Abstract
Magnetic iron oxide nanoparticles (IONPs) are used for various applications in biomedicine, for example as contrast agents in magnetic resonance imaging, for cell tracking and for anti-tumor treatment. However, IONPs are also known for their toxic effects on cells and tissues which are at least in part caused by iron-mediated radical formation and oxidative stress. The potential toxicity of IONPs is especially important concerning the use of IONPs for neurobiological applications as alterations in brain iron homeostasis are strongly connected with human neurodegenerative diseases. Since IONPs are able to enter the brain, potential adverse consequences of an exposure of brain cells to IONPs have to be considered. This article describes the pathways that allow IONPs to enter the brain and summarizes the current knowledge on the uptake, the metabolism and the toxicity of IONPs for the different types of brain cells in vitro and in vivo.
Similar content being viewed by others
References
Auffan M, Rose J, Bottero JY, Lowry GV, Jolivet JP, Wiesner MR (2009) Towards a definition of inorganic nanoparticles from an environmental, health and safety perspective. Nat Nanotechnol 4:634–641
Treccani L, Yvonne Klein T, Meder F, Pardun K, Rezwan K (2013) Functionalized ceramics for biomedical, biotechnological and environmental applications. Acta Biomater 9:7115–7150
Kim T, Hyeon T (2014) Applications of inorganic nanoparticles as therapeutic agents. Nanotechnology 25:012001
Roopan SM, Surendra TV, Elango G, Kumar SH (2014) Biosynthetic trends and future aspects of bimetallic nanoparticles and its medicinal applications. Appl Microbiol Biotechnol 98:5289–5300
Wang D, Lin B, Ai H (2014) Theranostic nanoparticles for cancer and cardiovascular applications. Pharm Res 31:1390–1406
Singh A, Sahoo SK (2014) Magnetic nanoparticles: a novel platform for cancer theranostics. Drug Discov Today 19:474–481
Raj S, Jose S, Sumod US, Sabitha M (2012) Nanotechnology in cosmetics: opportunities and challenges. J Pharm Bioallied Sci 4:186–193
Hajipour MJ, Fromm KM, Ashkarran AA, Jimenez de Aberasturi D, de Larramendi IR, Rojo T, Serpooshan V, Parak WJ, Mahmoudi M (2012) Antibacterial properties of nanoparticles. Trends Biotechnol 30:499–511
Banobre-Lopez M, Teijeiro A, Rivas J (2013) Magnetic nanoparticle-based hyperthermia for cancer treatment. Rep Pract Oncol Radiother 18:397–400
Hohnholt MC, Geppert M, Luther EM, Petters C, Bulcke F, Dringen R (2013) Handling of iron oxide and silver nanoparticles by astrocytes. Neurochem Res 38:227–239
Li L, Jiang W, Luo K, Song H, Lan F, Wu Y, Gu Z (2013) Superparamagnetic iron oxide nanoparticles as MRI contrast agents for non-invasive stem cell labeling and tracking. Theranostics 3:595–615
Mahmoudi M, Stroeve P, Milani AS, Arbab AS (2011) Superparamagnetic iron oxide nanoparticles: synthesis, surface engineering, cytotoxicity and biomedical applications. Nova Science, New York
Maier-Hauff K, Ulrich F, Nestler D, Niehoff H, Wust P, Thiesen B, Orawa H, Budach V, Jordan A (2011) Efficacy and safety of intratumoral thermotherapy using magnetic iron-oxide nanoparticles combined with external beam radiotherapy on patients with recurrent glioblastoma multiforme. J Neurooncol 103:317–324
Suh WH, Suslick KS, Stucky GD, Suh YH (2009) Nanotechnology, nanotoxicology, and neuroscience. Prog Neurobiol 87:133–170
Weinstein JS, Varallyay CG, Dosa E, Gahramanov S, Hamilton B, Rooney WD, Muldoon LL, Neuwelt EA (2010) Superparamagnetic iron oxide nanoparticles: diagnostic magnetic resonance imaging and potential therapeutic applications in neurooncology and central nervous system inflammatory pathologies, a review. J Cereb Blood Flow Metab 30:15–35
Winer JL, Kim PE, Law M, Liu CY, Apuzzo MLJ (2011) Visualizing the future: enhancing neuroimaging with nanotechnology. World Neurosurg 75:626–637
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 112:2323–2338
Soenen SJ, De Cuyper M, De Smedt SC, Braeckmans K (2012) Investigating the toxic effects of iron oxide nanoparticles. Methods Enzymol 509:195–224
Hare D, Ayton S, Bush A, Lei P (2013) A delicate balance: iron metabolism and diseases of the brain. Front Aging Neurosci 5:34
Rouault TA (2013) Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat Rev Neurosci 14:551–564
Turcheniuk K, Tarasevych AV, Kukhar VP, Boukherroub R, Szunerits S (2013) Recent advances in surface chemistry strategies for the fabrication of functional iron oxide based magnetic nanoparticles. Nanoscale 5:10729–10752
Akbarzadeh A, Samiei M, Davaran S (2012) Magnetic nanoparticles: preparation, physical properties, and applications in biomedicine. Nanoscale Res Lett 7:1–13
Gupta AK, Gupta M (2005) Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials 26:3995–4021
Laurent S, Forge D, Port M, Roch A, Robic C, Elst LV, Muller RN (2008) Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. Chem Rev 108:2064–2110
Zhang L, Dong WF, Sun HB (2013) Multifunctional superparamagnetic iron oxide nanoparticles: design, synthesis and biomedical photonic applications. Nanoscale 5:7664–7684
Santhosh PB, Ulrih NP (2013) Multifunctional superparamagnetic iron oxide nanoparticles: promising tools in cancer theranostics. Cancer Lett 336:8–17
Colombo M, Carregal-Romero S, Casula MF, Gutierrez L, Morales MP, Bohm IB, Heverhagen JT, Prosperi D, Parak WJ (2012) Biological applications of magnetic nanoparticles. Chem Soc Rev 41:4306–4334
Lodhia J, Mandarano G, Ferris N, Eu P, Cowell S (2010) Development and use of iron oxide nanoparticles (Part 1): synthesis of iron oxide nanoparticles for MRI. Biomed Imaging Interv J 6:e12
Babes L, Denizot B, Tanguy G, Le Jeune JJ, Jallet P (1999) Synthesis of iron oxide nanoparticles used as MRI contrast agents: a parametric study. J Colloid Interface Sci 212:474–482
Schladt TD, Schneider K, Schild H, Tremel W (2011) Synthesis and bio-functionalization of magnetic nanoparticles for medical diagnosis and treatment. Dalton Trans 40:6315–6343
Nel AE, Madler L, Velegol D, Xia T, Hoek EM, Somasundaran P, Klaessig F, Castranova V, Thompson M (2009) Understanding biophysicochemical interactions at the nano–bio interface. Nat Mater 8:543–557
Bertorelle F, Wilhelm C, Roger J, Gazeau F, Menager C, Cabuil V (2006) Fluorescence-modified superparamagnetic nanoparticles: intracellular uptake and use in cellular imaging. Langmuir 22:5385–5391
Ge YQ, Zhang Y, He SY, Nie F, Teng GJ, Gu N (2009) Fluorescence modified chitosan-coated magnetic nanoparticles for high-efficient cellular imaging. Nanoscale Res Lett 4:287–295
Petters C, Bulcke F, Thiel K, Bickmeyer U, Dringen R (2014) Uptake of fluorescent iron oxide nanoparticles by oligodendroglial OLN-93 cells. Neurochem Res 39:372–383
Yan F, Wang Y, He SZ, Ku ST, Gu W, Ye L (2013) Transferrin-conjugated, fluorescein-loaded magnetic nanoparticles for targeted delivery across the blood-brain barrier. J Mater Sci Mater Med 24:2371–2379
Agemy L, Friedmann-Morvinski D, Kotamraju VR, Roth L, Sugahara KN, Girard OM, Mattrey RF, Verma IM, Ruoslahti E (2011) Targeted nanoparticle enhanced proapoptotic peptide as potential therapy for glioblastoma. Proc Natl Acad Sci USA 108:17450–17455
Kumar M, Singh G, Arora V, Mewar S, Sharma U, Jagannathan NR, Sapra S, Dinda AK, Kharbanda S, Singh H (2012) Cellular interaction of folic acid conjugated superparamagnetic iron oxide nanoparticles and its use as contrast agent for targeted magnetic imaging of tumor cells. Int J Nanomed 7:3503–3516
Hassan EE, Gallo JM (1993) Targeting anticancer drugs to the brain. I: enhanced brain delivery of oxantrazole following administration in magnetic cationic microspheres. J Drug Target 1:7–14
Jenkins SI, Pickard MR, Granger N, Chari DM (2011) Magnetic nanoparticle-mediated gene transfer to oligodendrocyte precursor cell transplant populations is enhanced by magnetofection strategies. ACS Nano 5:6527–6538
Krotz F, de Wit C, Sohn HY, Zahler S, Gloe T, Pohl U, Plank C (2003) Magnetofection—a highly efficient tool for antisense oligonucleotide delivery in vitro and in vivo. Mol Ther 7:700–710
Kumar M, Yigit M, Dai G, Moore A, Medarova Z (2010) Image-guided breast tumor therapy using a small interfering RNA nanodrug. Cancer Res 70:7553–7561
Lam T, Pouliot P, Avti PK, Lesage F, Kakkar AK (2013) Superparamagnetic iron oxide based nanoprobes for imaging and theranostics. Adv Colloid Interface Sci 199–200:95–113
Pai AB, Garba AO (2012) Ferumoxytol: a silver lining in the treatment of anemia of chronic kidney disease or another dark cloud? J Blood Med 3:77–85
McCormack PL (2012) Ferumoxytol: in iron deficiency anaemia in adults with chronic kidney disease. Drugs 72:2013–2022
Fauconnier N, Pons JN, Roger J, Bee A (1997) Thiolation of maghemite nanoparticles by dimercaptosuccinic acid. J Colloid Interface Sci 194:427–433
Maurizi L, Bisht H, Bouyer F, Millot N (2009) Easy route to functionalize iron oxide nanoparticles via long-term stable thiol groups. Langmuir 25:8857–8859
He X, Wu X, Cai X, Lin S, Xie M, Zhu X, Yan D (2012) Functionalization of magnetic nanoparticles with dendritic–linear–brush-like triblock copolymers and their drug release properties. Langmuir 28:11929–11938
Amiri H, Bordonali L, Lascialfari A, Wan S, Monopoli MP, Lynch I, Laurent S, Mahmoudi M (2013) Protein corona affects the relaxivity and MRI contrast efficiency of magnetic nanoparticles. Nanoscale 5:8656–8665
Mu QX, Li ZW, Li X, Mishra SR, Zhang B, Si ZK, Yang L, Jiang W, Yan B (2009) Characterization of protein clusters of diverse magnetic nanoparticles and their dynamic interactions with human cells. J Phys Chem C 113:5390–5395
Jansch M, Stumpf P, Graf C, Ruhl E, Muller RH (2012) Adsorption kinetics of plasma proteins on ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles. Int J Pharm 428:125–133
Saptarshi SR, Duschl A, Lopata AL (2013) Interaction of nanoparticles with proteins: relation to bio-reactivity of the nanoparticle. J Nanobiotechnol 11:26–37
Mahmoudi M, Lynch I, Ejtehadi MR, Monopoli MP, Bombelli FB, Laurent S (2011) Protein-nanoparticle interactions: opportunities and challenges. Chem Rev 111:5610–5637
Monopoli MP, Aberg C, Salvati A, Dawson KA (2012) Biomolecular coronas provide the biological identity of nanosized materials. Nat Nanotechnol 7:779–786
Mahmoudi M, Meng J, Xue X, Liang XJ, Rahman M, Pfeiffer C, Hartmann R, Gil PR, Pelaz B, Parak WJ, Del Pino P, Carregal-Romero S, Kanaras AG, Tamil Selvan S (2014) Interaction of stable colloidal nanoparticles with cellular membranes. Biotechnol Adv 32:679–692
Bajaj A, Samanta B, Yan HH, Jerry DJ, Rotello VM (2009) Stability, toxicity and differential cellular uptake of protein passivated-Fe3O4 nanoparticles. J Mater Chem 19:6328–6331
Geppert M, Petters C, Thiel K, Dringen R (2013) The presence of serum alters the properties of iron oxide nanoparticles and lowers their accumulation by cultured brain astrocytes. J Nanopart Res 15:1349–1363
Safi M, Courtois J, Seigneuret M, Conjeaud H, Berret JF (2011) The effects of aggregation and protein corona on the cellular internalization of iron oxide nanoparticles. Biomaterials 32:9353–9363
Wang B, Feng WY, Wang M, Shi JW, Zhang F, Ouyang H, Zhao YL, Chai ZF, Huang YY, Xie YN, Wang HF, Wang J (2007) Transport of intranasally instilled fine Fe2O3 particles into the brain: micro-distribution, chemical states, and histopathological observation. Biol Trace Elem Res 118:233–243
Wu J, Ding TT, Sun J (2013) Neurotoxic potential of iron oxide nanoparticles in the rat brain striatum and hippocampus. Neurotoxicology 34:243–253
Kim JS, Yoon TJ, Yu KN, Kim BG, Park SJ, Kim HW, Lee KH, Park SB, Lee JK, Cho MH (2006) Toxicity and tissue distribution of magnetic nanoparticles in mice. Toxicol Sci 89:338–347
Kwon JT, Hwang SK, Jin H, Kim DS, Minai-Tehrani A, Yoon HJ, Choi M, Yoon TJ, Han DY, Kang YW, Yoon BI, Lee JK, Cho MH (2008) Body distribution of inhaled fluorescent magnetic nanoparticles in the mice. J Occup Health 50:1–6
Liu CH, Ren JQ, You Z, Yang J, Liu CM, Uppal R, Liu PK (2012) Noninvasive detection of neural progenitor cells in living brains by MRI. FASEB J 26:1652–1662
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 5:316–327
Wang J, Chen Y, Chen B, Ding J, Xia G, Gao C, Cheng J, Jin N, Zhou Y, Li X, Tang M, Wang XM (2010) Pharmacokinetic parameters and tissue distribution of magnetic Fe(3)O(4) nanoparticles in mice. Int J Nanomed 5:861–866
Ku S, Yan F, Wang Y, Sun Y, Yang N, Ye L (2010) The blood-brain barrier penetration and distribution of PEGylated fluorescein-doped magnetic silica nanoparticles in rat brain. Biochem Biophys Res Commun 394:871–876
Fishman JB, Rubin JB, Handrahan JV, Connor JR, Fine RE (1987) Receptor-mediated transcytosis of transferrin across the blood–brain-barrier. J Neurosci Res 18:299–304
Dan M, Cochran DB, Yokel RA, Dziubla TD (2013) Binding, transcytosis and biodistribution of anti-PECAM-1 iron oxide nanoparticles for brain-targeted delivery. PLoS One 8:e81051
Cupaioli FA, Zucca FA, Boraschi D, Zecca L (2014) Engineered nanoparticles. How brain friendly is this new guest? Prog Neurobiol (in press)
Krol S, Macrez R, Docagne F, Defer G, Laurent S, Rahman M, Hajipour MJ, Kehoe PG, Mahmoudi M (2013) Therapeutic benefits from nanoparticles: the potential significance of nanoscience in diseases with compromise to the blood brain barrier. Chem Rev 113:1877–1903
Hoff D, Sheikh L, Bhattacharya S, Nayar S, Webster TJ (2013) Comparison study of ferrofluid and powder iron oxide nanoparticle permeability across the blood–brain barrier. Int J Nanomed 8:703–710
Thomsen LB, Linemann T, Pondman KM, Lichota J, Kim KS, Pieters RJ, Visser GM, Moos T (2013) Uptake and transport of superparamagnetic iron oxide nanoparticles through human brain capillary endothelial cells. ACS Chem Neurosci 4:1352–1360
Kenzaoui BH, Bernasconi CC, Hofmann H, Juillerat-Jeanneret L (2012) Evaluation of uptake and transport of ultrasmall superparamagnetic iron oxide nanoparticles by human brain-derived endothelial cells. Nanomedicine 7:39–53
Weise G, Stoll G (2012) Magnetic resonance imaging of blood brain/nerve barrier dysfunction and leukocyte infiltration: closely related or discordant? Front Neurol 3:178
Mejias R, Perez-Yague S, Roca AG, Perez N, Villanueva A, Canete M, Manes S, Ruiz-Cabello J, Benito M, Labarta A, Batlle X, Veintemillas-Verdaguer S, Morales MP, Barber DF, Serna CJ (2010) Liver and brain imaging through dimercaptosuccinic acid-coated iron oxide nanoparticles. Nanomedicine (Lond) 5:397–408
Taschner CA, Wetzel SG, Tolnay M, Froehlich J, Merlo A, Radue EW (2005) Characteristics of ultrasmall superparamagnetic iron oxides in patients with brain tumors. Am J Roentgenol 185:1477–1486
van Landeghem FKH, Maier-Hauff K, Jordan A, Hoffmann KT, Gneveckow U, Scholz R, Thiesen B, Bruck W, von Deimling A (2009) Post-mortem studies in glioblastoma patients treated with thermotherapy using magnetic nanoparticles. Biomaterials 30:52–57
Zimmer C, Weissleder R, Oconnor D, Lapointe L, Brady TJ, Enochs WS (1995) Cerebral iron-oxide distribution: in vivo mapping with MR imaging. Radiology 196:521–527
Wang Y, Wang B, Zhu MT, Li M, Wang HJ, Wang M, Ouyang H, Chai ZF, Feng WY, Zhao YL (2011) Microglial activation, recruitment and phagocytosis as linked phenomena in ferric oxide nanoparticle exposure. Toxicol Lett 205:26–37
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 36:296–305
Muldoon LL, Sandor M, Pinkston KE, Neuwelt EA (2005) Imaging, distribution, and toxicity of superparamagnetic iron oxide magnetic resonance nanoparticles in the rat brain and intracerebral tumor. Neurosurgery 57:785–796
Wang FH, Kim DK, Yoshitake T, Johansson SM, Bjelke B, Muhammed M, Kehr J (2011) Diffusion and clearance of superparamagnetic iron oxide nanoparticles infused into the rat striatum studied by MRI and histochemical techniques. Nanotechnology 22:015103
Neuwelt EA, Várallyay P, Bagó AG, Muldoon LL, Nesbit G, Nixon R (2004) Imaging of iron oxide nanoparticles by MR and light microscopy in patients with malignant brain tumours. Neuropathol Appl Neurobiol 30:456–471
Kim Y, Kong SD, Chen LH, Pisanic TR 2nd, Jin S, Shubayev VI (2013) In vivo nanoneurotoxicity screening using oxidative stress and neuroinflammation paradigms. Nanomedicine 9:1057–1066
Dobson J (2001) Nanoscale biogenic iron oxides and neurodegenerative disease. FEBS Lett 496:1–5
An L, Liu S, Yang Z, Zhang T (2012) Cognitive impairment in rats induced by nano-CuO and its possible mechanisms. Toxicol Lett 213:220–227
Hu R, Gong X, Duan Y, Li N, Che Y, Cui Y, Zhou M, Liu C, Wang H, Hong F (2010) Neurotoxicological effects and the impairment of spatial recognition memory in mice caused by exposure to TiO2 nanoparticles. Biomaterials 31:8043–8050
Sharma HS, Sharma A (2012) Neurotoxicity of engineered nanoparticles from metals. CNS Neurol Disord Drug Targets 11:65–80
Levy M, Lagarde F, Maraloiu VA, Blanchin MG, Gendron F, Wilhelm C, Gazeau F (2010) Degradability of superparamagnetic nanoparticles in a model of intracellular environment: follow-up of magnetic, structural and chemical properties. Nanotechnology 21:395103
Voinov MA, Pagan JOS, Morrison E, Smirnova TI, Smirnov AI (2011) Surface-mediated production of hydroxyl radicals as a mechanism of iron oxide nanoparticle biotoxicity. J Am Chem Soc 133:35–41
Tulpule K, Hohnholt MC, Hirrlinger J, Dringen R (2014) Primary cultures of astrocytes and neurons as model systems to study the metabolism and metabolite export from brain cells. In: Waagepetersen H, Hirrlinger J (eds) Neuromethods: brain energy metabolism. Springer, Heidelberg (in press)
Lange SC, Bak LK, Waagepetersen HS, Schousboe A, Norenberg MD (2012) Primary cultures of astrocytes: their value in understanding astrocytes in health and disease. Neurochem Res 37:2569–2588
Hohnholt MC, Dringen R (2013) Uptake and metabolism of iron and iron oxide nanoparticles in brain astrocytes. Biochem Soc Trans 41:1588–1592
Sun ZZ, Yathindranath V, Worden M, Thliveris JA, Chu S, Parkinson FE, Hegmann T, Miller DW (2013) Characterization of cellular uptake and toxicity of aminosilane-coated iron oxide nanoparticles with different charges in central nervous system-relevant cell culture models. Int J Nanomed 8:961–970
Lamkowsky MC, Geppert M, Schmidt MM, Dringen R (2012) Magnetic field-induced acceleration of the accumulation of magnetic iron oxide nanoparticles by cultured brain astrocytes. J Biomed Mater Res A 100A:323–334
Kenzaoui BH, Vila MR, Miquel JM, Cengelli F, Juillerat-Jeanneret L (2012) Evaluation of uptake and transport of cationic and anionic ultrasmall iron oxide nanoparticles by human colon cells. Int J Nanomed 7:1275–1286
Schweiger C, Hartmann R, Zhang F, Parak WJ, Kissel TH, Rivera Gil P (2012) Quantification of the internalization patterns of superparamagnetic iron oxide nanoparticles with opposite charge. J Nanobiotechnology 10:28–38
Geppert M, Hohnholt M, Gaetjen L, Grunwald I, Baumer M, Dringen R (2009) Accumulation of iron oxide nanoparticles by cultured brain astrocytes. J Biomed Nanotechnol 5:285–293
Geppert M, Hohnholt MC, Thiel K, Nurnberger S, Grunwald I, Rezwan K, Dringen R (2011) Uptake of dimercaptosuccinate-coated magnetic iron oxide nanoparticles by cultured brain astrocytes. Nanotechnology 22:145101
Pickard MR, Jenkins SI, Koller CJ, Furness DN, Chari DM (2010) Magnetic nanoparticle labeling of astrocytes derived for neural transplantation. Tissue Eng Part C Methods 17:89–99
Geppert M, Hohnholt MC, Nurnberger S, Dringen R (2012) Ferritin up-regulation and transient ROS production in cultured brain astrocytes after loading with iron oxide nanoparticles. Acta Biomater 8:3832–3839
Pinkernelle J, Calatayud P, Goya GF, Fansa H, Keilhoff G (2012) Magnetic nanoparticles in primary neural cell cultures are mainly taken up by microglia. BMC Neurosci 13:32–48
Fleige G, Nolte C, Synowitz M, Seeberger F, Kettenmann H, Zimmer C (2001) Magnetic labeling of activated microglia in experimental gliomas. Neoplasia 3:489–499
Luther EM, Petters C, Bulcke F, Kaltz A, Thiel K, Bickmeyer U, Dringen R (2013) Endocytotic uptake of iron oxide nanoparticles by cultured brain microglial cells. Acta Biomater 9:8454–8465
Wu HY, Chung MC, Wang CC, Huang CH, Liang HJ, Jan TR (2013) Iron oxide nanoparticles suppress the production of IL-1beta via the secretory lysosomal pathway in murine microglial cells. Part Fibre Toxicol 10:46–56
Jenkins SI, Pickard MR, Furness DN, Yiu HH, Chari DM (2013) Differences in magnetic particle uptake by CNS neuroglial subclasses: implications for neural tissue engineering. Nanomedicine (Lond) 8:951–968
Pickard MR, Chari DM (2010) Robust uptake of magnetic nanoparticles (MNPs) by central nervous system (CNS) microglia: implications for particle uptake in mixed neural cell populations. Int J Mol Sci 11:967–981
Nayak D, Roth TL, McGavern DB (2014) Microglia development and function. Annu Rev Immunol 32:367–402
Xue Y, Wu J, Sun J (2012) Four types of inorganic nanoparticles stimulate the inflammatory reaction in brain microglia and damage neurons in vitro. Toxicol Lett 214:91–98
Cengelli F, Maysinger D, Tschudi-Monnet F, Montet X, Corot C, Petri-Fink A, Hofmann H, Juillerat-Jeanneret L (2006) Interaction of functionalized superparamagnetic iron oxide nanoparticles with brain structures. J Pharmacol Exp Ther 318:108–116
Richter-Landsberg C, Heinrich M (1996) OLN-93: a new permanent oligodendroglia cell line derived from primary rat brain glial cultures. J Neurosci Res 45:161–173
Hohnholt M, Geppert M, Dringen R (2010) Effects of iron chelators, iron salts, and iron oxide nanoparticles on the proliferation and the iron content of oligodendroglial OLN-93 cells. Neurochem Res 35:1259–1268
Hohnholt MC, Dringen R (2011) Iron-dependent formation of reactive oxygen species and glutathione depletion after accumulation of magnetic iron oxide nanoparticles by oligodendroglial cells. J Nanopart Res 13:6761–6774
Hohnholt MC, Geppert M, Dringen R (2011) Treatment with iron oxide nanoparticles induces ferritin synthesis but not oxidative stress in oligodendroglial cells. Acta Biomater 7:3946–3954
Kim JA, Lee N, Kim BH, Rhee WJ, Yoon S, Hyeon T, Park TH (2011) Enhancement of neurite outgrowth in PC12 cells by iron oxide nanoparticles. Biomaterials 32:2871–2877
Deng M, Huang Z, Zou Y, Yin G, Liu J, Gu J (2014) Fabrication and neuron cytocompatibility of iron oxide nanoparticles coated with silk-fibroin peptides. Colloids Surf B Biointerfaces 116C:465–471
Pisanic TR 2nd, Blackwell JD, Shubayev VI, Finones RR, Jin S (2007) Nanotoxicity of iron oxide nanoparticle internalization in growing neurons. Biomaterials 28:2572–2581
Soenen SJ, Himmelreich U, Nuytten N, De Cuyper M (2011) Cytotoxic effects of iron oxide nanoparticles and implications for safety in cell labelling. Biomaterials 32:195–205
Rivet CJ, Yuan Y, Borca-Tasciuc DA, Gilbert RJ (2012) Altering iron oxide nanoparticle surface properties induce cortical neuron cytotoxicity. Chem Res Toxicol 25:153–161
Gramowski A, Flossdorf J, Bhattacharya K, Jonas L, Lantow M, Rahman Q, Schiffmann D, Weiss DG, Dopp E (2010) Nanoparticles induce changes of the electrical activity of neuronal networks on microelectrode array neurochips. Environ Health Perspect 118:1363–1369
Winer JL, Liu CY, Apuzzo MLJ (2012) The use of nanoparticles as contrast media in neuroimaging: a statement on toxicity. World Neurosurg 78:709–711
Mahmoudi M, Laurent S, Shokrgozar MA, Hosseinkhani M (2011) Toxicity evaluations of superparamagnetic iron oxide nanoparticles: cell “vision” versus physicochemical properties of nanoparticles. ACS Nano 5:7263–7276
Urrutia PJ, Mena NP, Nunez MT (2014) The interplay between iron accumulation, mitochondrial dysfunction, and inflammation during the execution step of neurodegenerative disorders. Front Pharmacol 5:38
Wong BX, Duce JA (2014) The iron regulatory capability of the major protein participants in prevalent neurodegenerative disorders. Front Pharmacol 5:81
Singh N, Pillay V, Choonara YE (2007) Advances in the treatment of Parkinson’s disease. Prog Neurobiol 81:29–44
Wankhede M, Bouras A, Kaluzova M, Hadjipanayis CG (2012) Magnetic nanoparticles: an emerging technology for malignant brain tumor imaging and therapy. Expert Rev Clin Pharmacol 5:173–186
Lee Titsworth W, Murad GJ, Hoh BL, Rahman M (2014) Fighting fire with fire: the revival of thermotherapy for gliomas. Anticancer Res 34:565–574
Jordan A, Scholz R, Maier-Hauff K, van Landeghem FK, Waldoefner N, Teichgraeber U, Pinkernelle J, Bruhn H, Neumann F, Thiesen B, von Deimling A, Felix R (2006) The effect of thermotherapy using magnetic nanoparticles on rat malignant glioma. J Neurooncol 78:7–14
Ding J, Tao K, Li J, Song S, Sun K (2010) Cell-specific cytotoxicity of dextran-stabilized magnetite nanoparticles. Colloids Surf B Biointerfaces 79:184–190
Acknowledgments
The authors would very much like to thank Dr. Thomas Frederichs (University of Bremen) and Dr. Karsten Thiel (IFAM, Bremen) for their support in the characterization of our IONPs.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Petters, C., Irrsack, E., Koch, M. et al. Uptake and Metabolism of Iron Oxide Nanoparticles in Brain Cells. Neurochem Res 39, 1648–1660 (2014). https://doi.org/10.1007/s11064-014-1380-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-014-1380-5