisation with chromosome-specific centromeric probes: a sensitive method to detect aneuploidy. Mutat Res Mol Mech Mutagen 372:233–245CrossRefGoogle Scholar
  221. McCaffrey TA, Agarwal LA, Weksler BB (1988) A rapid fluorometric DNA assay for the measurement of cell density and proliferation in vitro. Vitr Cell Dev Biol 24:247–252CrossRefGoogle Scholar
  222. McKelvey-Martin VJ et al (1993) The single cell gel electrophoresis assay (comet assay): a European review. Mutat Res Mol Mech Mutagen 288:47–63CrossRefGoogle Scholar
  223. Mejías R et al (2013) Long term biotransformation and toxicity of dimercaptosuccinic acid-coated magnetic nanoparticles support their use in biomedical applications. J Control Release 171:225–233CrossRefGoogle Scholar
  224. Miao X, Leng X, Zhang Q (2017) The current state of nanoparticle-induced macrophage polarization and reprogramming research. Int J Mol Sci 18Google Scholar
  225. Miernicki M, Hofmann T, Eisenberger I, von der Kammer F, Praetorius A (2019) Legal and practical challenges in classifying nanomaterials according to regulatory definitions. Nat Nanotechnol 14:208–216CrossRefGoogle Scholar
  226. Mishra SK, Khushu S, Gangenahalli G (2018) Effects of iron oxide contrast agent in combination with various transfection agents during mesenchymal stem cells labelling: An in vitro toxicological evaluation. Toxicol Vitr 50:179–189CrossRefGoogle Scholar
  227. Mitjans M, Nogueira-Librelotto DR, Vinardell MP, Nogueira-Librelotto DR, Vinardell MP (2018) Nanotoxicity In vitro: limitations of the main cytotoxicity assays. In: Kumar V, Dasgupta N, Ranjan S (eds) Nanotoxicology: toxicity evaluation, risk assessment and management. CRC Press, pp 171–192.
  228. Moghimi SM, Hunter AC, Andresen TL (2011) Factors controlling nanoparticle pharmacokinetics: an integrated analysis and perspective. Annu Rev Pharmacol Toxicol 52:481–503CrossRefGoogle Scholar
  229. Mok H et al (2010) pH-sensitive sirna nanovector for targeted gene silencing and cytotoxic effect in cancer cells. Mol Pharm 7:1930–1939CrossRefGoogle Scholar
  230. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63CrossRefGoogle Scholar
  231. Mueller-Klieser W (1987) Multicellular spheroids—a review on cellular aggregates in cancer research. J Cancer Res Clin Oncol. Scholar
  232. Mueller-Klieser W (2017) Three-dimensional cell cultures: from molecular mechanisms to clinical applications. Am J Physiol Physiol. Scholar
  233. Mulder WJ et al (2007) Magnetic and fluorescent nanoparticles for multimodality imaging. Nanomedicine 2:307–324CrossRefGoogle Scholar
  234. Müller K et al (2007) Effect of ultrasmall superparamagnetic iron oxide nanoparticles (Ferumoxtran-10) on human monocyte-macrophages in vitro. Biomaterials 28:1629–1642CrossRefGoogle Scholar
  235. Müller E et al (2018) Magnetic nanoparticles interact and pass an in vitro co-culture blood-placenta barrier model. Nanomaterials 8:108CrossRefGoogle Scholar
  236. Nabiev I et al (2007) Nonfunctionalized nanocrystals can exploit a cell’s active transport machinery delivering them to specific nuclear and cytoplasmic compartments. Nano Lett. Scholar
  237. Nachlas MM, Margulies SI, Goldberg JD, Seligman AM (1960) The determination of lactic dehydrogenase with a tetrazolium salt. Anal Biochem 1:317–326CrossRefGoogle Scholar
  238. Nakamura H, Watano S (2018) Direct permeation of nanoparticles across cell membrane: a review. KONA Powder Part J 35:49–65Google Scholar
  239. Nakayama GR, Caton MC, Nova MP, Parandoosh Z (1997) Assessment of the Alamar Blue assay for cellular growth and viability in vitro. J Immunol Methods 204:205–208CrossRefGoogle Scholar
  240. Narayanan S et al (2012) Biocompatible magnetite/gold nanohybrid contrast agents via green chemistry for MRI and CT bioimaging. ACS Appl Mater Interfaces 4:251–260CrossRefGoogle Scholar
  241. Nederman T, Twentyman P (1984) Spheroids for studies of drug effects. In: Acker H, Carlsson J, Durand R, Sutherland RM (eds) Spheroids in cancer research: methods and perspectives, pp 84–102. Springer, Berlin.
  242. Nel A, Xia T, Mädler L, Li N (2006) Toxic potential of materials at the nanolevel. Science (80–.) 311:622–627Google Scholar
  243. Nel A, Xia T, Mädler L, Li N (2006b) Toxic potential of materials at the nanolevel. Science. Scholar
  244. Neri M et al (2007) Efficient in vitro labeling of human neural precursor cells with superparamagnetic iron oxide particles: relevance for in vivo cell tracking. Stem Cells. Scholar
  245. Neuwelt EA et al (2009) Ultrasmall superparamagnetic iron oxides (USPIOs): a future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)? Kidney Int 75:465–474CrossRefGoogle Scholar
  246. Nguyen VH, Lee B-J (2017) Protein corona: a new approach for nanomedicine design. Int J Nanomed 12:3137–3151CrossRefGoogle Scholar
  247. Nguyen TA, Yin TI, Reyes D, Urban GA (2013) Microfluidic chip with integrated electrical cell-impedance sensing for monitoring single cancer cell migration in three-dimensional matrixes. Anal Chem. Scholar
  248. Niles AL, Moravec RA, Riss TL (2008) Update on in vitro cytotoxicity assays for drug development. Expert Opin Drug Discov 3:655–670CrossRefGoogle Scholar
  249. Nima ZA et al (2019) Bioinspired magnetic nanoparticles as multimodal photoacoustic, photothermal and photomechanical contrast agents. Sci Rep 9:887CrossRefGoogle Scholar
  250. O’Brien J, Wilson I, Orton T, Pognan F (2000) Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity. Eur J Biochem 5426:5421–5426Google Scholar
  251. O’Brien LE et al (2001) Rac1 orientates epithelial apical polarity through effects on basolateral laminin assembly. Nat Cell Biol. Scholar
  252. Oberdörster G et al (2004) Translocation of inhaled ultrafine particles to the brain. Inhal Toxicol 16:437–445CrossRefGoogle Scholar
  253. Oberdörster G, Oberdörster E, Oberdörster J (2005) Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 113:823–839CrossRefGoogle Scholar
  254. Oh N, Park JH (2014) Endocytosis and exocytosis of nanoparticles in mammalian cells. Int J Nanomed 9(Suppl 1):51Google Scholar
  255. Oliveira H et al (2013) Magnetic field triggered drug release from polymersomes for cancer therapeutics. J Control Release 169:165–170CrossRefGoogle Scholar
  256. Ostling O, Johanson KJ (1984) Microelectrophoretic study of radiation-induced DNA damages in individual mammalian cells. Biochem Biophys Res Commun 123:291–298CrossRefGoogle Scholar
  257. Owens DE, Peppas NA (2006) Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm 307:93–102CrossRefGoogle Scholar
  258. Palmer LS et al (1930) Milchuntersuchung. Fresenius’ Zeitschrift für Anal Chemie 82:268–271CrossRefGoogle Scholar
  259. Pan DC et al (2018) Nanoparticle properties modulate their attachment and effect on carrier red blood cells. Sci Rep 8:1615CrossRefGoogle Scholar
  260. Pankhurst QA, Connolly J, Jones SK, Dobson J (2003) Applications of magnetic nanoparticles in biomedicine. J Phys D Appl Phys 36:R167–R181CrossRefGoogle Scholar
  261. Park E-J et al (2014) Magnetic iron oxide nanoparticles induce autophagy preceding apoptosis through mitochondrial damage and ER stress in RAW264.7 cells. Toxicol Vitr 28:1402–1412Google Scholar
  262. Paul W, Sharma CP (2010) Inorganic nanoparticles for targeted drug delivery. Biointegr Med Implant Mater 204–235.
  263. Paull KD et al (1988) The synthesis of XTT: a new tetrazolium reagent that is bioreducible to a water-soluble formazan. J Heterocycl Chem 25:911–914CrossRefGoogle Scholar
  264. Perez RP, Godwin AK, Handel LM, Hamilton TC (1993) A comparison of clonogenic, microtetrazolium and sulforhodamine B assays for determination of cisplatin cytotoxicity in human ovarian carcinoma cell lines. Eur J Cancer 29:395–399CrossRefGoogle Scholar
  265. Pham BTT et al (2018) Biodistribution and clearance of stable superparamagnetic maghemite iron oxide nanoparticles in mice following intraperitoneal administration. Int J Mol Sci 19Google Scholar
  266. Pietroiusti A (2012) Health implications of engineered nanomaterials. Nanoscale 4:1231CrossRefGoogle Scholar
  267. Pietroiusti A, Campagnolo L, Fadeel B (2013) Interactions of engineered nanoparticles with organs protected by internal biological barriers. Small 9:1557–1572CrossRefGoogle Scholar
  268. Pincu M, Bass D, Norman A (1984) An improved micronuclear assay in lymphocytes. Mutat Res Lett 139:61–65CrossRefGoogle Scholar
  269. Pöttler M et al (2015) Genotoxicity of superparamagnetic iron oxide nanoparticles in granulosa cells. Int J Mol Sci 16:26280–26290CrossRefGoogle Scholar
  270. Prabhakarpandian B et al (2008) Synthetic microvascular networks for quantitative analysis of particle adhesion. Biomed Microdev. Scholar
  271. Prabhu S, Mutalik S, Rai S, Udupa N, Rao BSS (2015) PEGylation of superparamagnetic iron oxide nanoparticle for drug delivery applications with decreased toxicity: an in vivo study. J Nanoparticle Res 17Google Scholar
  272. Präbst K, Engelhardt H, Ringgeler S, Hübner H (2017) Basic colorimetric proliferation assays: MTT, WST, and resazurin. In: Gilbert D, Friedrich O (eds) Cell viability assays: methods and protocols. Methods in molecular biology, vol 1601. Humana Press, New York, pp 1–17.
  273. Prosen L et al (2013) Magnetofection: a reproducible method for gene delivery to melanoma cells. Biomed Res Int 2013:209452CrossRefGoogle Scholar
  274. Qiao R et al (2012) Receptor-mediated delivery of magnetic nanoparticles across the blood-brain barrier. ACS Nano. Scholar
  275. Reddy ST et al (2007) Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat Biotechnol 25:1159–1164CrossRefGoogle Scholar
  276. Reichel D, Tripathi M, Perez JM (2019) Biological effects of nanoparticles on macrophage polarization in the tumor microenvironment. Nanotheranostics 3:66–88CrossRefGoogle Scholar
  277. Repetto G, del Peso A, Zurita JL (2008) Neutral red uptake assay for the estimation of cell viability/ cytotoxicity. Nat Protoc 3:1125–1131CrossRefGoogle Scholar
  278. Riss TL, Moravec RA (2006) Cell proliferation assays: improved homogeneous methods used to measure the number of cells in culture. In: Celis JE (ed) Cell biology: a laboratory handbook, vol 1. Elsevier Academic Press, pp 25–33Google Scholar
  279. Riss TL, Moravec RA, O’Brien MA, Hawkins EM, Niles A (2006) Homogeneous multiwell assays for measuring cell viability, cytotoxicity and apoptosis. In: Minor L (ed) Handbook of assay development in drug discovery. Taylor & Francis Group, pp 385–406Google Scholar
  280. Riss TL, Moravec RA, Niles AL (2010) Assay development for cell viability and apoptosis for high-throughput screening. In: Chen T (ed) A practical guide to assay development and high-throughput screening in drug discovery. Critical reviews in combinatorial chemistry. CRC Press, pp 99–122Google Scholar
  281. Riss TL, Moravec RA, Niles AL (2011) Cytotoxicity testing: measuring viable cells, dead cells, and detecting mechanism of cell death. In: Stoddart M (ed) Mammalian cell viability: methods and protocols. Humana Press, pp 103–114.
  282. Rivera Gil P, Oberdörster G, Elder A, Puntes V, Parak WJ (2010) Correlating physico-chemical with toxicological properties of nanoparticles: the present and the future. ACS Nano 4:5227–5231Google Scholar
  283. Rizzo LY et al (2013) In vivo nanotoxicity testing using the zebrafish embryo assay. J Mater Chem B1:3918CrossRefGoogle Scholar
  284. Rodrigues RM et al (2013) Assessment of an automated in vitro basal cytotoxicity test system based on metabolically-competent cells. Toxicol Vitr 27:760–767CrossRefGoogle Scholar
  285. Rosano JM et al (2009) A physiologically realistic in vitro model of microvascular networks. Biomed Microdev. Scholar
  286. Rubinstein LV et al (1990) Comparison of in vitro anticancer-drug-screening data generated with a tetrazolium assay versus a protein assay against a diverse panel of human tumor cell lines. J Natl Cancer Inst 82:1113–1118CrossRefGoogle Scholar
  287. Ruponen M, Ylä-Herttuala S, Urtti A (1999) Interactions of polymeric and liposomal gene delivery systems with extracellular glycosaminoglycans: physicochemical and transfection studies. Biochim Biophys Acta Biomembr. Scholar
  288. Sadeghi L, Tanwir F, Yousefi Babadi V (2015) In vitro toxicity of iron oxide nanoparticle: oxidative damages on Hep G2 cells. Exp Toxicol Pathol 67:197–203Google Scholar
  289. Sadiq R, Khan QM, Mobeen A, Hashmat AJ (2015) In vitro toxicological assessment of iron oxide, aluminium oxide and copper nanoparticles in prokaryotic and eukaryotic cell types. Drug Chem Toxicol 38:152–161CrossRefGoogle Scholar
  290. Sahu SC, Casciano DA (2009) Nanotoxicity: from in vivo and in vitro models to health risks.
  291. Sahu SC, Hayes AW (2017) Toxicity of nanomaterials found in human environment. Toxicol Res Appl 1:239784731772635Google Scholar
  292. Salatin S, Dizaj SM, Khosroushahi AY (2015) Effect of the surface modification, size, and shape on cellular uptake of nanoparticles. Cell Biol Int 39:881–890CrossRefGoogle Scholar
  293. Same S, Aghanejad A, Nakhjavani SA, Barar J, Omidi Y (2016) Radiolabeled theranostics: magnetic and gold nanoparticles. Bioimpacts 6:169–181CrossRefGoogle Scholar
  294. Sargent LM et al (2009) Induction of aneuploidy by single-walled carbon nanotubes. Environ Mol Mutagen 50:708–717CrossRefGoogle Scholar
  295. Sayes CM, Reed KL, Warheit DB (2007) Assessing toxicology of fine and nanoparticles: comparing in vitro measurements to in vivo pulmonary toxicity profiles. Toxicol Sci 97:163–180CrossRefGoogle Scholar
  296. Schleich N et al (2013) Dual anticancer drug/superparamagnetic iron oxide-loaded PLGA-based nanoparticles for cancer therapy and magnetic resonance imaging. Int J Pharm 447:94–101CrossRefGoogle Scholar
  297. Schuurs AHWM, Van Weemen BK (1980) Enzyme-immunoassay: a powerful analytical tool. J Immunoassay 1:229–249Google Scholar
  298. Scudiero DA et al (1988) Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res 48:4827–4833Google Scholar
  299. Seabra AB et al (2014) Preparation, characterization, cytotoxicity, and genotoxicity evaluations of thiolated- and S-nitrosated superparamagnetic iron oxide nanoparticles: Implications for cancer treatment. Chem Res Toxicol 27:1207–1218CrossRefGoogle Scholar
  300. Seo DY, Jin M, Ryu JC, Kim YJ (2017) Investigation of the genetic toxicity by dextran-coated superparamagnetic iron oxide nanoparticles (SPION) in HepG2 cells using the comet assay and cytokinesis-block micronucleus assay. Toxicol Environ Health Sci 9:23–29CrossRefGoogle Scholar
  301. Shah V et al (2013) Genotoxicity of different nanocarriers: possible modifications for the delivery of nucleic acids. Curr Drug Discov Technol 10:8–15Google Scholar
  302. Shamir ER, Ewald AJ (2014) Three-dimensional organotypic culture: Experimental models of mammalian biology and disease. Nat Rev Mol Cell Biol. Scholar
  303. Shanavas A, Sasidharan S, Bahadur D, Srivastava R (2017) Magnetic core-shell hybrid nanoparticles for receptor targeted anti-cancer therapy and magnetic resonance imaging. J Colloid Interface Sci 486:112–120CrossRefGoogle Scholar
  304. Sharifi S et al (2012) Toxicity of nanomaterials. Chem Soc Rev 41:93CrossRefGoogle Scholar
  305. Sharkey J et al (2017) Functionalized superparamagnetic iron oxide nanoparticles provide highly efficient iron-labeling in macrophages for magnetic resonance–based detection in vivo. Cytotherapy 19:555–569CrossRefGoogle Scholar
  306. Sharma A et al (2018) Physical characterization and in vivo organ distribution of coated iron oxide nanoparticles. Sci Rep 8:1–12CrossRefGoogle Scholar
  307. Shaw J, Raja SO, Dasgupta AK (2014) Modulation of cytotoxic and genotoxic effects of nanoparticles in cancer cells by external magnetic field. Cancer Nanotechnol 5:2CrossRefGoogle Scholar
  308. Shi J et al (2012) Hemolytic properties of synthetic nano- and porous silica particles: the effect of surface properties and the protection by the plasma corona. Acta Biomater. Scholar
  309. Shi J et al (2013) PEGylated fullerene/iron oxide nanocomposites for photodynamic therapy, targeted drug delivery and MR imaging. Biomaterials 34:9666–9677CrossRefGoogle Scholar
  310. Shi D, Mi G, Bhattacharya S, Nayar S, Webster TJ (2016) Optimizing superparamagnetic iron oxide nanoparticles as drug carriers using an in vitro blood–brain barrier model. Int J Nanomed. Scholar
  311. Shvedova AA, Kagan VE, Fadeel B (2010) Close encounters of the small kind: adverse effects of man-made materials interfacing with the nano-cosmos of biological systems. Annu Rev Pharmacol Toxicol 50:63–88CrossRefGoogle Scholar
  312. Shydlovska O et al (2017) Synthesis and comparative characteristics of biological activities of (La, Sr)MnO3 and Fe3O4 nanoparticles. Eur J Nanomed 9:33–43CrossRefGoogle Scholar
  313. Sierra LM, Gaivão I (2014) Genotoxicity and DNA repair: a practical approach. Methods in pharmacology and toxicology. Humana PressGoogle Scholar
  314. Singamaneni S, Bliznyuk VN, Binek C, Tsymbal EY (2011) Magnetic nanoparticles: recent advances in synthesis, self-assembly and applications. J Mater Chem 21:16819CrossRefGoogle Scholar
  315. Singh N et al (2017) Exposure to engineered nanomaterials: impact on DNA Repair Pathways. Int J Mol Sci 18Google Scholar
  316. Singh NP, McCoy MT, Tice RR, Schneider EL (1988) A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175:184–191CrossRefGoogle Scholar
  317. Singh N et al (2009) Nanogenotoxicology: the DNA damaging potential of engineered nanomaterials. Biomaterials 30:3891–3914CrossRefGoogle Scholar
  318. Singh N, Jenkins GJS, Asadi R, Doak SH (2010) Potential toxicity of superparamagnetic iron oxide nanoparticles (SPION). Nano Rev 1:5358CrossRefGoogle Scholar
  319. Sitbon G et al (2014) Multimodal Mn-doped I-III-VI quantum dots for near infrared fluorescence and magnetic resonance imaging: from synthesis to in vivo application. Nanoscale 6:9264–9272CrossRefGoogle Scholar
  320. Skehan P et al (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 82:1107–1112CrossRefGoogle Scholar
  321. Soenen SJH, Nuytten N, De Meyer SF, De Smedt SC, De Cuyper M (2010) High intracellular iron oxide nanoparticle concentrations affect cellular cytoskeleton and focal adhesion kinase-mediated signaling. Small 6:832–842CrossRefGoogle Scholar
  322. Stafford S et al (2018) Multimodal magnetic-plasmonic nanoparticles for biomedical applications. Appl Sci 8:97CrossRefGoogle Scholar
  323. Stern ST, Adiseshaiah PP, Crist RM (2012) Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity. Part Fibre Toxicol 9:20CrossRefGoogle Scholar
  324. Stevenson R, Hueber AJ, Hutton A, McInnes IB, Graham D (2011) Nanoparticles and inflammation. Sci World J 11:1300–1312CrossRefGoogle Scholar
  325. Stocke NA et al (2017) Toxicity evaluation of magnetic hyperthermia induced by remote actuation of magnetic nanoparticles in 3D micrometastasic tumor tissue analogs for triple negative breast cancer. Biomaterials. Scholar
  326. Stoddart MJ (2011) Mammalian cell viability: methods and protocols. Methods in molecular biology, vol 740. Humana PressGoogle Scholar
  327. Streuli CH, Bailey N, Bissell MJ (1991) Control of mammary epithelial differentiation: basement membrane induces tissue-specific gene expression in the absence of cell-cell interaction and morphological polarity. J Cell Biol. Scholar
  328. Stroh A et al (2004) Iron oxide particles for molecular magnetic resonance imaging cause transient oxidative stress in rat macrophages. Free Radic Biol Med 36:976–984CrossRefGoogle Scholar
  329. Sun C et al (2008) Tumor-targeted drug delivery and MRI contrast enhancement by chlorotoxin-conjugated iron oxide nanoparticles. Nanomedicine 3:495–505CrossRefGoogle Scholar
  330. Sutariya VB et al (2015) Introduction—biointeractions of nanomaterials challenges and solutions. In: Sutariya VB, Pathak Y (eds) Biointeractions of nanomaterials, pp 1–48. CRC PressGoogle Scholar
  331. Sutariya VB, Pathak Y (2014) Biointeractions of nanomaterials. Biointeractions of Nanomaterials. Scholar
  332. Sylvester PW (2011) Optimization of the tetrazolium dye (MTT) colorimetric assay for cellular growth and viability. In: Satyanarayanajois S (ed) Drug design and discovery: methods and protocols. Methods in molecular biology, vol 716. Humana Press, pp 157–168.
  333. Tasso M et al (2015) Sulfobetaine-vinylimidazole block copolymers: a robust quantum dot surface chemistry expanding bioimaging’s horizons. ACS Nano 9:11479–11489CrossRefGoogle Scholar
  334. Teeguarden JG et al (2014) Comparative iron oxide nanoparticle cellular dosimetry and response in mice by the inhalation and liquid cell culture exposure routes. Part Fibre Toxicol 11:1–18CrossRefGoogle Scholar
  335. Territo MC, Cline MJ (1975) Mononuclear phagocyte proliferation, maturation and function. Clin Haematol 4:685–703Google Scholar
  336. Theumer A et al (2015) Superparamagnetic iron oxide nanoparticles exert different cytotoxic effects on cells grown in monolayer cell culture versus as multicellular spheroids. J Magn Magn Mater 380:27–33CrossRefGoogle Scholar
  337. Thorek DLJ, Tsourkas A (2008) Size, charge and concentration dependent uptake of iron oxide particles by non-phagocytic cells. Biomaterials 29:3583–3590CrossRefGoogle Scholar
  338. Thu MS et al (2009) Iron labeling and pre-clinical MRI visualization of therapeutic human neural stem cells in a murine glioma model. PLoS One 4:e7218Google Scholar
  339. Tice RR et al (2000) Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environ Mol Mutagen 35:206–221CrossRefGoogle Scholar
  340. Timmins NE, Nielsen LK (2007) Generation of multicellular tumor spheroids by the hanging-drop method. Tissue Eng.
  341. Tominaga H et al (1999) A water-soluble tetrazolium salt useful for colorimetric cell viability assay. Anal Commun 36:47–50CrossRefGoogle Scholar
  342. Tomitaka A et al (2019) Surface-engineered multimodal magnetic nanoparticles to manage CNS diseases. Drug Discov Today 24:873–882CrossRefGoogle Scholar
  343. Tse BW-C et al (2015) PSMA-targeting iron oxide magnetic nanoparticles enhance MRI of preclinical prostate cancer. Nanomedicine 10:375–386CrossRefGoogle Scholar
  344. Turiel-Fernández D, Bettmer J, Montes-Bayón M (2018) Evaluation of the uptake, storage and cell effects of nano-iron in enterocyte-like cell models. J Trace Elem Med Biol 49:98–104CrossRefGoogle Scholar
  345. Twigg RS (1945) Oxidation-reduction aspects of resazurin. Nature 155:401–402CrossRefGoogle Scholar
  346. Vedantam P, Huang G, Tzeng TRJ (2013) Size-dependent cellular toxicity and uptake of commercial colloidal gold nanoparticles in DU-145 cells. Cancer Nanotechnol 4:13–20CrossRefGoogle Scholar
  347. Veiseh O et al (2009a) Specific targeting of brain tumors with an optical/magnetic resonance imaging nanoprobe across the blood-brain barrier. Cancer Res 69:6200–6207CrossRefGoogle Scholar
  348. Veiseh O et al (2009b) Specific targeting of brain tumors with an optical/magnetic resonance imaging nanoprobe across the blood-brain barrier. Cancer Res. Scholar
  349. Vichai V, Kirtikara K (2006) Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 1:1112–1116CrossRefGoogle Scholar
  350. Vinci M et al (2012) Advances in establishment and analysis of three-dimensional tumor spheroid-based functional assays for target validation and drug evaluation. BMC Biol. Scholar
  351. Walkey CD, Chan WCW (2012) Understanding and controlling the interaction of nanomaterials with proteins in a physiological environment. Chem Soc Rev 41:2780–2799CrossRefGoogle Scholar
  352. Wan R et al (2017) Cobalt nanoparticles induce lung injury, DNA damage and mutations in mice. Part Fibre Toxicol 14:38CrossRefGoogle Scholar
  353. Wang B et al (2009) Neurotoxicity of low-dose repeatedly intranasal instillation of nano- and submicron-sized ferric oxide particles in mice. J Nanoparticle Res 11:41–53CrossRefGoogle Scholar
  354. Wang X et al (2012) Cancer stem cell labeling using poly(l-lysine)-modified iron oxide nanoparticles. Biomaterials. Scholar
  355. Wang D et al (2014) Targeted iron-oxide nanoparticle for photodynamic therapy and imaging of head and neck cancer. ACS Nano 8:6620–6632CrossRefGoogle Scholar
  356. Wang Q et al (2015) Low toxicity and long circulation time of polyampholyte-coated magnetic nanoparticles for blood pool contrast. Sci Rep 5:1–8Google Scholar
  357. Wang F, Salvati A, Boya P (2018) Lysosome-dependent cell death and deregulated autophagy induced by amine-modified polystyrene nanoparticles. Open Biol 8Google Scholar
  358. Warren EAK, Payne CK (2015) Cellular binding of nanoparticles disrupts the membrane potential. RSC Adv 5:13660–13666CrossRefGoogle Scholar
  359. Wei Y et al (2016) Iron overload by superparamagnetic iron oxide nanoparticles is a high risk factor in cirrhosis by a systems toxicology assessment. Sci Rep 6:29110CrossRefGoogle Scholar
  360. Weir MP, Gibson JF, Peters TJ (1984) Haemosiderin and tissue damage. Cell Biochem Funct. Scholar
  361. Weselsky P (1871) Ueber die Azoverbindungen des Resorcins. Berichte der Dtsch Chem Gesellschaft 4:613–619CrossRefGoogle Scholar
  362. Wȩsierska-Ga̧dek J, Gueorguieva M, Ranftler C, Zerza-Schnitzhofer G (2005) A new multiplex assay allowing simultaneous detection of the inhibition of cell proliferation and induction of cell death. J Cell Biochem 96:1–7Google Scholar
  363. Wittekind D (2003) Traditional staining for routine diagnostic pathology including the role of tannic acid. 1. Value and limitations of the hematoxylin-eosin stain. Biotech Histochem 78:261–270Google Scholar
  364. Wolff I, Müller P (2006) Micronuclei and comet assay. In: Celis JE (2006) Cell biology: a laboratory handbook, vol 1. Elsevier Academic Press, pp 325–331Google Scholar
  365. Woolston C, Martin S (2011) Analysis of tumor and endothelial cell viability and survival using sulforhodamine B and clonogenic assays. In: Stoddart MJ (ed) Mammalian cell viability: methods and protocols. Methods in molecular biology, vol 740; Humana Press, pp 45–56.
  366. Wottrich R, Diabate S, Krug HF (2004) Biological effects of ultrafine model particles in human macrophages and epithelial cells in mono- and co-culture. Int J Hyg Environ Heal 207:353–361CrossRefGoogle Scholar
  367. Wu Y et al (2009) Multiplexed assay panel of cytotoxicity in HK-2 cells for detection of renal proximal tubule injury potential of compounds. Toxicol Vitr 23:1170–1178CrossRefGoogle Scholar
  368. Wu K, Su D, Liu J, Saha R, Wang J-P (2018) Magnetic nanoparticles in nanomedicineGoogle Scholar
  369. Xia T, Kovochich M, Liong M, Zink JI, Nel AE (2008) Cationic polystyrene nanosphere toxicity depends on cell-specific endocytic and mitochondrial injury pathways. ACS Nano 2:85–96CrossRefGoogle Scholar
  370. Xia T, Li N, Nel AE (2009) Potential health impact of nanoparticles. Annu Rev Public Health 30:137–150CrossRefGoogle Scholar
  371. Xie Y et al (2016) Size-dependent cytotoxicity of Fe3O4 nanoparticles induced by biphasic regulation of oxidative stress in different human hepatoma cells. Int J Nanomed 11:3557–3570CrossRefGoogle Scholar
  372. Xu S, Olenyuk BZ, Okamoto CT, Hamm-Alvarez SF (2013) Targeting receptor-mediated endocytotic pathways with nanoparticles: rationale and advances. Adv Drug Deliv Rev 65:121–138CrossRefGoogle Scholar
  373. Xuan S et al (2011) Synthesis of biocompatible, mesoporous Fe3O4 nano/microspheres with large surface area for magnetic resonance imaging and therapeutic applications. ACS Appl Mater Interfaces 3:237–244CrossRefGoogle Scholar
  374. Yallapu MM et al (2015) Implications of protein corona on physico-chemical and biological properties of magnetic nanoparticles. Biomaterials 46:1–12CrossRefGoogle Scholar
  375. Yang S-A, Choi S, Jeon SM, Yu J (2018) Silica nanoparticle stability in biological media revisited. Sci Rep 8:185CrossRefGoogle Scholar
  376. Yu W et al (2007) Formation of cysts by alveolar type II cells in three-dimensional culture reveals a novel mechanism for epithelial morphogenesis. Mol Biol Cell. Scholar
  377. Zanoni M et al (2016) 3D tumor spheroid models for in vitro therapeutic screening: a systematic approach to enhance the biological relevance of data obtained. Sci Rep. Scholar
  378. Zelazna K, Rudnicka K, Tejs S (2011) In vitro micronucleus test assessment of polycyclic aromatic hydrocarbons. Environ Biotechnol 7Google Scholar
  379. Zhang X-Q et al (2012a) Interactions of nanomaterials and biological systems: implications to personalized nanomedicine. Adv Drug Deliv Rev 64:1363CrossRefGoogle Scholar
  380. Zhang T et al (2012b) Evaluation on cytotoxicity and genotoxicity of the l-glutamic acid coated iron oxide nanoparticles. J Nanosci Nanotechnol 12:2866–2873CrossRefGoogle Scholar
  381. Zhang M, Xu C, Jiang L, Qin J (2018) A 3D human lung-on-a-chip model for nanotoxicity testing. Toxicol Res. Scholar
  382. Zhen X, Cheng P, Pu K (2019) Recent advances in cell membrane-camouflaged nanoparticles for cancer phototherapy. Small 15:1804105CrossRefGoogle Scholar
  383. Zheng X-C et al (2018) The theranostic efficiency of tumor-specific, pH-responsive, peptide-modified, liposome-containing paclitaxel and superparamagnetic iron oxide nanoparticles. Int J Nanomed 13:1495–1504CrossRefGoogle Scholar
  384. Zhu MT et al (2008) Comparative study of pulmonary responses to nano- and submicron-sized ferric oxide in rats. Toxicology 247:102–111CrossRefGoogle Scholar
  385. Zhu M-T et al (2011) Endothelial dysfunction and inflammation induced by iron oxide nanoparticle exposure: Risk factors for early atherosclerosis. Toxicol Lett 203:162–171CrossRefGoogle Scholar
  386. Zhu M et al (2013a) Physicochemical properties determine nanomaterial cellular uptake, transport, and fate. Acc Chem Res 46:622–631CrossRefGoogle Scholar
  387. Zhu L et al (2013b) Multifunctional pH-sensitive superparamagnetic iron-oxide nanocomposites for targeted drug delivery and MR imaging. J Control Rel 169:228–238CrossRefGoogle Scholar
  388. Zou P et al (2010) Superparamagnetic iron oxide nanotheranostics for targeted cancer cell imaging and pH-dependent intracellular drug release. Mol Pharm 7:1974–1984CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Mariana Tasso
    • 1
  • Maria Amparo Lago Huvelle
    • 2
  • Ines Diaz Bessone
    • 2
  • Agustin S. Picco
    • 1
    Email author
  1. 1.Departamento de Química, Facultad de Ciencias Exactas, Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas (INIFTA)Universidad Nacional de La Plata—CONICETLa PlataArgentina
  2. 2.Instituto de Nanosistemas, Universidad Nacional de San MartínVilla LynchArgentina

Personalised recommendations