Role of physicochemical properties in nanoparticle toxicity

Nanomaterials

Volumn 5, Issue 3, 2015, Pages 1351-1365

  Shin, Seung Won ^a   Song, In Hyun ^a   Um, Soong Ho ^a,b  

^a Sungkyunkwan University   (South Korea)

^b Sungkyunkwan University   (South Korea)

Author keywords

Nanomaterials; Nanotoxicology; Physiological properties

Indexed keywords

EID: 84940539158     PISSN: None     EISSN: 20794991     Source Type: Journal    
DOI: 10.3390/nano5031351     Document Type: Review

References (95)

1. Maskos, M.; Stauber, R.H. 3.319-Characterization of nanoparticles in biological environments. In Comprehensive Biomaterials, Ducheyne, P., Ed.; Elsevier: Oxford, UK, 2011; pp. 329-339.
2. Lewinski, N.; Colvin, V.; Drezek, R. Cytotoxicity of nanoparticles. Small 2008, 4, 26-49.
3. Favi, P.M.; Gao, M.; Johana Sepúlveda Arango, L.; Ospina, S.P.; Morales, M.; Pavon, J.J.; Webster, T.J. Shape and surface effects on the cytotoxicity of nanoparticles: Gold nanospheres versus gold nanostars. J. Biomed. Mater. Res. Part A 2015, doi:10.1002/jbm.a.35491.
4. Pan, Y.; Neuss, S.; Leifert, A.; Fischler, M.; Wen, F.; Simon, U.; Schmid, G.; Brandau, W.; Jahnen-Dechent, W. Size-dependent cytotoxicity of gold nanoparticles. Small 2007, 3, 1941-1949.
5. Napierska, D.; Thomassen, L.C.; Rabolli, V.; Lison, D.; Gonzalez, L.; Kirsch-Volders, M.; Martens, J.A.; Hoet, P.H. Size-dependent cytotoxicity of monodisperse silica nanoparticles in human endothelial cells. Small 2009, 5, 846-853.
6. Carlson, C.; Hussain, S.M.; Schrand, A.M.; K. Braydich-Stolle; Hess, K.L.; Jones, R.L.; Schlager, J.J. Unique cellular interaction of silver nanoparticles: Size-dependent generation of reactive oxygen species. J. Phys. Chem. B 2008, 112, 13608-13619.
7. Oberdörster, G.; Oberdörster, E.; Oberdörster, J. Nanotoxicology: An emerging discipline evolving from studies of ultrafine particles. Environ. Health Perspect. 2005, 113, 823-839.
8. Handy, R.D.; Owen, R.; Valsami-Jones, E. The ecotoxicology of nanoparticles and nanomaterials: Current status, knowledge gaps, challenges, and future needs. Ecotoxicology 2008, 17, 315-325.
9. Hussain, S.; Hess, K.; Gearhart, J.; Geiss, K.; Schlager, J. In vitro toxicity of nanoparticles in BRL 3A rat liver cells. Toxicol. Vitr. 2005, 19, 975-983.
10. Brown, J.S.; Zeman, K.L.; Bennett, W.D. Ultrafine particle deposition and clearance in the healthy and obstructed lung. Am. J. Respir. Crit. Care Med. 2002, 166, 1240-1247.
11. Holsapple, M.P.; Farland, W.H.; Landry, T.D.; Monteiro-Riviere, N.A.; Carter, J.M.; Walker, N.J.; Thomas, K.V. Research strategies for safety evaluation of nanomaterials, part ii: Toxicological and safety evaluation of nanomaterials, current challenges and data needs. Toxicol. Sci. 2005, 88, 12-17.
12. Hoshino, A.; Fujioka, K.; Oku, T.; Nakamura, S.; Suga, M.; Yamaguchi, Y.; Suzuki, K.; Yasuhara, M.; Yamamoto, K. Quantum dots targeted to the assigned organelle in living cells. Microbiol. Immunol. 2004, 48, 985-994.
13. Salnikov, V.; Lukyanenko, Y.; Frederick, C.; Lederer, W.; Lukyanenko, V. Probing the outer mitochondrial membrane in cardiac mitochondria with nanoparticles. Biophys. J. 2007, 92, 1058-1071.
14. Donaldson, K.; Stone, V. Current hypotheses on the mechanisms of toxicity of ultrafine particles. Ann. Ist. Super. Sanita 2002, 39, 405-410.
15. Wilson, R.F. Nanotechnology: The challenge of regulating known unknowns. J. Law Med. Ethics 2006, 34, 704-713.
16. Wichmann, H.-E.; Spix, C.; Tuch, T.; Wölke, G.; Peters, A.; Heinrich, J.; Kreyling, W.G.; Heyder, J. Daily Mortality and Fine and Ultrafine Particles in Erfurt, Germany. Part I: Role Of Particle Number And Particle Mass; Research Report 98; Health Effects Institute: Boston, MA, USA, 2000.
17. Derfus, A.M.; Chan, W.C.; Bhatia, S.N. Probing the cytotoxicity of semiconductor quantum dots. Nano Lett. 2004, 4, 11-18.
18. Gupta, A.K.; Gupta, M. Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials 2005, 26, 3995-4021.
19. De Jong, W.H.; Borm, P.J. Drug delivery and nanoparticles: Applications and hazards. Int. J. Nanomed. 2008, 3, 133.
20. Alkilany, A.M.; Murphy, C.J. Toxicity and cellular uptake of gold nanoparticles: What we have learned so far? J. Nanoparticle Res. 2010, 12, 2313-2333.
21. Lefebvre, D.E.; Venema, K.; Gombau, L.; Valerio Jr, L.G.; Raju, J.; Bondy, G.S.; Bouwmeester, H.; Singh, R.P.; Clippinger, A.J.; Collnot, E.-M. Utility of models of the gastrointestinal tract for assessment of the digestion and absorption of engineered nanomaterials released from food matrices. Nanotoxicology 2015, 9, 523-542.
22. Bellmann, S.; Carlander, D.; Fasano, A.; Momcilovic, D.; Scimeca, J.A.; Waldman, W.J.; Gombau, L.; Tsytsikova, L.; Canady, R.; Pereira, D.I. Mammalian gastrointestinal tract parameters modulating the integrity, surface properties, and absorption of food-relevant nanomaterials. WIREs Nanomed. Nanobiotechnol. 2015, 7, 609-622.
23. Gliga, A.R.; Skoglund, S.; Wallinder, I.O.; Fadeel, B.; Karlsson, H.L. Size-dependent cytotoxicity of silver nanoparticles in human lung cells: The role of cellular uptake, agglomeration and ag release. Part. Fibre Toxicol. 2014, 11, 11.
24. Qiao, H.; Liu, W.; Gu, H.; Wang, D.; Wang, Y. The transport and deposition of nanoparticles in respiratory system by inhalation. J. Nanomater. 2015, 2015, 394507.
25. Braakhuis, H.M.; Cassee, F.R.; Fokkens, P.H.; de la Fonteyne, L.J.; Oomen, A.G.; Krystek, P.; de Jong, W.H.; van Loveren, H.; Park, M.V. Identification of the appropriate dose metric for pulmonary inflammation of silver nanoparticles in an inhalation toxicity study. Nanotoxicology 2015, doi:10.3109/17435390.2015.1012184.
26. Varna, M.; Ratajczak, P.; Ferreira, I.; Leboeuf, C.; Bousquet, G.; Janin, A. In vivo distribution of inorganic nanoparticles in preclinical models. J. Biomater. Nanobiotechnol. 2012, 3, 18986.
27. Albanese, A.; Tang, P.S.; Chan, W.C. The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu. Rev. Biomed. Eng. 2012, 14, 1-16.
28. Ballou, B.; Lagerholm, B.C.; Ernst, L.A.; Bruchez, M.P.; Waggoner, A.S. Noninvasive imaging of quantum dots in mice. Bioconjug. Chem. 2004, 15, 79-86.
29. De Jong, W.H.; Hagens, W.I.; Krystek, P.; Burger, M.C.; Sips, A.J.; Geertsma, R.E. Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials 2008, 29, 1912-1919.
30. Zhao, F.; Zhao, Y.; Liu, Y.; Chang, X.; Chen, C.; Zhao, Y. Cellular uptake, intracellular trafficking, and cytotoxicity of nanomaterials. Small 2011, 7, 1322-1337.
31. Kou, L.; Sun, J.; Zhai, Y.; He, Z. The endocytosis and intracellular fate of nanomedicines: Implication for rational design. Asian J. Pharm. Sci. 2013, 8, 1-10.
32. Li, W.; Chen, C.; Ye, C.; Wei, T.; Zhao, Y.; Lao, F.; Chen, Z.; Meng, H.; Gao, Y.; Yuan, H. The translocation of fullerenic nanoparticles into lysosome via the pathway of clathrin-mediated endocytosis. Nanotechnology 2008, 19, 145102.
33. Greulich, C.; Diendorf, J.; Simon, T.; Eggeler, G.; Epple, M.; Köller, M. Uptake and intracellular distribution of silver nanoparticles in human mesenchymal stem cells. Acta Biomater. 2011, 7, 347-354.
34. Harush-Frenkel, O.; Debotton, N.; Benita, S.; Altschuler, Y. Targeting of nanoparticles to the clathrin-mediated endocytic pathway. Biochem. Biophys. Res. Commun. 2007, 353, 26-32.
35. Oh, J.M.; Choi, S.J.; Lee, G.E.; Kim, J.E.; Choy, J.H. Inorganic metal hydroxide nanoparticles for targeted cellular uptake through clathrin-mediated endocytosis. Chem. Asian J. 2009, 4, 67-73.
36. Jiang, X.; Röcker, C.; Hafner, M.; Brandholt, S.; Dörlich, R.M.; Nienhaus, G.U. Endo-and exocytosis of zwitterionic quantum dot nanoparticles by live hela cells. ACS Nano 2010, 4, 6787-6797.
37. Jiang, X.; Dausend, J.; Hafner, M.; Musyanovych, A.; Röcker, C.; Landfester, K.; Mailänder, V.; Nienhaus, G.U. Specific effects of surface amines on polystyrene nanoparticles in their interactions with mesenchymal stem cells. Biomacromolecules 2010, 11, 748-753.
38. Kam, N.W.S.; Liu, Z.; Dai, H. Carbon nanotubes as intracellular transporters for proteins and DNA: An investigation of the uptake mechanism and pathway. Angew. Chem. 2006, 118, 591-595.
39. Huang, D.-M.; Hung, Y.; Ko, B.-S.; Hsu, S.-C.; Chen, W.-H.; Chien, C.-L.; Tsai, C.-P.; Kuo, C.-T.; Kang, J.-C.; Yang, C.-S. Highly efficient cellular labeling of mesoporous nanoparticles in human mesenchymal stem cells: Implication for stem cell tracking. FASEB J. 2005, 19, 2014-2016.
40. Jiang, W.; Kim, B.Y.; Rutka, J.T.; Chan, W.C. Nanoparticle-mediated cellular response is size-dependent. Nat. Nanotechnol. 2008, 3, 145-150.
41. Bohmer, N.; Jordan, A. Caveolin-1 and CDC42 mediated endocytosis of silica-coated iron oxide nanoparticles in hela cells. Beilstein J. Nanotechnol. 2015, 6, 167-176.
42. Klingberg, H.; Oddershede, L.B.; Loeschner, K.; Larsen, E.H.; Loft, S.; Møller, P. Uptake of gold nanoparticles in primary human endothelial cells. Toxicol. Res. 2015, 655-666.
43. Suresh, D.; Zambre, A.; Chanda, N.; Hoffman, T.J.; Smith, C.J.; Robertson, J.D.; Kannan, R. Bombesin peptide conjugated gold nanocages internalize via clathrin mediated endocytosis. Bioconjug. Chem. 2014, 25, 1565-1579.
44. Zhang, L.W.; Yang, J.; Barron, A.R.; Monteiro-Riviere, N.A. Endocytic mechanisms and toxicity of a functionalized fullerene in human cells. Toxicol. Lett. 2009, 191, 149-157.
45. Partlow, K.C.; Lanza, G.M.; Wickline, S.A. Exploiting lipid raft transport with membrane targeted nanoparticles: A strategy for cytosolic drug delivery. Biomaterials 2008, 29, 3367-3375.
46. Nishikawa, T.; Iwakiri, N.; Kaneko, Y.; Taguchi, A.; Fukushima, K.; Mori, H.; Morone, N.; Kadokawa, J.-I. Nitric oxide release in human aortic endothelial cells mediated by delivery of amphiphilic polysiloxane nanoparticles to caveolae. Biomacromolecules 2009, 10, 2074-2085.
47. Mo, Y.; Lim, L.Y. Mechanistic study of the uptake of wheat germ agglutinin-conjugated plga nanoparticles by A549 cells. J. Pharm. Sci. 2004, 93, 20-28.
48. Wang, Z.; Tiruppathi, C.; Minshall, R.D.; Malik, A.B. Size and dynamics of caveolae studied using nanoparticles in living endothelial cells. ACS Nano 2009, 3, 4110-4116.
49. Wang, L.; Liu, Y.; Li, W.; Jiang, X.; Ji, Y.; Wu, X.; Xu, L.; Qiu, Y.; Zhao, K.; Wei, T. Selective targeting of gold nanorods at the mitochondria of cancer cells: Implications for cancer therapy. Nano Lett. 2010, 11, 772-780.
50. Dausend, J.; Musyanovych, A.; Dass, M.; Walther, P.; Schrezenmeier, H.; Landfester, K.; Mailänder, V. Uptake mechanism of oppositely charged fluorescent nanoparticles in hela cells. Macromol. Biosci. 2008, 8, 1135-1143.
51. Ruan, G.; Agrawal, A.; Marcus, A.I.; Nie, S. Imaging and tracking of tat peptide-conjugated quantum dots in living cells: New insights into nanoparticle uptake, intracellular transport, and vesicle shedding. J. Am. Chem. Soc. 2007, 129, 14759-14766.
52. Meng, H.; Yang, S.; Li, Z.; Xia, T.; Chen, J.; Ji, Z.; Zhang, H.; Wang, X.; Lin, S.; Huang, C. Aspect ratio determines the quantity of mesoporous silica nanoparticle uptake by a small gtpase-dependent macropinocytosis mechanism. ACS Nano 2011, 5, 4434-4447.
53. Trefry, J.C.; Wooley, D.P. Silver nanoparticles inhibit vaccinia virus infection by preventing viral entry through a macropinocytosis-dependent mechanism. J. Biomed. Nanotechnol. 2013, 9, 1624-1635.
54. Gao, H.; Yang, Z.; Zhang, S.; Cao, S.; Shen, S.; Pang, Z.; Jiang, X. Ligand modified nanoparticles increases cell uptake, alters endocytosis and elevates glioma distribution and internalization. Sci. Rep. 2013, 3, 2543.
55. Chithrani, B.D.; Ghazani, A.A.; Chan, W.C. Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Lett. 2006, 6, 662-668.
56. Klabunde, K.J.; Stark, J.; Koper, O.; Mohs, C.; Park, D.G.; Decker, S.; Jiang, Y.; Lagadic, I.; Zhang, D. Nanocrystals as stoichiometric reagents with unique surface chemistry. J. Phys. Chem. 1996, 100, 12142-12153.
57. Campbell, C.T.; Parker, S.C.; Starr, D.E. The effect of size-dependent nanoparticle energetics on catalyst sintering. Science 2002, 298, 811-814.
58. Suttiponparnit, K.; Jiang, J.; Sahu, M.; Suvachittanont, S.; Charinpanitkul, T.; Biswas, P. Role of surface area, primary particle size, and crystal phase on titanium dioxide nanoparticle dispersion properties. Nanoscale Res. Lett. 2011, 6, 27.
59. Nel, A.; Xia, T.; Madler, L.; Li, N. Toxic potential of materials ar the nanolevel. Science 2006, 311, 622-627.
60. Oberdorster, G.; Maynard, A.; Donaldson, K.; Castranova, V.; Fitzpatrick, J.; Ausman, K.; Carter, J.; Karn, B.; Kreyling, W.; Lai, D.; et al. Principles for characterizing the potential human health effects from exposure to nanomaterials: Elements of a screening strategy. Part. Fibre Toxicol. 2005, 2, 8-43.
61. Duffine, R.; Tran, C.L.; Clouter, A.; Brown, D.M.; MacNee, W.; Stone, V.; Donaldson, K. The importance of surface area and specific reactivity in the acute pulmonary inflammatory respones to particles. Ann. Occup. Hyg. 2002, 46, 242-245.
62. Stoeger, T.; Reinhard, C.; Takenaka, S.; Schroeppel, A.; Karg, E.; Ritter, B.; Heyder, J.; Schulz, H. Instillation of six different ultrafine carbon particles indicates a surface area threshold dose for acute lung inflammation in mice. Environm. Health Perspect. 2005, 114, 328-333.
63. Sager, T.M.; Kommineni, C.; Castranova, V. Pulmonary response to intratracheal instillation of ultrafine versus fine titanium dioxide: Role of particle surface area. Part. Fibre Toxicol. 2008, 5, 17-32.
64. Sager, T.M.; Castranova, V. Surface area of particle administered versus mass in determining the pulmonary toxicity of ultrafine and fine carbon black: Comparison to ultrafine titanium dioxide. Part. Fibre Toxicol. 2009, 6, 15-46.
65. Warheit, D.B.; Reed, K.L.; Sayes, C.M. A role for nanoparticle surface reactivity in facilitating pulmonary toxicity and development of a base set of hazard assays as a component of nanoparticle risk management. Inhal. Toxicol. 2009, 21, 61-67.
66. Monteiller, C.; Tran, L.; MacNee, W.; Faux, S.; Jones, A.; Miller, B.; Donaldson, K. The pro-inflammatory effects of low-toxicity low-solubility particles, nanoparticles and fine particles, on epithelial cells in vitro: The role of surface area. Occup. Environ. Med. 2007, 64, 609-615.
67. Rabolli, V.; Thomassen, L.C.; Uwambayinema, F.; Martens, J.A.; Lison, D. The cytotoxic activity of amorphous silica nanoparticles is mainly influenced by surface area and not by aggregation. Toxicol. Lett. 2011, 206, 197-203.
68. Lin, W.; Huang, Y.W.; Zhou, X.D.; Ma, Y. In vitro toxicity of silica nanoparticles in human lung cancer cells. Toxicol. Appl. Pharm. 2006, 217, 252-259.
69. Wang, A.Z.; Langer, R.; Farokhzad, O.C. Nanoparticle delivery of cancer drugs. Annu. Rev. Med. 2012, 63, 185-198.
70. Verma, A.; Stellacci, F. Effect of surface properties on nanoparticle-cell interactions. Small 2010, 6, 12-21.
71. Albanese, A.; Lam, A.K.; Sykes, E.A.; Rocheleau, J.V.; Chan, W.C. Tumour-on-a-chip provides an optical window into nanoparticle tissue transport. Nat. Commun. 2013, 4, 2718.
72. Valencia, P.M.; Farokhzad, O.C.; Karnik, R.; Langer, R. Microfluidic technologies for accelerating the clinical translation of nanoparticles. Nat. Nanotechnol. 2012, 7, 623-629.
73. Esch, M.B.; King, T.L.; Shuler, M.L. The role of body-on-a-chip devices in drug and toxicity studies. Annu. Rev. Biomed. Eng. 2011, 13, 55-72.
74. Toh, Y.C.; Lim, T.C.; Tai, D.; Xiao, G.; van Noort, D.; Yu, H. A microfluidic 3D hepatocyte chip for drug toxicity testing. Lab Chip 2009, 9, 2026-2035.
75. He, C.; Hu, Y.; Yin, L.; Tang, C.; Yin, C. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials 2010, 31, 3657-3666.
76. Hirn, S.; Semmler-Behnke, M.; Schleh, C.; Wenk, A.; Lipka, J.; Schaffler, M.; Takenaka, S.; Moller, W.; Schmid, G.; Simon, U.; et al. Particle size-dependent and surface charge-dependent biodistribution of gold nanoparticles after intravenous administration. Eur. J. Pharm. Biopharm. 2011, 77, 407-416.
77. Malam, Y.; Loizidou, M.; Seifalian, A.M. Liposomes and nanoparticles: Nanosized vehicles for drug delivery in cancer. Trends Pharm. Sci. 2009, 30, 592-599.
78. Jiang, J.; Oberdörster, G.; Biswas, P. Characterization of size, surface charge, and agglomeration state of nanoparticle dispersions for toxicological studies. J. Nanopart. Res. 2008, 11, 77-89.
79. Asati, A.; Santra, S.; Kaittanis, C.; Perez, J.M. Surface-charge-dependent cell localization and cytotoxicity of cerium oxide nanoparticles. ACS Nano 2010, 4, 5321-5331.
80. Frohlich, E. The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles. Int. J. Nanomed. 2012, 7, 5577-5591.
81. Schaeublin, N.M.; Braydich-Stolle, L.K.; Schrand, A.M.; Miller, J.M.; Hutchison, J.; Schlager, J.J.; Hussain, S.M. Surface charge of gold nanoparticles mediates mechanism of toxicity. Nanoscale 2011, 3, 410-420.
82. Cha, K.E.; Myung, H. Cytotoxic effects of nanoparticles assessed in vitro and in vivo. J. Microbiol. Biotechnol. 2007, 17, 1573-1578.
83. Huczko, A.; Lange, H.; Całko, E.; Grubek-Jaworska, H.; Droszcz, P. Physiological testing of carbon nanotubes: Are they asbestos-like? Fuller. Sci. Technol. 2001, 9, 251-254.
84. Firme, C.P.; Bandaru, P.R. Toxicity issues in the application of carbon nanotubes to biological systems. Nanomed. Nanotechnol. Biol. Med. 2010, 6, 245-256.
85. Chalupa, D.C.; Morrow, P.E.; Oberdörster, G.; Utell, M.J.; Frampton, M.W. Ultrafine particle deposition in subjects with asthma. Environ. Health Perspect. 2004, 112, 879-882.
86. Handy, R.D.; Henry, T.B.; Scown, T.M.; Johnston, B.D.; Tyler, C.R. Manufactured nanoparticles: Their uptake and effects on fish—A mechanistic analysis. Ecotoxicology 2008, 17, 396-409.
87. Baker, G.L.; Gupta, A.; Clark, M.L.; Valenzuela, B.R.; Staska, L.M.; Harbo, S.J.; Pierce, J.T.; Dill, J.A. Inhalation toxicity and lung toxicokinetics of C60 fullerene nanoparticles and microparticles. Toxicol. Sci. 2008, 101, 122-131.
88. Elder, A.C.P.; Gelein, R.; Finkelstein, J.N.; Cox, C.; Oberdorster, G. Pulmonary inflammatory response to inhaled ultrafine particles is modified by age, ozone exposure, and bacterial toxin. Inhal. Toxicol. 2000, 12, 227-246.
89. Oberdörster, E. Manufactured nanomaterials (fullerenes, C60) induce oxidative stress in the brain of juvenile largemouth bass. Environ. Health Perspect. 2004, 112, 1058-1062.
90. Lovern, S.B.; Klaper, R. Daphnia magna mortality when exposed to titanium dioxide and fullerene (C60) nanoparticles. Environ. Toxicol. Chem. 2006, 25, 1132-1137.
91. Lyon, D.Y.; Adams, L.K.; Falkner, J.C.; Alvarez, P.J.J. Antibacterial activity of fullerene water suspensions: Effects of preparation method and particle size. Environ. Sci. Technol. 2006, 40, 4360-4366.
92. Lyon, D.Y.; Fortner, J.D.; Sayes, C.M.; Colvin, V.L.; Hughes, J.B. Bacterial cell association and antimicrobial activity of a c60 water suspension. Environ. Toxicol. Chem. 2005, 24, 2757-2762.
93. Li, Z.; Hulderman, T.; Salmen, R.; Chapman, R.; Leonard, S.S.; Young, S.H.; Shvedova, A.; Luster, M.I.; Simeonova, P.P. Cardiovascular effects of pulmonary exposure to single-wall carbon nanotubes. Environ. Health Perspect. 2007, 115, 377-382.
94. Bantz, C.; Koshkina, O.; Lang, T.; Galla, H.-J.; Kirkpatrick, C.J.; Stauber, R.H.; Maskos, M. The surface properties of nanoparticles determine the agglomeration state and the size of the particles under physiological conditions. Beilstein J. Nanotechnol. 2014, 5, 1774-1786.
95. Donaldson, K.; Aitken, R.; Tran, L.; Stone, V.; Duffin, R.; Forrest, G.; Alexander, A. Carbon nanotubes: A review of their properties in relation to pulmonary toxicology and workplace safety. Toxicol. Sci. 2006, 92, 5-22.