人造纳米颗粒呼吸系统毒性及生物效应的研究进展
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摘要
随着纳米技术在全球的迅猛发展,人造纳米颗粒已经广泛应用于生物医学领域,其生物安全性成为研究者的关注热点.由于呼吸道是人造纳米颗粒进入机体的主要途径之一,纳米颗粒对机体呼吸系统的毒性和生物效应的相关研究越来越多.本文介绍了人造纳米颗粒和纳米药物在治疗呼吸系统疾病中的应用,重点归纳了几种常见人造纳米颗粒对机体呼吸系统的毒性效应和可能的毒性作用机制,阐述了影响纳米颗粒毒性的几点因素,为今后人造纳米颗粒的研究和应用提供有价值的参考.
With the rapid development of nanotechnology in recent years, manufactured nanoparticles have been increasingly used in a wide range of applications in the bio-medicine field. Meanwhile, the bio-safety of manufactured nanoparticles have received more and more attention. As inhalation is one of the primary routes where manufactured nanoparticles can enter the body, a number of studies have investigated the toxic effects of nanoparticles on the respiratory system. This review briefly introduced the application of nano-drugs for the treatment of diseases associated with the respiratory system, and then focused on the toxic effects and potential toxicity mechanisms of several common manufactured nanoparticles on the body's respiratory system. Further considerations of the factors influencing the toxicity of nanoparticles have also been provided. This review intended to provide valuable clues for further research into manufactured nanoparticles and their applications.
With the rapid development of nanotechnology in recent years, manufactured nanoparticles have been increasingly used in a wide range of applications in the bio-medicine field. Meanwhile, the bio-safety of manufactured nanoparticles have received more and more attention. As inhalation is one of the primary routes where manufactured nanoparticles can enter the body, a number of studies have investigated the toxic effects of nanoparticles on the respiratory system. This review briefly introduced the application of nano-drugs for the treatment of diseases associated with the respiratory system, and then focused on the toxic effects and potential toxicity mechanisms of several common manufactured nanoparticles on the body's respiratory system. Further considerations of the factors influencing the toxicity of nanoparticles have also been provided. This review intended to provide valuable clues for further research into manufactured nanoparticles and their applications.
引文
1 Cao X Y,Du J J.Applicatin of nanotechnology in medicine(in Chinese).Meical Recapitulate,2009,15:969–971[曹献英,杜晶晶.纳米技术在医学中的应用.医学综述,2009,15:969–971]
2 Sciencemuseum.Nature’s nanoparticles.[2014-4-19].http://www.sciencemuseum.org.uk/antenna/nano/planet/143.asp
3 Andujar P,Lanone S,Brochard P,et al.Respiratory effects of manufactured nanoparticles.Revue Des Maladies Respiratoires,2011,28:e66–e75
4 Alexis F,Pridgen E M,Langer R,et al.Nanoparticle technologies for cancer therapy.In:Sch?fer-Korting M,ed.Handbook of Experimental Pharmacology:Drug Delivery.Berlin Heidelberg:Springer-Verlag,2010.55–86
5 Wang B,Feng W,Zhu M,et al.Neurotoxicity of low-dose repeatedly intranasal instillation of nano-and submicron-sized ferric oxide particles in mice.J Nanoparticle Res,2009,11:41–53
6 Elder A,Gelein R,Silva V,et al.Translocation of inhaled ultrafine manganese oxide particles to the central nervous system.Environ Health Perspect,2006,114:1172
7 Di Marco M,Shamsuddin S,Razak K A,et al.Overview of the main methods used to combine proteins with nanosystems:Absorption,bioconjugation,and encapsulation.Intl J Nanomed,2010,5:37
8 Bur M,Henning A,Hein S,et al.Inhalative nanomedicine-opportunities and challenges.Inhalat Toxicol,2009,21:137–143
9 Saraogi G K,Gupta P,Gupta U,et al.Gelatin nanocarriers as potential vectors for effective management of tuberculosis.Intl J Pharmaceut,2010,385:143–149
10 Beck-Broichsitter M,Gauss J,Gessler T,et al.Pulmonary targeting with biodegradable salbutamol-loaded nanoparticles.J Aerosol Medi Pulmonary Drug Delivery,2010,23:47–57
11 Kimura S,Egashira K,Chen L,et al.Nanoparticle-mediated delivery of nuclear factorκB decoy into lungs ameliorates monocrotalineinduced pulmonary arterial hypertension.Hypertension,2009,53:877–883
12 Matsuo Y,Ishihara T,Ishizaki J,et al.Effect of betamethasone phosphate loaded polymeric nanoparticles on a murine asthma model.Cell Immunol,2009,260:33–38
13 Surendiran A,Sandhiya S,Pradhan S,et al.Novel applications of nanotechnology in medicine.Ind J Med Res,2009,130:689–701
14 Li J J,Muralikrishnan S,Ng C T,et al.Nanoparticle-induced pulmonary toxicity.Exp Biol Med,2010,235:1025–1033
15 Mitchell L A,Gao J,Vander Wal R,et al.Pulmonary and systemic immune response to inhaled multiwalled carbon nanotubes.Toxicol Sci,2007,100:203–214
16 Ryman-Rasmussen J P,Cesta M F,Brody A R,et al.Inhaled carbon nanotubes reach the subpleural tissue in mice.Nat Nanotechnol,2009,4:747–751
17 Shvedova A A,Kisin E,Murray A R,et al.Inhalation vs.aspiration of single-walled carbon nanotubes in C57BL/6 mice:Inflammation,fibrosis,oxidative stress,and mutagenesis.Am J Physiol Lung Cell Mol Physiol,2008,295:L552
18 Morimoto Y,Hirohashi M,Kobayashi N,et al.Pulmonary toxicity of well-dispersed single-wall carbon nanotubes after inhalation.Nanotoxicology,2012,6:766–775
19 Ma-Hock L,Treumann S,Strauss V,et al.Inhalation toxicity of multiwall carbon nanotubes in rats exposed for 3 months.Toxicol Sci,2009,112:468–481
20 Inoue K I,Yanagisawa R,Koike E,et al.Repeated pulmonary exposure to single-walled carbon nanotubes exacerbates allergic inflammation of the airway:Possible role of oxidative stress.Free Rad Biol Med,2010,48:924–934
21 Wang X,Katwa P,Podila R,et al.Multi-walled carbon nanotube instillation impairs pulmonary function in C57BL/6 mice.Part Fibre Toxicol,2011,8:24
22 Cesta M F,Ryman-Rasmussen J P,Wallace D G,et al.Bacterial lipopolysaccharide enhances PDGF signaling and pulmonary fibrosis in rats exposed to carbon nanotubes.Am J Respirat Cell Mol Biol,2010,43:142
23 Shvedova A A,Fabisiak J P,Kisin E R,et al.Sequential exposure to carbon nanotubes and bacteria enhances pulmonary inflammation and infectivity.Am J Respirat Cell Mol Biol,2008,38:579
24 Yamashita K,Yoshioka Y,Higashisaka K,et al.Carbon nanotubes elicit DNA damage and inflammatory response relative to their size and shape.Inflammation,2010,33:276–280
25 Patlolla A K,Hussain S M,Schlager J J,et al.Comparative study of the clastogenicity of functionalized and nonfunctionalized multiwalled carbon nanotubes in bone marrow cells of Swiss-Webster mice.Environ Toxicol,2010,25:608–621
26 Donaldson K,Poland C A.Inhaled nanoparticles and lung cancer—What we can learn from conventional particle toxicology.Swiss Med Weekly,2012,142:w13547
27 Pauluhn J.Subchronic inhalation toxicity of iron oxide(magnetite,Fe3O4)in rats:Pulmonary toxicity is determined by the particle kinetics typical of poorly soluble particles.J Appl Toxicol,2012,32:488–504
28 Lin Z,Ma L,Zhu-ge X,et al.A comparative study of lung toxicity in rats induced by three types of nanomaterials.Nanoscale Res Lett,2013,8:1–11
29 Ahamed M,Alhadlaq H A,Alam J,et al.Iron oxide nanoparticle-induced oxidative stress and genotoxicity in human skin epithelial and lung epithelial cell lines.Curr Pharm Des,2013,19:6681–6690
30 Zhang T,Qian L,Tang M,et al.Evaluation on cytotoxicity and genotoxicity of the L-glutamic acid coated iron oxide nanoparticles.J Nanosci Nanotechnol,2012,12:2866–2873
31 Ma-Hock L,Burkhardt S,Strauss V,et al.Development of a short-term inhalation test in the rat using nano-titanium dioxide as a model substance.Inhalat Toxicol,2009,21:102–118
32 Nurkiewicz T R,Porter D W,Hubbs A F,et al.Nanoparticle inhalation augments particle-dependent systemic microvascular dysfunction.Part Fibre Toxicol,2008,5:1
33 Sun Q,Hong X,Wold L E.Cardiovascular effects of ambient particulate air pollution exposure.Circulation,2010,121:2755–2765
34 van Ravenzwaay B,Landsiedel R,Fabian E,et al.Comparing fate and effects of three particles of different surface properties:Nano-Ti O2,pigmentary Ti O2 and quartz.Toxicol Lett,2009,186:152–159
35 Roursgaard M,Jensen K A,Poulsen S S,et al.Acute and subchronic airway inflammation after intratracheal instillation of quartz and titanium dioxide agglomerates in mice.Scient World J,2011,11:801–825
36 Sun Q,Tan D,Ze Y,et al.Pulmotoxicological effects caused by long-term titanium dioxide nanoparticles exposure in mice.J Hazard Materials,2012,235:47–53
37 Lee K,Trochimowicz H,Reinhardt C.Pulmonary response of rats exposed to titanium dioxide(Ti O2)by inhalation for two years.Toxicol Appl Pharmacol,1985,79:179–192
38 IARC.Cobalt in Hard Metals and Cobalt Sulfate,Gallium Arsenide,Indium Phosphide and Vanadium Pentoxide.IARC Monogr Eval Carcinog Risks Hum,2006,86:1–294
39 Leo B F,Chen S,Kyo Y,et al.The stability of silver nanoparticles in a model of pulmonary surfactant.Environ Sci Technol,2013,47:11232–11240
40 Roberts J R,Mc Kinney W,Kan H,et al.Pulmonary and cardiovascular responses of rats to inhalation of silver nanoparticles.J Toxicol Environ Health,Part A,2013,76:651–668
41 Kaewamatawong T.Acute and subacute pulmonary toxicity caused by single intratracheal instillation of colloidal silver nanoparticles in mice:Pathobiological changes and metallothionien respon.J Environ Pathol Toxicol Oncol,2014,33:59–66
42 Wang X,Ji Z,Chang C H,et al.Use of coated silver nanoparticles to understand the relationship of particle dissolution and bioavailability to cell and lung toxicological potential.Small,2014,10:385–398
43 Gliga A R,Skoglund S,Wallinder I O,et al.Size-dependent cytotoxicity of silver nanoparticles in human lung cells:the role of cellular uptake,agglomeration and Ag release.Particle Fibre Toxicol,2014,11:11
44 Suliman Y,Omar A,Ali D,et al.Evaluation of cytotoxic,oxidative stress,proinflammatory and genotoxic effect of silver nanoparticles in human lung epithelial cells.Environ Toxicol,2013,doi:10.1002/tox.21880
45 Fukui H,Horie M,Endoh S,et al.Association of zinc ion release and oxidative stress induced by intratracheal instillation of Zn O nanoparticles to rat lung.Chemico-biological Interactions,2012,198:29–37
46 Sahu D,Kannan G,Vijayaraghavan R,et al.Nanosized zinc oxide induces toxicity in human lung cells.ISRN Toxicol,2013,doi:10 .1155/2013/316075
47 Yan Z,Xu L,Han J,et al.Transcriptional and posttranscriptional regulation and endocytosis were involved in zinc oxide nanoparticleinduced interleukin-8 overexpression in human bronchial epithelial cells.Cell Biol Toxicol,2014,30:79–88
48 Vandebriel R J,De Jong W H.A review of mammalian toxicity of Zn O nanoparticles.Nanotechnol Sci Appl,2012,5:61–71
49 Juang Y M,Lai B H,Chien H J,et al.Changes in protein expression in rat bronchoalveolar lavage fluid after exposure to zinc oxide nanoparticles:An i TRAQ proteomic approach.Rapid Commun Mass Spectrometry,2014,28:974–980
50 Jain S,Rachamalla M,Kulkarni A,et al.Pulmonary fibrotic response to inhalation of Zn O nanoparticles and toluene co-exposure through directed flow nose only exposure chamber.Inhalat Toxicol,2013,25:703–713
51 Leutwyler W K,Bürgi S L,Burgl H.Semiconductor clusters,nanocrystals,and quantum dots.Science,1996,271:933–937
52 Yong K T,Law W C,Hu R,et al.Nanotoxicity assessment of quantum dots:From cellular to primate studies.Chem Soc Rev,2013,42:1236–1250
53 Brunetti V,Chibli H,Fiammengo R,et al.In P/Zn S as a safer alternative to Cd Se/Zn S core/shell quantum dots:In vitro and in vivo toxicity assessment.Nanoscale,2013,5:307–317
54 King-Heiden T C,Wiecinski P N,Mangham A N,et al.Quantum dot nanotoxicity assessment using the zebrafish embryo.Environ Sci Technol,2009,43:1605–1611
55 Hoshino A,Hanada S,Manabe N,et al.Immune response induced by fluorescent nanocrystal quantum dots in vitro and in vivo.Nano Biosci,IEEE Trans on,2009,8:51–57
56 Bruneau A,Fortier M,Gagne F,et al.In vitro immunotoxicology of quantum dots and comparison with dissolved cadmium and tellurium.Environ Toxicol,2015,30:9–25
57 Sadaf A,Zeshan B,Wang Z,et al.Toxicity evaluation of hydrophilic Cd Te quantum dots and Cd Te@Si O2 nanoparticles in mice.J Nanosci Nanotechnol,2012,12:8287–8292
58 Roberts J R,Antonini J M,Porter D W,et al.Lung toxicity and biodistribution of Cd/Se-Zn S quantum dots with different surface functional groups after pulmonary exposure in rats.Part Fibre Toxicol,2013,10:5
59 Ma-Hock L,Brill S,Wohlleben W,et al.Short term inhalation toxicity of a liquid aerosol of Cd S/Cd(OH)2 core shell quantum dots in male Wistar rats.Toxico Lett,2012,208:115–124
60 Liu J,Erogbogbo F,Yong K T,et al.Assessing clinical prospects of silicon quantum dots:Studies in mice and monkeys.ACS Nano,2013,7:7303–7310
61 Mc Connachie L A,Botta D,White C C,et al.The glutathione synthesis gene Gclm modulates amphiphilic polymer-coated Cd Se/Zn S quantum dot-induced lung inflammation in mice.PLo S One,2013,8:e64165
62 Ho C C,Chang H,Tsai H T,et al.Quantum dot 705,a cadmium-based nanoparticle,induces persistent inflammation and granuloma formation in the mouse lung.Nanotoxicology,2013,7:105–115
63 Jacobsen N R,Moller P,Jensen K A,et al.Lung inflammation and genotoxicity following pulmonary exposure to nanoparticles in Apo E?/?mice.Part Fibre Toxicol,2009,6:2
64 Nagy A,Steinbruck A,Gao J,et al.Comprehensive analysis of the effects of Cd Se quantum dot size,surface charge,and functionalization on primary human lung cells.ACS Nano,2012,6:4748–4762
65 GagnéF,Fortier M,Yu L,et al.Immunocompetence and alterations in hepatic gene expression in rainbow trout exposed to Cd S/Cd Te quantum dots.J Environ Monit,2010,12:1556–1565
66 Choi A O,Brown S E,Szyf M,et al.Quantum dot-induced epigenetic and genotoxic changes in human breast cancer cells.J Mol Med(Berlin,Germany),2008,86:291–302
67 Borm P J,Kreyling W.Toxicological hazards of inhaled nanoparticles-potential implications for drug delivery.J Nanosci Nanotechnol,2004,4:521–531
68 Oberd rster G,Ferin J,Lehnert B E.Correlation between particle size,in vivo particle persistence,and lung injury.Environ Health Perspect,1994,102:173
69 Magrez A,Kasas S,Salicio V,et al.Cellular toxicity of carbon-based nanomaterials.Nano Lett,2006,6:1121–1125
70 Wu T,Tang M.Toxicity of quantum dots on respiratory system.Inhalat Toxicol,2014,26:128–139
71 Kendall M,Brown L,Trought K.Molecular adsorption at particle surfaces:A PM toxicity mediation mechanism.Inhalat Toxicol,2004,16 :99–105
72 Oberd rster G,Ferin J,Gelein R,et al.Role of the alveolar macrophage in lung injury:Studies with ultrafine particles.Environ Health Perspect,1992,97:193
73 Sharifi S,Behzadi S,Laurent S,et al.Toxicity of nanomaterials.Chem Soc Rev,2012,41:2323–2343
2 Sciencemuseum.Nature’s nanoparticles.[2014-4-19].http://www.sciencemuseum.org.uk/antenna/nano/planet/143.asp
3 Andujar P,Lanone S,Brochard P,et al.Respiratory effects of manufactured nanoparticles.Revue Des Maladies Respiratoires,2011,28:e66–e75
4 Alexis F,Pridgen E M,Langer R,et al.Nanoparticle technologies for cancer therapy.In:Sch?fer-Korting M,ed.Handbook of Experimental Pharmacology:Drug Delivery.Berlin Heidelberg:Springer-Verlag,2010.55–86
5 Wang B,Feng W,Zhu M,et al.Neurotoxicity of low-dose repeatedly intranasal instillation of nano-and submicron-sized ferric oxide particles in mice.J Nanoparticle Res,2009,11:41–53
6 Elder A,Gelein R,Silva V,et al.Translocation of inhaled ultrafine manganese oxide particles to the central nervous system.Environ Health Perspect,2006,114:1172
7 Di Marco M,Shamsuddin S,Razak K A,et al.Overview of the main methods used to combine proteins with nanosystems:Absorption,bioconjugation,and encapsulation.Intl J Nanomed,2010,5:37
8 Bur M,Henning A,Hein S,et al.Inhalative nanomedicine-opportunities and challenges.Inhalat Toxicol,2009,21:137–143
9 Saraogi G K,Gupta P,Gupta U,et al.Gelatin nanocarriers as potential vectors for effective management of tuberculosis.Intl J Pharmaceut,2010,385:143–149
10 Beck-Broichsitter M,Gauss J,Gessler T,et al.Pulmonary targeting with biodegradable salbutamol-loaded nanoparticles.J Aerosol Medi Pulmonary Drug Delivery,2010,23:47–57
11 Kimura S,Egashira K,Chen L,et al.Nanoparticle-mediated delivery of nuclear factorκB decoy into lungs ameliorates monocrotalineinduced pulmonary arterial hypertension.Hypertension,2009,53:877–883
12 Matsuo Y,Ishihara T,Ishizaki J,et al.Effect of betamethasone phosphate loaded polymeric nanoparticles on a murine asthma model.Cell Immunol,2009,260:33–38
13 Surendiran A,Sandhiya S,Pradhan S,et al.Novel applications of nanotechnology in medicine.Ind J Med Res,2009,130:689–701
14 Li J J,Muralikrishnan S,Ng C T,et al.Nanoparticle-induced pulmonary toxicity.Exp Biol Med,2010,235:1025–1033
15 Mitchell L A,Gao J,Vander Wal R,et al.Pulmonary and systemic immune response to inhaled multiwalled carbon nanotubes.Toxicol Sci,2007,100:203–214
16 Ryman-Rasmussen J P,Cesta M F,Brody A R,et al.Inhaled carbon nanotubes reach the subpleural tissue in mice.Nat Nanotechnol,2009,4:747–751
17 Shvedova A A,Kisin E,Murray A R,et al.Inhalation vs.aspiration of single-walled carbon nanotubes in C57BL/6 mice:Inflammation,fibrosis,oxidative stress,and mutagenesis.Am J Physiol Lung Cell Mol Physiol,2008,295:L552
18 Morimoto Y,Hirohashi M,Kobayashi N,et al.Pulmonary toxicity of well-dispersed single-wall carbon nanotubes after inhalation.Nanotoxicology,2012,6:766–775
19 Ma-Hock L,Treumann S,Strauss V,et al.Inhalation toxicity of multiwall carbon nanotubes in rats exposed for 3 months.Toxicol Sci,2009,112:468–481
20 Inoue K I,Yanagisawa R,Koike E,et al.Repeated pulmonary exposure to single-walled carbon nanotubes exacerbates allergic inflammation of the airway:Possible role of oxidative stress.Free Rad Biol Med,2010,48:924–934
21 Wang X,Katwa P,Podila R,et al.Multi-walled carbon nanotube instillation impairs pulmonary function in C57BL/6 mice.Part Fibre Toxicol,2011,8:24
22 Cesta M F,Ryman-Rasmussen J P,Wallace D G,et al.Bacterial lipopolysaccharide enhances PDGF signaling and pulmonary fibrosis in rats exposed to carbon nanotubes.Am J Respirat Cell Mol Biol,2010,43:142
23 Shvedova A A,Fabisiak J P,Kisin E R,et al.Sequential exposure to carbon nanotubes and bacteria enhances pulmonary inflammation and infectivity.Am J Respirat Cell Mol Biol,2008,38:579
24 Yamashita K,Yoshioka Y,Higashisaka K,et al.Carbon nanotubes elicit DNA damage and inflammatory response relative to their size and shape.Inflammation,2010,33:276–280
25 Patlolla A K,Hussain S M,Schlager J J,et al.Comparative study of the clastogenicity of functionalized and nonfunctionalized multiwalled carbon nanotubes in bone marrow cells of Swiss-Webster mice.Environ Toxicol,2010,25:608–621
26 Donaldson K,Poland C A.Inhaled nanoparticles and lung cancer—What we can learn from conventional particle toxicology.Swiss Med Weekly,2012,142:w13547
27 Pauluhn J.Subchronic inhalation toxicity of iron oxide(magnetite,Fe3O4)in rats:Pulmonary toxicity is determined by the particle kinetics typical of poorly soluble particles.J Appl Toxicol,2012,32:488–504
28 Lin Z,Ma L,Zhu-ge X,et al.A comparative study of lung toxicity in rats induced by three types of nanomaterials.Nanoscale Res Lett,2013,8:1–11
29 Ahamed M,Alhadlaq H A,Alam J,et al.Iron oxide nanoparticle-induced oxidative stress and genotoxicity in human skin epithelial and lung epithelial cell lines.Curr Pharm Des,2013,19:6681–6690
30 Zhang T,Qian L,Tang M,et al.Evaluation on cytotoxicity and genotoxicity of the L-glutamic acid coated iron oxide nanoparticles.J Nanosci Nanotechnol,2012,12:2866–2873
31 Ma-Hock L,Burkhardt S,Strauss V,et al.Development of a short-term inhalation test in the rat using nano-titanium dioxide as a model substance.Inhalat Toxicol,2009,21:102–118
32 Nurkiewicz T R,Porter D W,Hubbs A F,et al.Nanoparticle inhalation augments particle-dependent systemic microvascular dysfunction.Part Fibre Toxicol,2008,5:1
33 Sun Q,Hong X,Wold L E.Cardiovascular effects of ambient particulate air pollution exposure.Circulation,2010,121:2755–2765
34 van Ravenzwaay B,Landsiedel R,Fabian E,et al.Comparing fate and effects of three particles of different surface properties:Nano-Ti O2,pigmentary Ti O2 and quartz.Toxicol Lett,2009,186:152–159
35 Roursgaard M,Jensen K A,Poulsen S S,et al.Acute and subchronic airway inflammation after intratracheal instillation of quartz and titanium dioxide agglomerates in mice.Scient World J,2011,11:801–825
36 Sun Q,Tan D,Ze Y,et al.Pulmotoxicological effects caused by long-term titanium dioxide nanoparticles exposure in mice.J Hazard Materials,2012,235:47–53
37 Lee K,Trochimowicz H,Reinhardt C.Pulmonary response of rats exposed to titanium dioxide(Ti O2)by inhalation for two years.Toxicol Appl Pharmacol,1985,79:179–192
38 IARC.Cobalt in Hard Metals and Cobalt Sulfate,Gallium Arsenide,Indium Phosphide and Vanadium Pentoxide.IARC Monogr Eval Carcinog Risks Hum,2006,86:1–294
39 Leo B F,Chen S,Kyo Y,et al.The stability of silver nanoparticles in a model of pulmonary surfactant.Environ Sci Technol,2013,47:11232–11240
40 Roberts J R,Mc Kinney W,Kan H,et al.Pulmonary and cardiovascular responses of rats to inhalation of silver nanoparticles.J Toxicol Environ Health,Part A,2013,76:651–668
41 Kaewamatawong T.Acute and subacute pulmonary toxicity caused by single intratracheal instillation of colloidal silver nanoparticles in mice:Pathobiological changes and metallothionien respon.J Environ Pathol Toxicol Oncol,2014,33:59–66
42 Wang X,Ji Z,Chang C H,et al.Use of coated silver nanoparticles to understand the relationship of particle dissolution and bioavailability to cell and lung toxicological potential.Small,2014,10:385–398
43 Gliga A R,Skoglund S,Wallinder I O,et al.Size-dependent cytotoxicity of silver nanoparticles in human lung cells:the role of cellular uptake,agglomeration and Ag release.Particle Fibre Toxicol,2014,11:11
44 Suliman Y,Omar A,Ali D,et al.Evaluation of cytotoxic,oxidative stress,proinflammatory and genotoxic effect of silver nanoparticles in human lung epithelial cells.Environ Toxicol,2013,doi:10.1002/tox.21880
45 Fukui H,Horie M,Endoh S,et al.Association of zinc ion release and oxidative stress induced by intratracheal instillation of Zn O nanoparticles to rat lung.Chemico-biological Interactions,2012,198:29–37
46 Sahu D,Kannan G,Vijayaraghavan R,et al.Nanosized zinc oxide induces toxicity in human lung cells.ISRN Toxicol,2013,doi:10 .1155/2013/316075
47 Yan Z,Xu L,Han J,et al.Transcriptional and posttranscriptional regulation and endocytosis were involved in zinc oxide nanoparticleinduced interleukin-8 overexpression in human bronchial epithelial cells.Cell Biol Toxicol,2014,30:79–88
48 Vandebriel R J,De Jong W H.A review of mammalian toxicity of Zn O nanoparticles.Nanotechnol Sci Appl,2012,5:61–71
49 Juang Y M,Lai B H,Chien H J,et al.Changes in protein expression in rat bronchoalveolar lavage fluid after exposure to zinc oxide nanoparticles:An i TRAQ proteomic approach.Rapid Commun Mass Spectrometry,2014,28:974–980
50 Jain S,Rachamalla M,Kulkarni A,et al.Pulmonary fibrotic response to inhalation of Zn O nanoparticles and toluene co-exposure through directed flow nose only exposure chamber.Inhalat Toxicol,2013,25:703–713
51 Leutwyler W K,Bürgi S L,Burgl H.Semiconductor clusters,nanocrystals,and quantum dots.Science,1996,271:933–937
52 Yong K T,Law W C,Hu R,et al.Nanotoxicity assessment of quantum dots:From cellular to primate studies.Chem Soc Rev,2013,42:1236–1250
53 Brunetti V,Chibli H,Fiammengo R,et al.In P/Zn S as a safer alternative to Cd Se/Zn S core/shell quantum dots:In vitro and in vivo toxicity assessment.Nanoscale,2013,5:307–317
54 King-Heiden T C,Wiecinski P N,Mangham A N,et al.Quantum dot nanotoxicity assessment using the zebrafish embryo.Environ Sci Technol,2009,43:1605–1611
55 Hoshino A,Hanada S,Manabe N,et al.Immune response induced by fluorescent nanocrystal quantum dots in vitro and in vivo.Nano Biosci,IEEE Trans on,2009,8:51–57
56 Bruneau A,Fortier M,Gagne F,et al.In vitro immunotoxicology of quantum dots and comparison with dissolved cadmium and tellurium.Environ Toxicol,2015,30:9–25
57 Sadaf A,Zeshan B,Wang Z,et al.Toxicity evaluation of hydrophilic Cd Te quantum dots and Cd Te@Si O2 nanoparticles in mice.J Nanosci Nanotechnol,2012,12:8287–8292
58 Roberts J R,Antonini J M,Porter D W,et al.Lung toxicity and biodistribution of Cd/Se-Zn S quantum dots with different surface functional groups after pulmonary exposure in rats.Part Fibre Toxicol,2013,10:5
59 Ma-Hock L,Brill S,Wohlleben W,et al.Short term inhalation toxicity of a liquid aerosol of Cd S/Cd(OH)2 core shell quantum dots in male Wistar rats.Toxico Lett,2012,208:115–124
60 Liu J,Erogbogbo F,Yong K T,et al.Assessing clinical prospects of silicon quantum dots:Studies in mice and monkeys.ACS Nano,2013,7:7303–7310
61 Mc Connachie L A,Botta D,White C C,et al.The glutathione synthesis gene Gclm modulates amphiphilic polymer-coated Cd Se/Zn S quantum dot-induced lung inflammation in mice.PLo S One,2013,8:e64165
62 Ho C C,Chang H,Tsai H T,et al.Quantum dot 705,a cadmium-based nanoparticle,induces persistent inflammation and granuloma formation in the mouse lung.Nanotoxicology,2013,7:105–115
63 Jacobsen N R,Moller P,Jensen K A,et al.Lung inflammation and genotoxicity following pulmonary exposure to nanoparticles in Apo E?/?mice.Part Fibre Toxicol,2009,6:2
64 Nagy A,Steinbruck A,Gao J,et al.Comprehensive analysis of the effects of Cd Se quantum dot size,surface charge,and functionalization on primary human lung cells.ACS Nano,2012,6:4748–4762
65 GagnéF,Fortier M,Yu L,et al.Immunocompetence and alterations in hepatic gene expression in rainbow trout exposed to Cd S/Cd Te quantum dots.J Environ Monit,2010,12:1556–1565
66 Choi A O,Brown S E,Szyf M,et al.Quantum dot-induced epigenetic and genotoxic changes in human breast cancer cells.J Mol Med(Berlin,Germany),2008,86:291–302
67 Borm P J,Kreyling W.Toxicological hazards of inhaled nanoparticles-potential implications for drug delivery.J Nanosci Nanotechnol,2004,4:521–531
68 Oberd rster G,Ferin J,Lehnert B E.Correlation between particle size,in vivo particle persistence,and lung injury.Environ Health Perspect,1994,102:173
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