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Freese, Christian; Uboldi, Chiara; Gibson, Matthew I.; Unger, Ronald E.; Weksler, Babette B.; Romero, Ignacio A.; Couraud, Pierre-Olivier; Kirkpatrick, C. J. (C. James) (2012)
Publisher: BioMed Central Ltd.
Journal: Particle and Fibre Toxicology
Languages: English
Types: Article
Subjects: [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, QD, Toxicology. Poisons, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, RA1190-1270, Industrial hygiene. Industrial welfare, HD7260-7780.8, Research, QP

Abstract

Background

The use of gold nanoparticles (AuNPs) for diagnostic applications and for drug and gene-delivery is currently under intensive investigation. For such applications, biocompatibility and the absence of cytotoxicity of AuNPs is essential. Although generally considered as highly biocompatible, previous in vitro studies have shown that cytotoxicity of AuNPs in certain human epithelial cells was observed. In particular, the degree of purification of AuNPs (presence of sodium citrate residues on the particles) was shown to affect the proliferation and induce cytotoxicity in these cells. To expand these studies, we have examined if the effects are related to nanoparticle size (10, 11 nm, 25 nm), to the presence of sodium citrate on the particles' surface or they are due to a varying degree of internalization of the AuNPs. Since two cell types are present in the major barriers to the outside in the human body, we have also included endothelial cells from the vasculature and blood brain barrier.

Results

Transmission electron microscopy demonstrates that the internalized gold nanoparticles are located within vesicles. Increased cytotoxicity was observed after exposure to AuNPs and was found to be concentration-dependent. In addition, cell viability and the proliferation of both endothelial cells decreased after exposure to gold nanoparticles, especially at high concentrations. Moreover, in contrast to the size of the particles (10 nm, 11 nm, 25 nm), the presence of sodium citrate on the nanoparticle surface appeared to enhance these effects. The effects on microvascular endothelial cells from blood vessels were slightly enhanced compared to the effects on brain-derived endothelial cells. A quantification of AuNPs within cells by ICP-AES showed that epithelial cells internalized a higher quantity of AuNPs compared to endothelial cells and that the quantity of uptake is not correlated with the amount of sodium citrate on the nanoparticles’ surface.

Conclusions

In conclusion the higher amount of citrate on the particle surface resulted in a higher impairment of cell viability, but did not enhance or reduce the uptake behavior in endothelial or epithelial cells. In addition, epithelial and endothelial cells exhibited different uptake behaviors for citrate-stabilized gold nanoparticles, which might be related to different interactions occurring at the nanoparticle-cell-surface interface. The different uptake in epithelial cells might explain the higher reduction of proliferation of these cells after exposure to AuNPs treatment although more detailed investigations are necessary to determine subcellular events. Nevertheless an extrinsic effect of sodium-citrate stabilized particles could not be excluded. Thus, the amount of sodium citrate should be reduced to a level on which the stability of the particles and the safety for biomedical applications are guaranteed.

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    • 1. Sperling RA, Gil P, Zhang F, Zanella M, Parak WJ: Biological applications of gold nanoparticles. Chem Soc Rev 2008, 37(9):1896-1908.
    • 2. Boisselier E, Astruc D: Gold nanoparticles in nanomedicine: preparation, imaging, diagnostics, therapies and toxitiy. Chem Soc Rev 2009, 38(6):1759-1782.
    • 3. Sopjani M, Föller M, Lang F: Gold stimulates Ca2+ entry into and subsequent suicidal death of erythrocytes. Toxicology 2008, 244:271-279.
    • 4. Sereemaspun A, Rojanathanes R, Wiwanitkit V: Effect of gold nanoparticle on renal cell: an implication for exposure risk. Renal failure 2008, 30:323-325.
    • 5. Cho W-S, Cho M, Jeong J, Choi M, Cho H-Y, Han BS, Kim SH, Kim HO, Lim YT, Chung BH, Jeong J: Acute toxicity and pharmacokinetics of 13 nm-sized PEG-coated gold nanoparticles. Toxicology and Applied Pharmacology 2009, 236(1):16-24.
    • 6. Gibson MI, Danial M, Klok H-A: Sequentially Modified, Polymer-Stabilized Gold Nanoparticle Libraries: Convergent Synthesis and Aggregation Behavior. ACS Combinatorial Science 2011, 13(3):286-297.
    • 7. Pan Y, Leifert A, Ruau D, Neuss S, Bornemann J, Schmid G, Brandau W, Simon U, Jahnen-Dechent W: Gold nanoparticles of diameter 1.4 nm trigger necrosis by oxidative stress and mitochondrial damage. Small (Weinheim an der Bergstrasse, Germany) 2009, 5:2067-2076.
    • 8. Arvizo RR, Miranda OR, Thompson MA, Pabelick CM, Bhattacharya R, Robertson JD, Rotello VM, Prakash YS, Mukherjee P: Effect of nanoparticle surface charge at the plasma membrane and beyond. Nano letters 2010, 10:2543-2548.
    • 9. Hauck TS, Ghazani AA, Chan WCW: Assessing the effect of surface chemistry on gold nanorod uptake, toxicity, and gene expression in mammalian cells. Small (Weinheim an der Bergstrasse, Germany) 2008, 4:153-159.
    • 10. Uboldi C, Bonacchi D, Lorenzi G, Hermanns MI, Pohl C, Baldi G, Unger RE, Kirkpatrick CJ: Gold nanoparticles induce cytotoxicity in the alveolar type-II cell lines A549 and NCIH441. Part Fibre Toxicol 2009, 6:18.
    • 11. Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver RP, Pober JS, Wick TM, Konkle BA, Schwartz BS, et al: Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 1998, 91:3527-3561.
    • 12. Kirkpatrick CJ, Bittinger F, Klein CL, Hauptmann S, Klosterhalfen B: The role of the microcirculation in multiple organ dysfunction syndrome (MODS): a review and perspective. Virchows Arch 1996, 427:461-476.
    • 13. Kunzmann A, Andersson B, Thurnherr T, Krug H, Scheynius A, Fadeel B: Toxicology of engineered nanomaterials: Focus on biocompatibility, biodistribution and biodegradation. Biochimica et biophysica acta 2010, 1810(3):361-73.
    • 14. Bartczak D, Sanchez-Elsner T, Louafi F, Millar TM, Kanaras AG: ReceptorMediated Interactions between Colloidal Gold Nanoparticles and Human Umbilical Vein Endothelial Cells. Small 2010, 7(3):388-94.
    • 15. Bartczak D, Muskens OL, Nitti S, Sanchez-Elsner T, Millar TM, Kanaras AG: Interactions of Human Endothelial Cells with Gold Nanoparticles of Different Morphologies. Small 2012, 8:122-130.
    • 16. Chithrani BD, Ghazani AA, Chan WCW: Determining the Size and Shape Dependence of Gold Nanoparticle Uptake into Mammalian Cells. Nano Letters 2006, 6:662-668.
    • 17. Ma Y-J, Gu H-C: Study on the endocytosis and the internalization mechanism of aminosilane-coated Fe3O4 nanoparticles in vitro. Journal of materials science Materials in medicine 2007, 18:2145-2149.
    • 18. Nativo P, Prior IA, Brust M: Uptake and Intracellular Fate of Surface-Modified Gold Nanoparticles. ACS Nano 2008, 2:1639-1644.
    • 19. Scholzen T, Gerdes J: The Ki-67 protein: from the known and the unknown. Journal of cellular physiology 2000, 182:311-322.
    • 20. Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H: Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. Journal of immunology (Baltimore, Md: 1950) 1984, 133:1710-1715.
    • 21. Sasaki K, Murakami T, Kawasaki M, Takahashi M: The cell cycle associated change of the Ki-67 reactive nuclear antigen expression. Journal of cellular physiology 1987, 133:579-584.
    • 22. Dyer LA, Patterson C: Development of the endothelium: an emphasis on heterogeneity. Seminars in thrombosis and hemostasis 2010, 36:227-235.
    • 23. Mironava T, Hadjiargyrou M, Simon M, Jurukovski V, Rafailovich MH: Gold nanoparticles cellular toxicity and recovery: Effect of size, concentration and exposure time: Nanotoxicology. Nanotoxicology 2010, 4:120-137.
    • 24. Roa W, Zhang X, Guo L, Shaw A, Hu X, Xiong Y, Gulavita S, Patel S, Sun X, Chen J, et al: Gold nanoparticle sensitize radiotherapy of prostate cancer cells by regulation of the cell cycle. Nanotechnology 2009, 20:375101.
    • 25. Fang JL, Beland FA: Long-term exposure to zidovudine delays cell cycle progression, induces apoptosis, and decreases telomerase activity in human hepatocytes. Toxicol Sci 2009, 111:120-130.
    • 26. Zhang L, Zhang J, Hu C, Cao J, Zhou X, Hu Y, He Q, Yang B: Efficient activation of p53 pathway in A549 cells exposed to L2, a novel compound targeting p53-MDM2 interaction. Anticancer Drugs 2009, 20:416-424.
    • 27. Gosens I, Post JA, de la Fonteyne LJ, Jansen EH, Geus JW, Cassee FR, de Jong WH: Impact of agglomeration state of nano- and submicron sized gold particles on pulmonary inflammation. Part Fibre Toxicol 2010, 7:37.
    • 28. Nel AE, Madler L, Velegol D, Xia T, Hoek EMV, Somasundaran P, Klaessig F, Castranova V, Thompson M: Understanding biophysicochemical interactions at the nano-bio interface. Nat Mater 2009, 8:543-557.
    • 29. 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.
    • 30. Rothen-Rutishauser B, Mühlfeld C, Blank F, Musso C, Gehr P: Translocation of particles and inflammatory responses after exposure to fine particles and nanoparticles in an epithelial airway model. Part Fibre Toxicol 2007, 4:9.
    • 31. Xia T, Kovochich M, Liong M, Zink JI, Nel AE: Cationic Polystyrene Nanosphere Toxicity Depends on Cell-Specific Endocytic and Mitochondrial Injury Pathways. ACS Nano 2008, 2:85-96.
    • 32. Unger RE, Krump-Konvalinkova V, Peters K, Kirkpatrick CJ: In Vitro Expression of the Endothelial Phenotype: Comparative Study of Primary Isolated Cells and Cell Lines, Including the Novel Cell Line HPMEC-ST1.6R. Microvascular Research 2002, 64:384-397.
    • 33. Weksler BB, Subileau EA, Perrière N, Charneau P, Holloway K, Leveque M, Tricoire-Leignel H, Nicotra A, Bourdoulous S, Turowski P, et al: Blood-brain barrier-specific properties of a human adult brain endothelial cell line. The FASEB journal: official publication of the Federation of American Societies for Experimental Biology 2005, 19:1872-1874.
    • 1. Sperling RA, Gil P, Zhang F, Zanella M, Parak WJ: Biological applications of gold nanoparticles. Chem Soc Rev 2008, 37(9):1896-1908.
    • 2. Boisselier E, Astruc D: Gold nanoparticles in nanomedicine: preparation, imaging, diagnostics, therapies and toxitiy. Chem Soc Rev 2009, 38(6):1759-1782.
    • 3. Sopjani M, Föller M, Lang F: Gold stimulates Ca2+ entry into and subsequent suicidal death of erythrocytes. Toxicology 2008, 244:271-279.
    • 4. Sereemaspun A, Rojanathanes R, Wiwanitkit V: Effect of gold nanoparticle on renal cell: an implication for exposure risk. Renal failure 2008, 30:323-325.
    • 5. Cho W-S, Cho M, Jeong J, Choi M, Cho H-Y, Han BS, Kim SH, Kim HO, Lim YT, Chung BH, Jeong J: Acute toxicity and pharmacokinetics of 13 nm-sized PEG-coated gold nanoparticles. Toxicology and Applied Pharmacology 2009, 236(1):16-24.
    • 6. Gibson MI, Danial M, Klok H-A: Sequentially Modified, Polymer-Stabilized Gold Nanoparticle Libraries: Convergent Synthesis and Aggregation Behavior. ACS Combinatorial Science 2011, 13(3):286-297.
    • 7. Pan Y, Leifert A, Ruau D, Neuss S, Bornemann J, Schmid G, Brandau W, Simon U, Jahnen-Dechent W: Gold nanoparticles of diameter 1.4 nm trigger necrosis by oxidative stress and mitochondrial damage. Small (Weinheim an der Bergstrasse, Germany) 2009, 5:2067-2076.
    • 8. Arvizo RR, Miranda OR, Thompson MA, Pabelick CM, Bhattacharya R, Robertson JD, Rotello VM, Prakash YS, Mukherjee P: Effect of nanoparticle surface charge at the plasma membrane and beyond. Nano letters 2010, 10:2543-2548.
    • 9. Hauck TS, Ghazani AA, Chan WCW: Assessing the effect of surface chemistry on gold nanorod uptake, toxicity, and gene expression in mammalian cells. Small (Weinheim an der Bergstrasse, Germany) 2008, 4:153-159.
    • 10. Uboldi C, Bonacchi D, Lorenzi G, Hermanns MI, Pohl C, Baldi G, Unger RE, Kirkpatrick CJ: Gold nanoparticles induce cytotoxicity in the alveolar type-II cell lines A549 and NCIH441. Part Fibre Toxicol 2009, 6:18.
    • 11. Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver RP, Pober JS, Wick TM, Konkle BA, Schwartz BS, et al: Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 1998, 91:3527-3561.
    • 12. Kirkpatrick CJ, Bittinger F, Klein CL, Hauptmann S, Klosterhalfen B: The role of the microcirculation in multiple organ dysfunction syndrome (MODS): a review and perspective. Virchows Arch 1996, 427:461-476.
    • 13. Kunzmann A, Andersson B, Thurnherr T, Krug H, Scheynius A, Fadeel B: Toxicology of engineered nanomaterials: Focus on biocompatibility, biodistribution and biodegradation. Biochimica et biophysica acta 2010, 1810(3):361-73.
    • 14. Bartczak D, Sanchez-Elsner T, Louafi F, Millar TM, Kanaras AG: ReceptorMediated Interactions between Colloidal Gold Nanoparticles and Human Umbilical Vein Endothelial Cells. Small 2010, 7(3):388-94.
    • 15. Bartczak D, Muskens OL, Nitti S, Sanchez-Elsner T, Millar TM, Kanaras AG: Interactions of Human Endothelial Cells with Gold Nanoparticles of Different Morphologies. Small 2012, 8:122-130.
    • 16. Chithrani BD, Ghazani AA, Chan WCW: Determining the Size and Shape Dependence of Gold Nanoparticle Uptake into Mammalian Cells. Nano Letters 2006, 6:662-668.
    • 17. Ma Y-J, Gu H-C: Study on the endocytosis and the internalization mechanism of aminosilane-coated Fe3O4 nanoparticles in vitro. Journal of materials science Materials in medicine 2007, 18:2145-2149.
    • 18. Nativo P, Prior IA, Brust M: Uptake and Intracellular Fate of Surface-Modified Gold Nanoparticles. ACS Nano 2008, 2:1639-1644.
    • 19. Scholzen T, Gerdes J: The Ki-67 protein: from the known and the unknown. Journal of cellular physiology 2000, 182:311-322.
    • 20. Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H: Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. Journal of immunology (Baltimore, Md: 1950) 1984, 133:1710-1715.
    • 21. Sasaki K, Murakami T, Kawasaki M, Takahashi M: The cell cycle associated change of the Ki-67 reactive nuclear antigen expression. Journal of cellular physiology 1987, 133:579-584.
    • 22. Dyer LA, Patterson C: Development of the endothelium: an emphasis on heterogeneity. Seminars in thrombosis and hemostasis 2010, 36:227-235.
    • 23. Mironava T, Hadjiargyrou M, Simon M, Jurukovski V, Rafailovich MH: Gold nanoparticles cellular toxicity and recovery: Effect of size, concentration and exposure time: Nanotoxicology. Nanotoxicology 2010, 4:120-137.
    • 24. Roa W, Zhang X, Guo L, Shaw A, Hu X, Xiong Y, Gulavita S, Patel S, Sun X, Chen J, et al: Gold nanoparticle sensitize radiotherapy of prostate cancer cells by regulation of the cell cycle. Nanotechnology 2009, 20:375101.
    • 25. Fang JL, Beland FA: Long-term exposure to zidovudine delays cell cycle progression, induces apoptosis, and decreases telomerase activity in human hepatocytes. Toxicol Sci 2009, 111:120-130.
    • 26. Zhang L, Zhang J, Hu C, Cao J, Zhou X, Hu Y, He Q, Yang B: Efficient activation of p53 pathway in A549 cells exposed to L2, a novel compound targeting p53-MDM2 interaction. Anticancer Drugs 2009, 20:416-424.
    • 27. Gosens I, Post JA, de la Fonteyne LJ, Jansen EH, Geus JW, Cassee FR, de Jong WH: Impact of agglomeration state of nano- and submicron sized gold particles on pulmonary inflammation. Part Fibre Toxicol 2010, 7:37.
    • 28. Nel AE, Madler L, Velegol D, Xia T, Hoek EMV, Somasundaran P, Klaessig F, Castranova V, Thompson M: Understanding biophysicochemical interactions at the nano-bio interface. Nat Mater 2009, 8:543-557.
    • 29. 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.
    • 30. Rothen-Rutishauser B, Mühlfeld C, Blank F, Musso C, Gehr P: Translocation of particles and inflammatory responses after exposure to fine particles and nanoparticles in an epithelial airway model. Part Fibre Toxicol 2007, 4:9.
    • 31. Xia T, Kovochich M, Liong M, Zink JI, Nel AE: Cationic Polystyrene Nanosphere Toxicity Depends on Cell-Specific Endocytic and Mitochondrial Injury Pathways. ACS Nano 2008, 2:85-96.
    • 32. Unger RE, Krump-Konvalinkova V, Peters K, Kirkpatrick CJ: In Vitro Expression of the Endothelial Phenotype: Comparative Study of Primary Isolated Cells and Cell Lines, Including the Novel Cell Line HPMEC-ST1.6R. Microvascular Research 2002, 64:384-397.
    • 33. Weksler BB, Subileau EA, Perrière N, Charneau P, Holloway K, Leveque M, Tricoire-Leignel H, Nicotra A, Bourdoulous S, Turowski P, et al: Blood-brain barrier-specific properties of a human adult brain endothelial cell line. The FASEB journal: official publication of the Federation of American Societies for Experimental Biology 2005, 19:1872-1874.
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