Abstract
Nanomaterials (NM) offer great technological advantages but their risks to human health are still under discussion. For toxicological testing and evaluation, information on the toxicokinetics of NM is essential as it is different from that of most other xenobiotics. This review provides an overview on the toxicokinetics of NM available to date. The toxicokinetics of NM depends on particle size and shape, protein binding, agglomeration, hydrophobicity, surface charge and protein binding. In most studies with topical skin application, unintentional permeation and systemic availability were not observed; permeation for some NM with distinct properties was observed in animals. Upon inhalation, low levels of primary model nanoparticles became systemically available, but many real-world engineered NM aggregate in aerosols, do not disintegrate in the lung, and do not become systemically available. NM are prone to lymphatic transport, and many NM are taken up by the mononuclear phagocyte system (MPS) acting as a depot. Their half-life in blood depends on their uptake by MPS rather than their elimination from the body. NM reaching the GI tract are excreted with the feces, but of some NM low levels are absorbed and become systemically available. Some quantum dots were not observably excreted in urine nor in feces. Some model quantum dots, however, were efficiently excreted by the kidneys below, but not above 5–6 nm hydrodynamic diameter, while nanotubes 20–30 nm thick and 500–2,000 nm long were abundant in urine. NM are typically not metabolized. Some NM cross the blood–brain barrier favored by a negative surface charge.
Similar content being viewed by others
References
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 61:428–437
Al-Somali AM, Krueger KM, Falkner JC, Colvin VL (2004) Recycling size exclusion chromatography for the analysis and separation of nanocrystalline gold. Anal Chem 76:5903–5910
Ballou B, Lagerholm BC, Ernst LA, Bruchez MP, Waggoner AS (2004) Noninvasive imaging of quantum dots in mice. Bioconjug Chem 1:79–86
Baroli B (2010) Penetration of nanoparticles and nanomaterials in the skin: fiction OR reality? J Pharm Sci 99:21–50
Barrett EG, Johnston C, Oberdorster G, Finkelstein JN (1999) Silica binds serum proteins resulting in a shift of the dose-response for silica-induced chemokine expression in an alveolar type ii cell line. Toxicol Appl Pharmacol 161:111–122
Bastian S, Busch W, Kühnel D, Springer A, Meißner T, Holke R, Scholz S, Iwe M, Pompe W, Gelinsky M, Potthoff A, Richter V, Ikonomidou C, Schirmer K (2009) Toxicity of tungsten carbide and cobalt-doped tungsten carbide nanoparticles in mammalian cells in vitro. Environ Health Perspect 117:530–536
Baxter LT, Zhu H, Mackensen DG, Butler WF, Jain RK (1995) Biodistribution of monoclonal antibodies: scale-up from mouse to human using a physiologically based pharmacokinetic model. Cancer Res 55:4611–4622
Bermudez E, Mangum JB, Asgharian B, Wong BA, Revery EE, Janszen DB, Hext PM, Warheit DB, Everitt JI (2002) Longterm pulmonary responses of three laboratory rodent species to subchronic inhalation of pigment-grade titanium dioxide particles. Toxicol Sci 70:86–97
Bermudez E, Mangum JB, Wong BA, Asgharian B, Hext PM, Warheit DB, Everitt JI, Moss OR (2004) Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles. Toxicol Sci 77:347–357
Berret JF, Sandre O, Mauger A (2007) Size distribution of superparamagnetic particles determined by magnetic sedimentation. Langmuir 23:2993–2999
Bihari P, Vippola M, Schultes S, Prätner M, Khandoga AG, Reichel CA, Coester C, Tuomi T, Rehberg M, Krombach F (2008) Optimized dispersion of nanoparticles for biological in vitro and in vivo studies. Part Fibre Toxicol 5:14
Blunk T, Lück M, Calvör A, Hochstrasser DF, Sanchez JC, Müller BW, Müller RH (1996) Kinetics of plasma protein adsorption on model particles for controlled drug delivery and drug targeting. Eur J Pharm Biopharm 42:262–268
Bosman SJ, Nieto SP, Patton WC, Jacobson JD, Corselli JU, Chan PJ (2005) Development of mammalian embryos exposed to mixed-size nanoparticles. Clin Exp Obstet Gynecol 4:222–224
Boyes WK, Chen R, Chen C, Yokel RA (2012) The neurotoxic potential of engineered nanomaterials. Neurotoxicology. doi:10.1016/j.neuro.2011.12.013
Brannon-Peppa L, Blanchette JO (2004) Nanoparticle and targeted systems for cancer therapy. AdV Drug DeliVery ReV 56:1649–1659
Brioschi AM, Calderoni S, Zara GP, Priano L, Gasco MR, Mauro A (2009) Solid lipid nanoparticles for brain tumors therapy: state of the art and novel challenges. Prog Brain Res 180:193–223
Brown JS, Zeman KL, Bennett WD (2002) Ultrafine particle deposition and clearance in the healthy and obstructed lung. Am J Respir Crit Care Med 166:1240–1247
Brunauer S, Emmett PH, Teller E (1938) Adsorption of gases in multimolecular layers. J Am Chem Soc 60:309–319
Bur M, Henning A, Hein S, Schneider M, Lehr CM (2009) Inhalative nanomedicine–opportunities and challenges. Inhal Toxicol 21:137–143
Bücking W, Nann T (2006) Electrophoretic analysis of gold nanoparticles: size-dependent electrophoretic mobility of nanoparticles. IEE Proc Nanobiotechnol 153:47–53
Calabretta M, Jamison JA, Falkner JC, Liu Y, Yuhas BD, Matthews KS, Colvin VL (2005) Analytical ultracentrifugation for characterizing nanocrystals and their bioconjugates. Nano Lett 5:963–967
Carion O, Mahler B, Pons T, Dubertret B (2007) Synthesis, encapsulation, purification and coupling of single quantum dots in phospholipid micelles for their use in cellular and in vivo imaging. Nat Protoc 2:2383–2390
Cedervall T, Lynch I, Lindman S, Berggard T, Thulin E, Nilsson H, Dawson KA, Linse S (2007a) Understanding the nanoparticle–protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles. Proc Natl Acad Sci USA 104:2050–2055
Cedervall T, Lynch I, Foy M, Berggard T, Donnelly SC, Cagney G, Linse S, Dawson KA (2007b) Detailed identification of plasma proteins adsorbed on copolymer nanoparticles. Angew Chem Int Ed Engl 46:5754–5756
Choi HS, Liu W, Misra P, Tanaka E, Zimmer JP, Itty Ipe B, Bawendi MG, Frangioni JV (2007) Renal clearance of quantum dots. Nat Biotechnol 25:1165–1170
Cruz-Orive LM, Weibel ER (1981) Sampling designs for stereology. J Microsc 122:235–257
Davda JP, Jain M, Batra SK, Gwilt PR, Robinson DHA (2008) Physiologically based pharmacokinetic (pbpk) model to characterize and predict the disposition of monoclonal antibody cc49 and its single chain fv constructs. Int Immunopharmacol 8:401–413
De Jong WH, Hagens WI, Krystek P, Burger MC, Sips AJ, Geertsma RE (2008) Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials 29:1912–1919
de Lorenzo AJ (1970) The olfactory neuron and the blood-brain barrier. In: Wolstenholme G, Knight J (eds) Taste and smell in vertebrates. Churchill, London, pp 151–176
Deng X, Jia G, Wang H, Sun H, Wang X, Yang S, Wang T, Liu Y (2007) Translocation and fate of multi-walled carbon nanotubes in vivo. Carbon 45:1419–1424
Desai MP, Labhasetwar V, Amidon GL, Levy RJ (1996) Gastrointestinal uptake of biodegradable microparticles: effect of particle size. Pharm Res 12:1838–1845
Dutta D, Sundaram SK, Teeguarden JG, Riley BJ, Fifield LS, Jacobs JM, Addleman SR, Kaysen GA, Moudgil BM, Weber TJ (2007) Adsorbed proteins influence the biological activity and molecular targeting of nanomaterials. Toxicol Sci 100:303–315
Ehrenberg MS, Friedman AE, Finkelstein JN, Oberdorster G, McGrath JL (2009) The influence of protein adsorption on nanoparticle association with cultured endothelial cells. Biomaterials 30:603–610
Elder A, Gelein R, Finkelstein JN, Driscoll KE, Harkema J, Oberdörster G (2005) Effects of subchronically inhaled carbon black in three species. I. Retention kinetics, lung inflammation, and histopathology. Toxicol Sci 2:614–629
Elder A, Gelein R, Silva V, Feikert T, Opanashuk L, Carter J, Potter R, Maynard A, Ito Y, Finkelstein J, Oberdörster G (2006) Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ Health Perspect 8:1172–1178
Fabian E, Landsiedel R, Ma-Hock L, Wiench K, Wohlleben W, van Ravenzwaay B (2008) Tissue distribution and toxicity of intravenously administered titanium dioxide nanoparticles in rats. Arch Toxicol 82:151–157
Fang JY (2006) Nano- or submicron-sized liposomes as carriers for drug delivery. Chang Gung Med J 29:358–362
Ferin J, Oberdorster G, Penney DP (1992) Pulmonary retention of ultrafine and fine particles in rats. Am J Respir Cell Mol Biol 6:535–542
Fischer HC, Chan WC (2007) Nanotoxicity: the growing need for in vivo study. Curr Opin Biotechnol 18:565–571
Fischer HC, Liu L, Pang KS, Chan CW (2006) Pharmacokinetics of nanoscale quantum dots: in vivo distribution, sequestration and clearance in the rat. Adv Funct Mater 16:1299–1305
Florence AT (2005) Nanoparticle uptake by the oral route: fulfilling its potential? Drug Discov Today Technol 2:75–81
Furumoto K, Ogawara K, Yoshida M, Takakura Y, Hashida M, Higaki K, Kimura T (2001) Biliary excretion of polystyrene microspheres depends on the type of receptor-mediated uptake in rat liver. Biochim Biophys Acta 1526:221–226
Gamer AO, Leibold E, van Ravenzwaay B (2006) The in vitro absorption of microfine zinc oxide and titanium dioxide through porcine skin. Toxicol In Vitro 20:301–307
Gao H, Geng XP, Wang BH, Zhou Y (2010) Studies on the conformational change of adsorbed BSA onto a moderately hydrophobic surface at different denaturant concentrations and surface coverages. J Colloid Interface Sci 344:468–474
Gatti AM, Montanari S, Monari E, Gambarelli A, Capitani F, Parisini B (2004) Detection of micro- and nano-sized biocompatible particles in the blood. J Mater Sci Mater Med 15:469–472
Geiser M (2002) Morphological aspects of particle uptake by lung phagocytes. Micr Res Tech 57:512–522
Geiser M, Kreyling WG (2010) Deposition and biokinetics of inhaled nanoparticles. Part Fibre Toxicol 7(2):1–17
Geiser M, Cruz-Orive LM, Im Hof V, Gehr P (1990) Assessment of particle retention and clearance in the intrapulmonary conducting airways of hamster lungs with the fractionator. J Microsc 160:75–88
Geiser M, Rothen-Rutishauser B, Kapp N, Schurch S, Kreyling W, Schulz H, Semmler M, Im Hof V, Heyder J, Gehr P (2005) Ultrafine particles cross cellular membranes by nonphagocytic mechanisms in lungs and in cultured cells. Environ Health Perspect 113:1555–1560
Gerlowski LE, Jain RK (1983) Physiologically based pharmacokinetic modeling: principles and applications. J Pharm Sci 72:1103–1127
Gessner A, Waicz R, Lieske A, Paulke B, Mader K, Muller RH (2000) Nanoparticles with decreasing surface hydrophobicities: influence on plasma protein adsorption. Int J Pharm 196:245–249
Gessner A, Lieske A, Paulke B, Muller R (2002) Influence of surface charge density on protein adsorption on polymeric nanoparticles: analysis by two-dimensional Electrophoresis. Eur J Pharm Biopharm 54:165–170
Gessner A, Lieske A, Paulke BR, Muller RH (2003) Functional groups on polystyrene model nanoparticles: influence on protein adsorption. J Biomed Mater Res A 65:319–326
Gopee NV, Roberts DW, Webb P, Cozart CR, Siitonen PH, Warbritton AR, Yu WW, Colvin VL, Walker NJ, Howard PC (2007) Migration of intradermally injected quantum dots to sentinel organs in mice. Toxicol Sci 98:249–257
Gopee NV, Roberts DW, Webb P, Cozart CR, Siitonen PH, Latendresse JR, Warbitton AR, Yu WW, Colvin VL, Walker NJ, Howard PC (2009) Quantitative determination of skin penetration of PEG-coated CdSe quantum dots in dermabraded but not intact SKH-1 hairless mouse skin. Toxicol Sci 111:37–48
Göppert TM, Müller RH (2005a) Polysorbate-stabilized solid lipid nanoparticles as colloidal carriers for intravenous targeting of drugs to the brain: comparison of plasma protein adsorption patterns. J Drug Target 13:179–187
Göppert TM, Müller RH (2005b) Adsorption kinetics of plasma proteins on solid lipid nanoparticles for drug targeting. Int J Pharm 302:172–186
Grainger DW, Castner DG (2008) Nanobiomaterials and nanoanalysis: opportunities for improving the science to benefit biomedical technologies. Adv Mater 20:867–877
Gref R, Luck M, Quellec P, Marchand M, Dellacherie E, Harnisch S, Blunk T, Muller RH (2000) ‘Stealth’ corona–core nanoparticles surface modified by polyethylene glycol (PEG): influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption. Colloids Surf B Biointerfaces 18:301–313
Hagens WI, Oomen AG, de Jong WH, Cassee FR, Sips AJ (2007) What do we (need to) know about the kinetic properties of nanoparticles in the body? Regul Toxicol Pharmacol 49:217–229
Hanauer M, Pierrat S, Zins I, Lotz A, Sönnichsen C (2007) Separation of nanoparticles by gel electrophoresis according to size and shape. Nano Lett 7:2881–2885
Heckel K, Kiefmann R, Dorger M, Stoeckelhuber M, Goetz AE (2004) Colloidal gold particles as a new in vivo marker of earl acute lung injury. Am J Physiol Lung Cell Mol Physiol 287:L867–L878
Hillyer JF, Albrecht RM (2001) Gastrointestinal persorption and tissue distribution of differently sized colloidal gold nanoparticles. J Pharm Sci 90:1927–1936
Hoet PH, Bruske-Hohlfeld I, Salata OV (2004) Nanoparticles—known and unknown health risks. J Nanobiotechnol 2:12
Hunter DD, Dey RD (1998) Identification and neuropeptide content of trigeminal neurons innervating the rat nasal epithelium. Neuroscience 83:591–599
Hunter DD, Undem BJ (1999) Identification and substance P content of vagal afferent neurons innervating the epithelium of the guinea pig trachea. Am J Respir Crit Care Med 159:1943–1948
Hussain SM, Braydich-Stolle L, Schrand AM, Murdock RC, Yu KO, Mattie DM, Schlager JJ, Terrones M (2009) Toxicity evaluation for safe use of nanomaterials: recent achievements and technical challenges. Adv Mater 21:1–11
ICRP (International Commission on Radiological Protection) (1994) Human respiratory tract model for radiological protection. ICRP publication 66 annals of ICRP 24:231
ILSI (International Life Science Institute) (2000) The relevance of the rat lung response to particle overload for human risk assessment: a workshop consensus report—ILSI Risk Science Institute Workshop participants. Inhal Toxicol 12:1–17
ISO (International Standards Organization) (2007) ISO TR 27628
Israelachvili JN, Pashley RM (1984) Measurement of the hydrophobic interaction between two hydrophobic surfaces in aqueous electrolyte solutions. J Coll Interface Sci 98:500–514
Jamison JA, Krueger KM, Yavuz CT, Mayo JT, LeCrone D, Redden JJ, Colvin VL (2008) Size-dependent sedimentation properties of nanocrystals. ACS Nano 2:311–319
Jani P, Halbert GW, Langridge J, Florence AT (1989) The uptake and translocation of latex nanospheres and microspheres after oral administration to rats. J Pharm Pharmacol 41:809–812
Jani P, Halbert GW, Langridge J, Florence AT (1990) Nanoparticle uptake by the rat gastrointestinal mucosa: quantitation and particle size dependency. J Pharm Pharmacol 42:821–826
Jasanada F, Urizzi P, Souchard JP, Le Gaillard F, Favre G, Nepveu F (1996) Indium-111 labeling of low density lipoproteins with the DTPA-bis(stearylamide): evaluation as a potential radiopharmaceutical for tumor localization. Bioconjugate Chem 7:72–81
Joshi MD, Müller RH (2009) Lipid nanoparticles for parenteral delivery of actives. Eur J Pharm Biopharm 71:161–172
Kagan VE, Konduru NV, Feng W, Allen BL, Conroy J, Volkov Y, Vlasova II, Belikova NA, Yanamala N, Kapralov A, Tyurina YY, Shi J, Kisin ER, Murray AR, Franks J, Stolz D, Gou P, Klein-Seetharaman J, Fadeel B, Star A, Shvedova AA (2010) Carbon nanotubes degraded by neutrophil myeloperoxidase induce less pulmonary inflammation. Nat Nanotechnol 5:354–359
Keane MJ, Wallace WE (2005) A quantitative in vitro fluorescence imaging method for phospholipid loss from respirable mineral particles. Inhal Toxicol 17:287–292
Keelan JA (2011) Nanotoxicology: nanoparticles versus the placenta. Nat Nanotechnol 6:263–264
Kim S, Lim YT, Soltesz EG, De Grand AM, Lee J, Nakayama A, Parker JA, Mihaljevic T, Laurence RG, Dor DM, Cohn LH, Bawendi MG, Frangioni JV (2004) Near-infrared fluorescent type II quantum dots for sentinel lymph node mapping. Nat Biotechnol 22:93–97
Kiwada H, Miyajima T, Kato Y (1987) Studies on the uptake of mechanism of liposomes by perfused rat liver. II. An indispensable factor for liver uptake in serum. Chem Pharm Bull 35:1189–1195
Kneuer C, Sameti M, Haltner EG, Schiestel T, Schirra H, Schmidt H, Lehr CM (2000) Silica nanoparticles modified with aminosilanes as carriers for plasmid DNA. Int J Pharm 196:257–261
Kohli AK, Alpar HO (2004) Potential use of nanoparticles for transcutaneous vaccine delivery: effect of particle size and charge. Int J Pharm 275:13–17
Koutsoukos PG, Mumme-Young CA, Norde W, Lyklema J (1982) Effect of the nature of the substrate on the adsorption of human plasma albumin. Colloids Surf 5:93–104
Kreyling WG, Scheuch G (2000) Clearance of particles deposited in the lungs. In: Gehr P, Heyder J (eds) Particle-lung interactions. Marcel Dekker Inc., New York, pp 323–376
Kreyling WG, Semmler M, Erbe F, Mayer P, Takenaka S, Schulz H, Oberdörster G, Ziesenis A (2002) Translocation of ultrafine insoluble iridium particles from lung epithelium to extrapulmonary organs is size dependent but very low. J Toxicol Environ Health A 65:1513–1530
Krueger KM, Al-Somali AM, Falkner JC, Colvin VL (2005) Characterization of nanocrystalline CdSe by size exclusion chromatography. Anal Chem 77:3511–3515
Kuhlbusch TA, Fissan H (2006) Particle characteristics in the reactor and pelletizing areas of carbon black production. J Occup Environ Hyg 3:558–567
Kuhlbusch T, Neumann S, Fissan H (2004) Number size distribution, mass concentration, and particle composition of PM1, PM2.5, and PM10 in bag filling areas of carbon black production. J Occup Environ Hyg 1:660–671
Lacerda L, Herrero MA, Venner K, Bianco A, Prato M, Kostarelos K (2008a) Carbon-nanotube shape and individualization critical for renal excretion. Small 4:1130–1132
Lacerda L, Soundararajan A, Singh R, Pastorin G, Al-Jamal KT et al (2008b) Dynamic imaging of functionalized multi-walled carbon nanotube systemic circulation and urinary excretion. Adv Mater 20:225–230
Landsiedel R, Ma-Hock L, Van Ravenzwaay B, Schulz M, Wiench K, Champ S, Schulte S, Wohlleben W, Oesch F (2010a) Gene toxicity studies on titanium dioxide and zinc oxide nanomaterials used for UV-protection in cosmetic formulations. Nanotoxicol 4:364–381
Landsiedel R, Ma-Hock L, Kroll A, Hahn D, Schnekenburger J, Wiench K, Wohlleben W (2010b) Testing metal-oxide nanomaterials for human safety. Adv Mater 25(22):2601–2627
Lankveld DP, Oomen AG, Krystek P, Neigh A, Troostde Jong A, Noorlander CW, Van Eijkeren JC, Geertsma RE, De Jong WH (2010) The kinetics of the tissue distribution of silver nanoparticles of different sizes. Biomaterials 31:8350–8361
Lee HJ, Yeo SY, Jeong SH (2003) Antibacterial effect of nanosized silver colloidal solution on textile fabrics. J Mater Sci 38:2199–2204
Lee HA, Leavens TL, Mason SE, Monteiro-Riviere NA, Riviere JE (2009) Comparison of quantum dot biodistribution with a blood-flow-limited physiologically based pharmacokinetic model. Nano Lett 9:794–799
Lees EE, Gunzburg MJ, Nguyen TL, Howlett GJ, Rothacker J, Nice EC, Clayton AH, Mulvaney P (2008) Experimental determination of quantum dot size distributions, ligand packing densities, and bioconjugation using analytical ultracentrifugation. Nano Lett 8:2883–2890
Levchenko TS, Rammohan R, Lukyanov AN, Whiteman KR, Torchilin VP (2002) Liposome clearance in mice: the effect of a separate and combined presence of surface charge and polymer coating. Int J Pharm 240:95–102
Li SD, Huang L (2008) Pharmacokinetics and biodistribution of nanoparticles. Mol Pharmac 5:496–504
Li Z, Greden K, Alvarez PJJ, Gregory KB, Lowry GV (2010a) Adsorbed polymer and NOM limits adhesion and toxicity of nano scale zerovalent iron to E. coli. Environ Sci Technol 44:3462–3467
Li M, Al-Jamal KT, Kostarelos K, Reineke J (2010b) Physiologically based pharmacokinetic modeling of nanoparticles. ACS Nano 4:6303–6317
Liang YY, Zhang LM, Li W, Chen RF (2008) Polysaccharide-modeified iron oxide nanoparticles as an effective magnetic affinity adsorbent for bovine serum albumin. Colloid Polym Sci 285:1193–1199
Liao CM, Chiang YH, Chio CP (2008) Model-based assessment for human inhalation exposure risk to airborne nano/fine titanium dioxide particles. Sci Total Environ 407:165–177
Lin DH, Xing BS (2008) Tannic acid adsorption and its role for stabilizing carbon nanotube suspensions. Environ Sci Technol 42:5917–5923
Lin JH, Sugiyama Y, Awazu S, Hanano M (1982) In vitro and in vivo evaluation of the tissue-to-blood partition coefficient for physiological pharmacokinetic models. J Pharmacokinet Biopharm 10:637–647
Lin P, Chen JW, Chang LW, Wu JP, Redding L, Chang H, Yeh TK, Yang CS, Tsai MH, Wang HJ et al (2008) Computational and ultrastructural toxicology of a nanoparticle, quantum dot 705, in mice. Environ Sci Technol 42:6264–6270
Lindman S, Lynch I, Thulin E, Nilsson H, Dawson KA, Linse S (2007) Systematic investigation of the thermodynamics of HSA adsorption to N-iso propylacrylamide/N-tert-butylacrylamide copolymer nanoparticles. Effects of particle size and hydrophobicity. Nano Lett 7:914–920
Liu D, Mori A, Huang L (1992) Role of liposome size and RES blockade in controlling biodistribution and tumor uptake of GM1-containing liposomes. Biochim Biophys Acta 1104:95–101
Liu X, Hurt RH, Kane AB (2010) Biodurability of single-walled carbon nanotubes depends on surface functionalization. Carbon 48:1961–1969
Luck M, Paulke BR, Schroder W, Blunk T, Muller RH (1998) Analysis of plasma protein adsorption on polymeric nanoparticles with different surface characteristics. J Biomed Mat Res 39:478–485
Lundqvist M, Sethson I, Jonsson BH (2004) Protein adsorption onto silica nanoparticles: conformational changes depend on the particles’ curvature and the protein stability. Langmuir 20:10639–10647
Lundqvist M, Stigler J, Elia G, Lynch I, Cedervall T, Dawson KA (2008) Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc Nat Acad Sci 105:14265–14270
Lynch I, Dawson KA (2008) Protein–nanoparticle interactions. NanoToday 3:40–47
Lynch I, Cedervall T, Lundqvist M, Cabaleiro-Lago C, Linse S, Dawson KA (2007) The nanoparticle–protein complex as a biological entity; a complex fluids and surface science challenge for the 21st century. Adv Colloid Interface Sci 134–135:167–174
Ma-Hock L, Gamer A, Landsiedel R, Leibold E, Frechen T, Sens B, Huber G, van Ravenzwaay B (2007a) Characterization of aerosolized nano-materials. Inhal Toxicol 19:1–17
Ma-Hock L, Gamer A, Landsiedel R, Leibold E, Frechen T, Sens B, Linsenbuehler M, van Ravenzwaay B (2007b) Generation and characterization of test atmospheres with nanomaterials. Inhal Toxicol 19:833–848
Ma-Hock L, Burkhardt S, Strauss V, Gamer AO, Wiench K, van Ravenzwaay B, Landsiedel R (2009) Development of a short-term inhalation test in the rat using nano-titanium dioxide as a model substance. Inhal Toxicol 21:102–118
Maier M, Hannebauer B, Holldorf H, Albers P (2006) Titanium dioxide and lung surfactant. J Occup Environ Med 48:1314–1320
McHale K, Berglund AJ, Mabuchi H (2007) Quantum dot photon statistics measured by three-dimensional particle tracking. Nano Lett 7:3535–3539
Mehnert W, Mäder K (2001) Solid lipid nanoparticles: production, characerization and applications. Adv Drug Deliv Rev 47:165–196
Meissner T, Potthoff A, Richter V (2009) Suspension characterization as important key for toxicological investigations. J Phys Conf Ser 170:6
Meissner T, Kühnel D, Busch W, Oswald S, Richter V, Michaelis A, Schirmer K, Potthoff A (2010) Physical-chemical characterization of tungsten carbide nanoparticles as a basis for toxicological investigations. Nanotoxicol 4:196–206
MinChar Initiative (2008) Minimum information for nanomaterial charaterization initiative. http://characterizationmatters.org, retrieved 2010/01/25
Moghimi SM, Hunter AC (2001) Capture of stealth nanoparticles by the body’s defences. Crit Rev Ther Drug Carr Syst 18:527–550
Moghimi SM, Muir IS, Illum L, Davis SS, Kolb-Bachofen V (1993) Coating particles with a block co-polymer (poloxamine-908) suppresses opsonization but permits the activity of dysopsonins in the serum. Biochim Biophys Acta 1179:157–165
Moghimi SM, Hunter AC, Murray JC (2001) Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev 53:283–318
Monopoli MP, Bombelli FB, Dawson KA (2011) Nanobiotechnology: nanoparticle coronas take shape. Nat Nanotechnol 6:11–12
Monteiro-Riviere NA, Wiench K, Landsiedel R, Schulte S, Inman AO, Riviere JE (2011) Safety evaluation of sunscreen formulations containing titanium dioxide and zinc oxide nanoparticles in UVB sunburned skin: an in vitro and in vivo study. Toxicol Sci 123:264–280
Motskin M, Müller KH, Genoud C, Monteith AG, Skepper JN (2011) The sequestration of hydroxyapatite nanoparticles by human monocyte-macrophages in a compartment that allows free diffusion with the extracellular environment. Biomaterials 32:9470–9482
Muller RH, Keck CM (2004) Challenges and solutions for the delivery of biotech drugs—Cl review of drug nanocrystal technology and lipid nanoparticlcs. J Biotech 113:151–170
Nagayama S, Ogawara K, Fukuoka Y, Higaki K, Kimura T (2007a) Time-dependent changes in opsonin amount associated on nanoparticles alter their hepaticuptake characteristics. Int J Pharm 342:215–221
Nagayama S, Ogawara K, Minato K, Fukuoka Y, Takakura Y, Hashida M, Higaki K, Kimura T (2007b) Fetuin mediates hepatic uptake of negatively charged nanoparticles via scavenger receptor. Int J Pharm 329:192–198
National Science and Technology Council (2000) National nanotechnology initiative: the initiative and its implementation plan. USA
Nemmar A, Vanbilloen H, Hoylaerts MF, Hoet PH, Verbruggen A, Nemery B (2001) Passage of intratracheally instilled ultrafine particles from the lung into the systemic circulation in hamster. Am J Respir Crit Care Med 164:1665–1668
Nemmar A, Hoet PH, Vanquickenborne B, Dinsdale D, Thomeer M, Hoylaerts MF, Vanbilloen H, Mortelmans L, Nemery B (2002) Passage of inhaled particles into the blood circulation in humans. Circulation 105:411–414
Nepal D, Geckeler KE (2007) Proteins and carbon nanotubes: close encounter in water. Small 3:1259–1265
Oberdörster G, Sharp Z, Atudorei V, Elder A, Gelein R, Lunts A, Kreyling W, Cox C (2002) Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats. J Toxicol Environ Health A 65:1531–1543
Oberdörster G, Sharp Z, Atudorei V, Elder A, Gelein R, Kreyling W, Cox C (2004) Translocation of inhaled ultrafine particles to the brain. Inhal Toxicol 16:437–445
Oberdörster G, Oberdörster E, Oberdörster J (2005) Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 113:823–839
Ogawara K, Yoshida M, Furumoto K, Takakura Y, Hashida M, Higaki K, Kimura T (1999) Uptake by hepatocytes and biliary excretion of intravenously administered polystyrene microspheres in rats. J Drug Target 7:213–221
Ogawara K, Furumoto K, Nagayama S, Minato K, Higaki K, Kai T, Kimura T (2004) Precoating with serum albumin reduces receptor-mediated hepatic disposition of polystyrene nanosphere: implications for rational design of nanoparticles. J. Control Release 100:451–455
Ohl L, Mohaupt M, Czeloth N, Hintzen G, Kiafard Z, Zwirner J et al (2004) CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21:279–288
Okon E, Pouliquen D, Okon P, Kovaleva ZV, Stepanova TP, Lavit SG, Kudryavtsev BN, Jallet P (1994) Biodegradation of magnetite dextran nanoparticles in the rat. A histologic and biophysical study. Lab Invest 71:895–903
Oldfors A, Fardeau M (1983) The permeability of the basal lamina at the neuromuscular junction. An ultrastructural study of rat skeletal muscle using particulate tracers. Neuropathol Appl Neurobiol 9:419–432
Opanasopit P, Nishikawa M, Hashida M (2002) Factors affecting drug and gene delivery: effects of interaction with blood components. Crit Rev Ther Drug Carrier Syst 19:191–233
Owens DE, Peppas NA (2006) Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm 307:93–102
Park S, Hamad-Schifferli K (2008) Evaluation of hydrodynamic size and zeta-potential of surface-modified Au nanoparticle-DNA conjugates via Ferguson analysis. J Phys Chem C 112:7611–7616
Patel HM (1992) Serum opsonins and liposomes: their interaction and opsonophagocytosis. Crit Rev Ther Drug Carr Syst 9:39–90
Patil S, Sanberg A, Heckert E, Self W, Seal S (2007) Protein adsorption and cellular uptake of cerium oxide nanoparticles as a function of zeta potential. Biomaterials 28:4600–4607
Pauluhn J (2009) Pulmonary toxicity and fate of agglomerated 10 and 40 nm aluminum oxyhydroxides following 4-week inhalation exposure of rats: toxic effects are determined by agglomerated, not primary particle size. Toxicol Sci 109:152–167
Peira E, Marzola P, Podio V, Aime S, Sbarbati A et al (2003) In vitro and in vivo study of solid lipid nanoparticles loaded with superparamagnetic iron oxide. J Drug Target 11:19–24
Pery ARR, Brochot C, Hoet PHM, Nemmar A, Bois FY (2009) Development of a physiologically based kinetic model for 99 m-technetium-labelled carbon nanoparticles inhaled by humans. Inhalation Toxicol 21:1099–1107
Pflücker F, WendelV HohenbergH, Gärtner E, WillT PfeifferS, Wepf R, Gers-Barlag H (2001) The human stratum corneum layer: an effective barrier against dermal uptake of different forms of topically applied micronised titanium dioxide. Skin Pharmacol Appl Skin Physiol 14:92–97
Pinaud F, King D, Moore HP, Weiss S (2004) Bioactivation and cell targeting of semiconductor CdSe/ZnSnanocrystals with phytochelatin-related peptides.J Am Chem Soc 126:6115–6123
Porter CJH, Edwards GA, Charman SA (2001) Lymphatic transport of proteins after s.c. injection: implications of animal model selection. Adv Drug Deliv Rev 50:157–171
Potts RO, Francoeur ML (1991) The influence of stratum corneum morphology on water permeability. J Invest Dermatol 96:495–499
Price OT, Asgharian B, Miller FJ, Cassee FR, de Winter-Sorkina R (2002) Multiple path particle dosimetry model (MPPD v1.0): a model for human and rat airway particle dosimetry. RIVM report 650010030
Reddy ST, van der Vlies AJ, Simeoni E, Angeli V, Randolph GJ, O’Neil CP, Lee LK, Swartz MA, Hubbell JA (2007) Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat Biotechnol 25:1159–1164
Rejman J, Oberle V, Zuhorn IS, Hoekstra D (2004) Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochem J 377:159–169
Rivière JE (2009) Pharmacokinetics of nanomaterials: an overview of carbon nanotubes, fullerenes and quantum dots. Wiley Interdiscip Rev Nanomed Nanobiotechnol 1:26–34
Rocker C, Potzl M, Zhang F, Parak WJ, Nienhaus GU (2009) A quantitative fluorescence study of protein monolayer formation on colloidal nanoparticles. Nat Nanotechnol 4:577–580
Roser M, Fischer D, Kissel T (1998) Surface-modified biodegradable albumin nano- and microspheres. II: effect of surface charges on in vitro phagocytosis and biodistribution in rats. Eu. J Pharm Biopharm 46:255–263
Roszek B, de Jong WH, Geertsma RE (2005) Nanotechnology in medical applications: state-of-the-art in materials and devices. RIVM report 265001001
Rothen-Rutishauser BM, Schurch S, Haenni B, Kapp N, Gehr P (2006) Interaction of fine particles and nanoparticles with red blood cells visualized with advanced microscopic techniques. Environ Sci Technol 40:4353–4359
Rouse JG, Yang J, Ryman-Rasmussen JP, Barron AR, Monteiro-Riviere NA (2007) Effects of mechanical flexion on the penetration of fullerene amino acid-derivatized peptide nanoparticles through skin. Nano Lett 7:155–160
Ryman-Rasmussen JP, Riviere JE, Monteiro-Riviere NA (2006) Penetration of intact skin by quantum dots with diverse physicochemical properties. Toxicol Sci 91:159–165
Sadrieh N, Wokovich AM, Gopee NV, Zheng J, Haines D, Parmiter D, Siitonen PH, Cozart CR, Patri AK, McNeil SE, Howard PC, Doub WH, Buhse LF (2010) Toxicol Sci 115:156–166. http://www.ncbi.nlm.nih.gov/pubmed/20156837
Sato K, Imai Y, Irimura RT (1998) Contribution of dermal macrophage trafficking in the sensitization phase of contact hypersensitivity. J Immunol 161:6835–6844
Sayes CM, Reed KL, Warheit DB (2007) Assessing toxicity of fine and nanoparticles: comparing in vitro measurements to in vivo pulmonary toxicity profiles. Toxicol Sci 97:163–180
Schulz J, Hohenberg H, Pflücker F, Gartner E, Will T, Pfeiffer S, Wepf R, Wendel V, Gers-Barlag H, Wittern KP (2002) Distribution of sunscreens on skin. Adv Drug Deliv Rev 54(Suppl 1):S157–S163
Schulze C, Kroll A, Lehr CM, Schäfer UF, Becker K, Schnekenburger J, Schulze Isfort C, Landsiedel R, Wohlleben W (2008) Not ready to use—overcoming pitfalls when disperging nanoparticles in physiological media. Nanotox 2:51–61
Schulze C, Schäfer UF, Ruge C, Wohlleben W, Lehr CM (2011) Interaction of metal oxide nanoparticles with lung surfactant protein A. Eur J Pharm Biopharm 77:376–383
Schäfer J, Schulze C, Marxer EEJ, Schäfer UF, Wohlleben W, Bakowsky U, Lehr CM. Biorelevant protein adsorption to CeO2 nanoparticles by atomic force microscopy and analytical ultracentrifugation. ACS Nano submitted
Seipenbusch M, Binder A, Kasper G (2008) Temporal evolution of nanoparticle aerosols in workplace exposure. Ann Occup Hyg 52:707–716
Shamim N, Hong L, Hidajat K, Uddin MS (2006) Thermosensitive-polymer-coated magnetic nanoparticles: adsorption and desorption of bovine serum albumin. J Colloid Interface Sci 304:1–8
Shelley ML, Wagner AJ, Hussain SM, Bleckmann C (2008) Modeling the in vivo case with in vitro nanotoxicity data. Int J Toxicol 27:359–367
Simonson AB, Schnitzer JE (2007) Vascular proteomic mapping in vivo. J Thromb Haemostasis 5(Suppl 1):183–187
Singh R, Pantarotto D, Lacerda L, Pastorin G, Klumpp C, Prato M, Bianco A, Kostarelos K (2006) Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers. Proc Natl Acad Sci USA 103:3357–3362
Smith AM, Nie S (2008) Minimizing the hydrodynamic size of quantum dots with multifunctional multidentate polymer ligands. J Am Chem Soc 130:11278–11279
Soltesz EG, Kim S, Laurence RG, DeGrand AM, Parungo CP et al (2005) Intraoperative sentinel lymph node mapping of the lung using near-infrared fluorescent quantum dots. Ann Thorac Surg 79:269–277
Sonavane G, Tomoda K, Makino K (2008) Biodistribution of colloidal gold nanoparticles after intravenous administration: effect of particle size. Colloids Surf B Biointerfaces 66:274–280
Stern ST, McNeil SE (2008) Nanotechnology safety concerns revisited. Toxicol Sci 101:4–21
Stern ST, Hall JB, Yu LL, Wood LJ, Paciotti GF, Tamarkin L, Long SE, McNeil SE (2010) Translational considerations for cancer nanomedicine. J Contr Release 146:164–174
Sturm RA (2007) Computer model for the clearance of insoluble particles from the tracheobronchial tree of the human lung. Comput Biol Med 37:680–690
Takeda K, K-i Suzuki, Ishihara A, Kubo-Irie M, Fujimoto R, Tabata M et al (2009) Nanoparticles transferred from pregnant mice to their offspring can damage the genital and cranial nerve systems. J Health Sci 55:95–102
Thompson CM, Johns DO, Sonawane B, Barton HA, Hattis D, Tardif R, Krishnan K (2009) Database for physiologically based pharmacokinetic (PBPK) modeling: physiological data for healthy and health-impaired elderly. J Toxicol Environ Hlth Part B 12:1–24
Torchilin VP, Lukyanov AN, Gao Z, Papahadjopoulos-Sternberg B (2003) Immunomicelles: targeted pharmaceutical carriers for poorly soluble drugs. Proc Natl Acad Sci USA 100:6039–6044
Tsuji JS, Maynard AD, Howard PC, James JT, Lam CW, Warheit DB, Santamaria AB (2006) Research strategies for safety evaluation of nanomaterials, part IV: risk assessment of nanoparticles. Toxicol Sci 89:42–50
Umbreit TH, Francke-Carroll S, Weaver JL, Miller TJ, Goering PL, Sadrieh N, Stratmeyer ME (2011) Tissue distribution and histopathological effects of titanium dioxide nanoparticles after intravenous or subcutaneous injection in mice. J Appl Toxicol. doi:10.1002/jat.1700
van Ravenzwaay B, Landsiedel R, Fabian E, Burkhardt S, Strauss V, Ma-Hock L (2009) Comparing fate and effects of three particles of different surface properties: nano-TiO(2), pigmentary TiO(2) and quartz. Toxicol Lett 186:152–159
Vermylen J, Nemmar A, Nemery B, Hoylaerts MF (2005) Ambient air pollution and acute myocardial infarction. Thromb Haemost 3:1955–1961
Videira MA, Botelho MF, Santos AC, Gouveia LF, de Lima JJ, Almeida AJ (2002) Lymphatic uptake of pulmonary delivered radiolabelled solid lipid nanoparticles. J Drug Target 10:607–613
Vippola M, Falck GCM, Lindberg HK, Suhonen S, Vanhala E, Norppa H, Savolainen K, Tossavainen A, Tuomi T (2009) Preparation of nanoparticle dispersions for in vitro toxicity testing. Human Expl Toxicol 28:377–385
Vroman L, Adams AL, Fischer GC, Munoz PC (1980) Interaction of highmolecular weight kininogen, factorXII, and fibrinogen in plasma at interfaces. Blood 55:156–159
Walczyk D, Bombelli FB, Monopoli MP, Lynch I, Dawson KA (2010) What the cell “sees” in bionanoscience. J Am Chem Soc 132:5761–5768
Wallace WE, Keane MJ, Murray DK, Chisholm WP, Maynard AD, Ong TM (2007) Phospholipid lung surfactant and nanoparticle surface toxicity: lessons from diesel soots and silicate dusts. J Nanopart Res 9:23–38
Wang H, Wang J, Deng X, Sun H, Shi Z, Gu Z, Liu Y, Zhao Y (2004) Biodistribution of carbon single-wall carbon nanotubes in mice. J Nanosci Nanotechnol 4:1019–1024
Wang J, Zhou G, Chen C, Yu H, Wang T, Ma Y, Jia G, Gao Y, Li B, Sun J, Li Y, Jiao F, Zhao Y, Chai Z (2007) Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. Toxicol Lett 168:176–185
Wang J, Chen C, Liu Y, Jiao F, Li W, Lao F et al (2008) Potential neurological lesion after nasal instillation of TiO2 nanoparticles in the anatase and rutile crystal phases. Toxicol Lett 183:72–80
Warheit DB, Webb TR, Reed KL, Frerichs S, Sayes CM (2007) Pulmonary toxicity study in rats with three forms of ultrafineTiO2- particles: differential responses related to surface properties. Toxicology 230:90–104
Wasdo SC, Barber DS, Denslow ND, Powers KW, Palazuelos M, Stevens SM, Moudgil BM, Roberts SM (2008) Differential binding of serum proteins to nanoparticles. Int J Nanotechnol 5:92–115
Wu J, Liu W, Xue C, Zhou S, Lan F, Bi L et al (2009) Toxicity and penetration of TiO2 nanoparticles in hairless mice and porcine skin after subchronic dermal exposure. Toxicol Lett 191:1–8
Xie G, Sun J, Zhong G, Shi L, Zhang D (2010) Biodistribution and toxicity of intravenously administered silica nanoparticles in mice. Arch Toxicol 84:183–190
Xie G, Wang C, Sun J, Zhong G (2011) Tissue distribution and excretion of intravenously administered titanium dioxide nanoparticles. Toxicol Lett 205:55–61
Yamago S, Tokuyama H, Nakamura E, Kikuchi K, Kananishi S, Sueki K, Nakahara H, Enomoto S, Ambe F (1995) Chem Biol 2:385–389
Yamashita K, Yoshioka Y, Higashisaka K, Mimura K, Morishita Y, Nozaki M, Yoshida T, Ogura T, Nabeshi H, Nagano K, Abe Y, Kamada H, Monobe Y, Imazawa T, Aoshima H, Shishido K, Kawai Y, Mayumi T, Tsunoda S, Itoh N, Yoshikawa T, Yanagihara I, Saito S, Tsutsumi Y (2011) Silica and titanium dioxide nanoparticles cause pregnancy complications in mice. Nat Nanotechnol 6:321–328
Yang ST, Guo W, Lin Y, Deng XY, Wang HF, Sun HF et al (2007a) Biodistribution of pristine single-walled carbon nanotubes in vivo. J Phys Chem C 111:17761–17764
Yang RSH, Chang LW, Wu JP, Tsai MH, Wang HJ et al (2007b) Persistent tissue kinetics and redistribution of nanoparticles, quantum dot 705, in mice. Environ Health Perspect 115:1339–1343
Yang W, Peters JI, Williams RO 3rd (2008) Inhaled nanoparticles—a current review. Int J Pharm 356:239–247
Yang K, Lin D, Xing B (2009) Interactions of humic acid with nanosized inorganic oxides. Langmuir 25:3571–3576
Yokel RA, Florence R, Tseng M, Graham U, Sultana R, Butterfield DA, Wu P, Grulke E (2008) Biodistribution and toxicity of systemically-introduced nanoscale ceria. Nanotox 2008:87
Yoon JY, Kim JH, Kim WS (1999) The relationship of interaction forces in the protein adsorption onto polymeric microspheres. Colloids Surf A 153:413–419
Zensi A, Begley D, Ponlikis C, Legros C, Mihoreanu L, Wagner V, Buchel C, von Briesen H, Kreuter J (2009) Albumin nanoparticles targeted with ApoE enter the CNS by transcytosis and are delivered to neurones. J Control Release 137:78
Zhang LW, Monteiro-Riviere NA (2008) Assessment of quantum dot penetration into intact, tape-stripped, abraded and flexed rat skin. Skin Pharmacol Physiol 21:166–180
Zhang JS, Liu F, Huang L (2005) Implications of pharmacokinetic behavior of lipoplex for its inflammatory toxicity. Adv Drug Delivery Rev 57:689–698
Zhang LW, Yu WW, Colvin VL, Monteiro-Riviere NA (2008) Biological interactions of quantum dot nanoparticles in skin and in human epidermal keratinocytes. Toxicol Appl Pharm 228:200–211
Acknowledgments
The authors alone are responsible for the content and writing of the paper. However, Robert Landsiedel, Eric Fabian, Lan Ma-Hock, Karin Wiench and Wendel Wohlleben are employees of BASF SE, a company marketing nanomaterials.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Landsiedel, R., Fabian, E., Ma-Hock, L. et al. Toxico-/biokinetics of nanomaterials. Arch Toxicol 86, 1021–1060 (2012). https://doi.org/10.1007/s00204-012-0858-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-012-0858-7