Abstract
With the development of nanotechnology, nanometer-sized products smaller than several 100 nm have been applied for all areas of science and technology. The nanometer-sized products, including carbon nanotubes, fullerene derivatives, and nanocrystals made of various materials, are widely employed as novel tools in various fields, not only in material engineering, electronics, plastics, automobile, aviation, and aerospace industries, but also even in cellular biology, molecular biology, and basic and clinical medical fields. In particular, nanocrystal quantum dots (QDs) have been widely used in biological and medical studies because of their far brighter photoemission and photostability. The physical and chemical properties of QDs have been circumstantially investigated, but little is known about the potential harmful effects of QDs on human health. In addition to the physical and chemical properties of the QDs, their toxicity and biological behavior are generally regulated by three other conditions: (1) the QD core material itself, (2) the surface modifications of the QD, and (3) the external environmental condition of the QDs. We herein report on the in vitro and in vivo toxicity and biological behavior of nanocrystals such as QDs. Accumulating evidence suggests that the QD-capping material, rather than the core metalloid complex, is responsible for the majority of their toxicity and biological activity. For example, molecules covered with a toxic agent showed cytotoxicity, whereas QDs conjugated with biomolecules retained the biological effects of the conjugate.
Similar content being viewed by others
References
Adams LK, Lyon DY, Alvarez PJ (2006) Comparative eco-toxicity of nanoscale TiO(2), SiO(2), and ZnO water suspensions. Water Res 40(19):3527–3532
Akerman ME, Chan WC, Laakkonen P, Bhatia SN, Ruoslahti E (2002) Nanocrystal targeting in vivo. Proc Natl Acad Sci USA 99(20):12617–12621
Alsharif NH, Berger CE, Varanasi SS, Chao Y, Horrocks BR, Datta HK (2009) Alkyl-capped silicon nanocrystals lack cytotoxicity and have enhanced intracellular accumulation in malignant cells via cholesterol-dependent endocytosis. Small 5(2):221–228
Anas A, Okuda T, Kawashima N et al (2009) Clathrin-mediated endocytosis of quantum dot-peptide conjugates in living cells. ACS Nano 3(8):2419–2429
Ballou B (2005) Quantum dot surfaces for use in vivo and in vitro. Curr Top Dev Biol 70:103–120
Ballou B, Lagerholm BC, Ernst LA, Bruchez MP, Waggoner AS (2004) Noninvasive imaging of quantum dots in mice. Bioconjug Chem 15(1):79–86
Bhakta G, Mitra S, Maitra A (2005) DNA encapsulated magnesium and manganous phosphate nanoparticles: potential non-viral vectors for gene delivery. Biomaterials 26(14):2157–2163
Bharali DJ, Klejbor I, Stachowiak EK et al (2005) Organically modified silica nanoparticles: a nonviral vector for in vivo gene delivery and expression in the brain. Proc Natl Acad Sci USA 102(32):11539–11544
Bianco A, Kostarelos K, Prato M (2005) Applications of carbon nanotubes in drug delivery. Curr Opin Chem Biol 9(6):674–679
Biju V, Muraleedharan D, Nakayama K et al (2007) Quantum dot-insect neuropeptide conjugates for fluorescence imaging, transfection, and nucleus targeting of living cells. Langmuir 23(20):10254–10261
Borm PJ, Robbins D, Haubold S et al (2006) The potential risks of nanomaterials: a review carried out for ECETOC. Part Fibre Toxicol 3:11
Bottero JY, Rose J, Wiesner MR (2006) Nanotechnologies: tools for sustainability in a new wave of water treatment processes. Integr Environ Assess Manag 2(4):391–395
Braydich-Stolle L, Hussain S, Schlager JJ, Hofmann MC (2005) In vitro cytotoxicity of nanoparticles in mammalian germline stem cells. Toxicol Sci 88(2):412–419
Bruchez M, Moronne M, Gin P, Weiss S, Alivisatos AP (1998) Semiconductor nanocrystals as fluorescent biological labels. Science 281:2013–2016
Cao L, Huang S, Shulin E (2004) ZnS/CdS/ZnS quantum dot quantum well produced in inverted micelles. J Colloid Interface Sci 273(2):478–482
Champion CI, Kickhoefer VA, Liu G et al (2009) A vault nanoparticle vaccine induces protective mucosal immunity. PLoS One 4(4):e5409
Chan WC, Nie S (1998) Quantum dot bioconjugates for ultrasensitive nonisotopic detection. Science 281(5385):2016–2018
Chan WC, Maxwell DJ, Gao X, Bailey RE, Han M, Nie S (2002) Luminescent quantum dots for multiplexed biological detection and imaging. Curr Opin Biotechnol 13(1):40–46
Cordero SR, Carson PJ, Estabrook RA, Strouse GF, Buratto SK (2000) Photo-activated luminescence of CdSe quantum dot monolayers. J Phys Chem B 104(15):12137–12142
Dabbousi BO, Rodriguez-Viejo J, Mikulec FV et al (1997) (CdSe)ZnS core-shell quantum dots: synthesis and characterization of a size series of highly luminescent nanocrystallites. J Phys Chem 101:9463–9475
Demento SL, Eisenbarth SC, Foellmer HG et al (2009) Inflammasome-activating nanoparticles as modular systems for optimizing vaccine efficacy. Vaccine 27(23):3013–3021
Dubertret B, Skourides P, Norris DJ, Noireaux V, Brivanlou AH, Libchaber A (2002) In vivo imaging of quantum dots encapsulated in phospholipid micelles. Science 298(5599):1759–1762
Eiha N, Maenosono S, Hanaki K, Yamamoto K, Yamaguchi Y (2003) Collective fluorescence oscillation in a water dispersion of colloidal quantum dots. Jpn J Appl Phys 42:310–313
Fischer HC, Liu L, Pang KS, Chan WCW (2006) Pharmacokinetics of nanoscale quantum dots: in vivo distribution, sequestration, and clearance in the rat. Adv Funct Mater 16(10):1299–1305
Fortner JD, Lyon DY, Sayes CM et al (2005) C60 in water: nanocrystal formation and microbial response. Environ Sci Technol 39(11):4307–4316
Fujioka K, Hiruoka M, Sato K et al (2008) Luminescent passive-oxidized silicon quantum dots as biological staining labels and their cytotoxicity effects at high concentration. Nanotechnology 19(41):415102
Gao X, Nie S (2005) Quantum dot-encoded beads. Methods Mol Biol 303:61–71
Garnett MC, Kallinteri P (2006) Nanomedicines and nanotoxicology: some physiological principles. Occup Med (Lond) 56(5):307–311
Geys J, Nemmar A, Verbeken E et al (2008) Acute toxicity and prothrombotic effects of quantum dots: impact of surface charge. Environ Health Perspect 116(12):1607–1613
Guzman KA, Taylor MR, Banfield JF (2006) Environmental risks of nanotechnology: National Nanotechnology Initiative funding, 2000–2004. Environ Sci Technol 40(5):1401–1407
Hanaki K, Momo A, Oku T et al (2003) Semiconductor quantum dot/albumin complex is a long-life and highly photostable endosome marker. Biochem Biophys Res Commun 302(3):496–501
Hardman R (2006) A toxicologic review of quantum dots: toxicity depends on physicochemical and environmental factors. Environ Health Perspect 114(2):165–172
Hauck TS, Anderson RE, Fischer HC, Newbigging S, Chan WC (2009) In vivo quantum-dot toxicity assessment. Small 6(1):138–144
Hines MA, Guyot-Sionnest P (1996) Synthesis and characterization of strongly luminescing ZnS-capped CdSe nanocrystals. J Phys Chem 100:468–471
Hohng S, Ha T (2004) Near-complete suppression of quantum dot blinking in ambient conditions. J Am Chem Soc 126(5):1324–1325
Hoshino A, Fujioka K, Oku T et al (2004a) Physicochemical properties and cellular toxicity of nanocrystal quantum dots depend on their surface modification. Nano Lett 4(11):2163–2169
Hoshino A, Hanaki K, Suzuki K, Yamamoto K (2004b) Applications of T-lymphoma labeled with fluorescent quantum dots to cell tracing markers in mouse body. Biochem Biophys Res Commun 314(1):46–53
Hoshino A, Fujioka K, Oku T et al (2004c) Quantum dots targeted to the assigned organelle in living cells. Microbiol Immunol 48(12):985–994
Hoshino A, Manabe N, Fujioka K, Suzuki K, Yasuhara M, Yamamoto K (2007a) Use of fluorescent quantum dot bioconjugates for cellular imaging of immune cells, cell organelle labeling, and nanomedicine: surface modification regulates biological function, including cytotoxicity. J Artif Organs 10(3):149–157
Hoshino A, Nagao T, Ito-Ihara T et al (2007b) Trafficking of QD-conjugated MPO-ANCA in murine systemic vasculitis and glomerulonephritis model mice. Microbiol Immunol 51(5):551–566
Hoshino A, Kawamura YI, Yasuhara M et al (2007c) Inhibition of CCL1-CCR8 interaction prevents aggregation of macrophages and development of peritoneal adhesions. J Immunol 178(8):5296–5304
Hoshino A, Manabe N, Fujioka K et al (2008) GFP expression by intracellular gene delivery of GFP-coding fragments using nanocrystal quantum dots. Nanotechnology 19(49):495102
Hoshino A, Hanada S, Manabe N, Nakayama T, Yamamoto K (2009) Immune response induced by fluorescent nanocrystal quantum dots in vitro and in vivo. IEEE Trans Nanobiosci 8(1):51–57
Hsieh MS, Shiao NH, Chan WH (2009) Cytotoxic effects of CdSe quantum dots on maturation of mouse oocytes, fertilization, and fetal development. Int J Mol Sci 10(5):2122–2135
Jacobsen NR, Moller P, Jensen KA et al (2009) Lung inflammation and genotoxicity following pulmonary exposure to nanoparticles in ApoE-/- mice. Part Fibre Toxicol 6:2
Jaiswal JK, Mattoussi H, Mauro JM, Simon SM (2003) Long-term multiple color imaging of live cells using quantum dot bioconjugates. Nat Biotechnol 21(1):47–51
Jia N, Lian Q, Shen H, Wang C, Li X, Yang Z (2007) Intracellular delivery of quantum dots tagged antisense oligodeoxynucleotides by functionalized multiwalled carbon nanotubes. Nano Lett 7(10):2976–2980
Kako S, Santori C, Hoshino K, Gotzinger S, Yamamoto Y, Arakawa Y (2006) A gallium nitride single-photon source operating at 200 K. Nat Mater 5(11):887–892
Kim S, Fisher B, Eisler HJ, Bawendi M (2003) Type-II quantum dots: CdTe/CdSe(core/shell) and CdSe/ZnTe(core/shell) heterostructures. J Am Chem Soc 125(38):11466–11467
Kim JS, Yoon TJ, Yu KN et al (2006) Toxicity and tissue distribution of magnetic nanoparticles in mice. Toxicol Sci 89(1):338–347
Kimura J, Uematsu T, Maenosono S, Yamaguchi Y (2004) Photoinduced fluorescence enhancement in CdSe/ZnS quantum dot submonolayers sandwiched between insulating layers: influence of dot proximity. J Phys Chem B 108:13258–13264
Kubo R (1957) Statistical-mechanical theory of irreversible processes. J Phys Soc Jpn 12:570–586
Kubo R (1962a) Generalized cumulant expansion method. J Phys Soc Jpn 17:1100–1120
Kubo R (1962b) Stochastic Liouville equations. J Math Phys 4:174–183
Laffan R, Goldberg M, High J, Schaeffer T, Waugh M, Rubin B (1978) Antihypertensive activity in rats for SQ 14225, an orally active inhibitor of angiotensin I-converting enzyme. J Parmacol Exp Ther 204:281–288
Lanone S, Boczkowski J (2006) Biomedical applications and potential health risks of nanomaterials: molecular mechanisms. Curr Mol Med 6(6):651–663
Lawson CC, Grajewski B, Daston GP et al (2006) Workgroup report: implementing a national occupational reproductive research agenda–decade one and beyond. Environ Health Perspect 114(3):435–441
Lin H, Datar RH (2006) Medical applications of nanotechnology. Natl Med J India 19(1):27–32
Lovric J, Bazzi HS, Cuie Y, Fortin GR, Winnik FM, Maysinger D (2005a) Differences in subcellular distribution and toxicity of green and red emitting CdTe quantum dots. J Mol Med 83(5):377–385
Lovric J, Cho SJ, Winnik FM, Maysinger D (2005b) Unmodified cadmium telluride quantum dots induce reactive oxygen species formation leading to multiple organelle damage and cell death. Chem Biol 12(11):1227–1234
Maenosono S, Dushkin C, Saita S, Yamaguchi Y (2000) Optical memory media based on excitation-time dependent luminescence from a thin film of semiconductor nanocrystals. Jpn J Appl Phys 39(7):4006–4012
Magrez A, Kasas S, Salicio V et al (2006) Cellular toxicity of carbon-based nanomaterials. Nano Lett 6(6):1121–1125
Mahendra S, Zhu H, Colvin VL, Alvarez PJ (2008) Quantum dot weathering results in microbial toxicity. Environ Sci Technol 42(24):9424–9430
Manabe N, Hoshino A, Liang YQ, Goto T, Kato N, Yamamoto K (2006) Quantum dot as a drug tracer in vivo. IEEE Trans Nanobiosci 5(4):263–267
Mancini MC, Kairdolf BA, Smith AM, Nie S (2008) Oxidative quenching and degradation of polymer-encapsulated quantum dots: new insights into the long-term fate and toxicity of nanocrystals in vivo. J Am Chem Soc 130(33):10836–10837
Mansson A, Sundberg M, Balaz M et al (2004) In vitro sliding of actin filaments labelled with single quantum dots. Biochem Biophys Res Commun 314(2):529–534
Michalet X, Pinaud FF, Bentolila LA et al (2005) Quantum dots for live cells, in vivo imaging, and diagnostics. Science 307(5709):538–544
Moore MN (2006) Do nanoparticles present ecotoxicological risks for the health of the aquatic environment? Environ Int 32(8):967–976
Mortensen LJ, Oberdorster G, Pentland AP, Delouise LA (2008) In vivo skin penetration of quantum dot nanoparticles in the murine model: the effect of UVR. Nano Lett 8(9):2779–2787
Nel A, Xia T, Madler L, Li N (2006) Toxic potential of materials at the nanolevel. Science 311(5761):622–627
Neuhauser RG, Shimizu KT, Woo WK, Empedocles SA, Bawendy MG (2000) Correlation between fluorescence intermittency and spectral diffusion in single semiconductor quantum dots. Phys Rev Lett 85:3301–3304
Oberdorster G, Oberdorster E, Oberdorster J (2005) Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 113(7):823–839
Peng X, Schlamp MC, Kadavanich AV, Alivisatos AP (1997) Epitaxial growth of highly luminescent CdSe/CdS core/shell nanocrystals with photostability and electronic accessibility. J Am Chem Soc 119(30):7019–7029
Pison U, Welte T, Giersig M, Groneberg DA (2006) Nanomedicine for respiratory diseases. Eur J Pharmacol 533(1–3):341–350
Powell JJ, Faria N, Thomas-McKay E, Pele LC (2010) Origin and fate of dietary nanoparticles and microparticles in the gastrointestinal tract. J Autoimmun 34:226–233
Robichaud C, Tanzil D, Weilenmann U, Wiesner M (2005) Relative risk analysis of several manufactured nanomaterials: an insurance industry context. Environ Sci Technol 39(22):8985–8994
Rubin B, Laffan R, Kotler D, O’Keefe E, Demaio D, Goldberg M (1978) SQ 14225 (D-3 mercapto-2-methylpropanoyl-l-proline), a novel orally active inhibitor of angiotensin I-converting enzyme. Parmacol Exp Ther 204:271–280
Ryman-Rasmussen JP, Riviere JE, Monteiro-Riviere NA (2007) Surface coatings determine cytotoxicity and irritation potential of quantum dot nanoparticles in epidermal keratinocytes. J Invest Dermatol 127:143–153
Santra S, Yang H, Holloway PH, Stanley JT, Mericle RA (2005) Synthesis of water-dispersible fluorescent, radio-opaque, and paramagnetic CdS:Mn/ZnS quantum dots: a multifunctional probe for bioimaging. J Am Chem Soc 127(6):1656–1657
Sapra S, Prakash A, Ghangrekar A, Periasamy N, Sarma DD (2005) Emission properties of manganese-doped ZnS nanocrystals. J Phys Chem B 109(5):1663–1668
Sayes CM, Gobin AM, Ausman KD, Mendez J, West JL, Colvin VL (2005) Nano-C60 cytotoxicity is due to lipid peroxidation. Biomaterials 26(36):7587–7595
Sayes CM, Wahi R, Kurian PA et al (2006) Correlating nanoscale titania structure with toxicity: a cytotoxicity and inflammatory response study with human dermal fibroblasts and human lung epithelial cells. Toxicol Sci 92(1):174–185
Schneider R, Wolpert C, Guilloteau H, Balan L, Lambert J, Merlin C (2009) The exposure of bacteria to CdTe-core quantum dots: the importance of surface chemistry on cytotoxicity. Nanotechnology 20(22):225101
Service RF (2005) Nanotechnology. Calls rise for more research on toxicology of nanomaterials. Science 310(5754):1609
Shiohara A, Hoshino A, Hanaki K, Suzuki K, Yamamoto K (2004) On the cyto-toxicity caused by quantum dots. Microbiol Immunol 48(9):669–675
Shiohara A, Hanada S, Prabakar S et al (2010) Chemical reactions on surface molecules attached to silicon quantum dots. J Am Chem Soc 132(1):248–253
Springholz G, Holy VV, Pinczolits M, Bauer G (1998) Self-organized growth of three-dimensional quantum-dot crystals with fcc-like stacking and a tunable lattice constant. Science 282(5389):734–737
Srinivasan C, Lee J, Papadimitrakopoulos F, Silbart LK, Zhao M, Burgess DJ (2006) Labeling and intracellular tracking of functionally active plasmid DNA with semiconductor quantum dots. Mol Ther 14(2):192–201
Stern ST, Zolnik BS, McLeland CB, Clogston J, Zheng J, McNeil SE (2008) Induction of autophagy in porcine kidney cells by quantum dots: a common cellular response to nanomaterials? Toxicol Sci 106(1):140–152
Talapin DV, Murray CB (2005) PbSe nanocrystal solids for n- and p-channel thin film field-effect transistors. Science 310(5745):86–89
Tang J, Marcus RA (2005) Mechanisms of fluorescence blinking in semiconductor nanocrystal quantum dots. J Chem Phys 123:054704
Tian F, Cui D, Schwarz H, Estrada GG, Kobayashi H (2006) Cytotoxicity of single-wall carbon nanotubes on human fibroblasts. Toxicol Vitro 20(7):1202–1212
Uematsu T, Kimura J, Yamaguchi Y (2004) The reversible photoluminescence enhancement of a CdSe/ZnS nanocrystal thin film. Nanotechnology 15:822–827
Wiesner MR (2006) Responsible development of nanotechnologies for water and wastewater treatment. Water Sci Technol 53(3):45–51
Worle-Knirsch JM, Pulskamp K, Krug HF (2006) Oops they did it again! Carbon nanotubes hoax scientists in viability assays. Nano Lett 6(6):1261–1268
Wu X, Liu H, Liu J et al (2003) Immunofluorescent labeling of cancer marker Her2 and other cellular targets with semiconductor quantum dots. Nat Biotechnol 21(1):41–46
Xu H, Sha MY, Wong EY et al (2003) Multiplexed SNP genotyping using the Qbead system: a quantum dot-encoded microsphere-based assay. Nucleic Acids Res 31(8):e43
Yamawaki H, Iwai N (2006) Cytotoxicity of water-soluble fullerene in vascular endothelial cells. Am J Physiol Cell Physiol 290(6):C1495–C1502
Yang H, Holloway PH, Santra S (2004a) Water-soluble silica-overcoated CdS:Mn/ZnS semiconductor quantum dots. J Chem Phys 121(15):7421–7426
Yang H, Holloway PH, Cunningham G, Schanze KS (2004b) CdS:Mn nanocrystals passivated by ZnS: synthesis and luminescent properties. J Chem Phys 121(20):10233–10240
Yang K, Zhu L, Xing B (2006) Adsorption of polycyclic aromatic hydrocarbons by carbon nanomaterials. Environ Sci Technol 40(6):1855–1861
Yang RS, Chang LW, Wu JP et al (2007) Persistent tissue kinetics and redistribution of nanoparticles, quantum dot 705, in mice: ICP-MS quantitative assessment. Environ Health Perspect 115(9):1339–1343
Yao J, Larson DR, Vishwasrao HD, Zipfel WR, Webb WW (2005) Blinking and nonradiant dark fraction of water-soluble quantum dots in aqueous solution. Proc Natl Acad Sci 102:14284–14289
Zhang LW, Monteiro-Riviere NA (2009) Mechanisms of quantum dot nanoparticle cellular uptake. Toxicol Sci 110(1):138–155
Zhang T, Stilwell JL, Gerion D et al (2006) Cellular effect of high doses of silica-coated quantum dot profiled with high throughput gene expression analysis and high content cellomics measurements. Nano Lett 6(4):800–808
Zheng J, Ghazani AA, Song Q, Mardyani S, Chan WC, Wang C (2006) Cellular imaging and surface marker labeling of hematopoietic cells using quantum dot bioconjugates. Lab Hematol 12(2):94–98
Zhu S, Oberdorster E, Haasch ML (2006) Toxicity of an engineered nanoparticle (fullerene, C60) in two aquatic species, Daphnia and fathead minnow. Mar Environ Res 62(Suppl):S5–S9
Acknowledgments
This work was mainly supported by grants “H14-nano-004” and “H19-nano-012” from the Ministry of Health, Labor and Welfare to K.Y.; in parts by KAKENHI Grant-in-aid for young scientists B (#22790359) and by a research fellowship of the Japan Society for the Promotion of Science for Young Scientists (2007–2009) to A.H.; in parts by a grant from the Ministry of Health, Labor and welfare of Japan (H22-Chemical-Young-009) to S.H.
Author information
Authors and Affiliations
Corresponding author
Additional information
An erratum to this article can be found at http://dx.doi.org/10.1007/s00204-011-0708-z
Rights and permissions
About this article
Cite this article
Hoshino, A., Hanada, S. & Yamamoto, K. Toxicity of nanocrystal quantum dots: the relevance of surface modifications. Arch Toxicol 85, 707–720 (2011). https://doi.org/10.1007/s00204-011-0695-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-011-0695-0