纳米生物效应与安全性研究展望
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摘要
当物质达到纳米尺度时,会具有一些特殊的物理化学性质,如量子尺寸效应、表面效应以及宏观量子隧道效应等.即使化学组成相同,纳米物质的生物学效应也可能不同于微米尺寸以上的常规物质.因此,根据常规宏观物质研究所得到的生物学效应与安全性评价结果,可能并不适用于纳米物质.自2003年Science发表文章关注纳米生物效应与毒理学效应之后,各国政府先后启动了对纳米生物效应的研究,并且支持力度不断增加.我国是世界上较早开展纳米生物效应与安全性研究的国家之一,研究工作在国际上产生了重要影响.国家纳米科学中心与中国科学院高能物理研究所共同建立的"中国科学院纳米生物效应与安全性重点实验室",作为我国第一个也是国际上少有的以纳米材料生物效应与安全性为研究方向的专业实验室,在了解纳米材料的基本性质-活性关系的基础上,对更深层次的理化效应展开了深入的研究,并建立了适用于纳米生物效应与安全性评价的多层次模型,发展了高灵敏、高分辨率的适用于纳米生物效应和安全性评价的实验技术和研究方法,为保证纳米科技的可持续发展做出了重要的贡献.本文综述了本实验室近年来在纳米生物效应与安全性领域的研究进展.
Nanomaterials have lots of unique physical and chemical properties,such as quantum size effect,surface effect and macroscopic quantum tunnel effect.The biological effects of nanomaterials might be different from those of bulk materials larger than microns even if their chemical compositions are same.Therefore,the biological effects and safety evaluation results obtained from the bulk materials might not be suitable for the nanomaterials.Since 2003,governments worldwide have initiated the researches on biological effects and safety issues of nanomaterials with increasing financial support.China is one of the earliest countries in the world to carry out researches on biological effects and safety issues of nanomaterials.And some research fields have entered the forefront of the world.The "CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety" established jointly by National Center for Nanoscience and Technology(NCNST) and Institute of High Energy Physics of Chinese Academy of Sciences(IHEP of CAS) was the first professional laboratory focusing on the biological effects and safety of nanomaterials in China.Scientists in this laboratory have done many in-depth studies of the relationship between the physical-chemical properties and biological responses of nanomaterials.They found several factors which affected the biological effects of carbon nanotubes significantly,such as nanoparticle-Crona,metal impurities,surface,size,shape and so on.They have also established multiple models for hazard recognition and risk assessment.Nanomaterials/nanoparticles(NMs/NPs) are exposed to human beings mostly through four routes,i.e.,oral intake,skin contact,inhalation,and intravenous injection.Upon entering the body,NMs/NPs are quickly distributed into specific organs and then metabolized primarily by the liver.The final excretion of NMs/NPs usually occurs in the liver and kidney in the form of urine and feces.In general,the most important issues regarding the absorption,distribution,metabolism and excretion(ADME) processes of NMs/NPs include:(1) Where do and how much NMs/NPs get in(via absorption)?(2) Where do and how much NMs/NPs go(via distribution)?(3) How much,when do,and what form of NMs/NPs remain intact(via metabolism)?(4) Where do,how much,and what form of NMs/NPs stay in the system(via excretion)? At various stages of the ADME processes,the challenges for in vivo analysis of NMs/NPs may become largely different.Important analytical methods to resolve the analytical challenges for each absorption,distribution,metabolism and excretion(ADME) process are summarized.The state-of-the art techniques with high sensitivity and high resolution suitable for safety evaluation have been developed to ensure the sustainable development of nanotechnology,such as inductively coupled plasma mass spectrometry(ICPMS),inductively coupled plasma optical emission spectrometry(ICP-OES),nuclear analysis such as neutron activation analysis(NAA),laser ablation inductively coupled plasma mass spectrometry(LAICPMS),secondary ion mass spectrometry(SIMS),synchrotron radiation X-ray fluorescence spectroscopy(SRXRF),X-ray absorption spectroscopy(XAS),X-ray fluorescence spectroscopy(XRF),scanning transmission X-ray microscopy(STXM),transmission X-ray microscopy(TXM) and so on.In this review,we summarize these research progresses in recent years.
Nanomaterials have lots of unique physical and chemical properties,such as quantum size effect,surface effect and macroscopic quantum tunnel effect.The biological effects of nanomaterials might be different from those of bulk materials larger than microns even if their chemical compositions are same.Therefore,the biological effects and safety evaluation results obtained from the bulk materials might not be suitable for the nanomaterials.Since 2003,governments worldwide have initiated the researches on biological effects and safety issues of nanomaterials with increasing financial support.China is one of the earliest countries in the world to carry out researches on biological effects and safety issues of nanomaterials.And some research fields have entered the forefront of the world.The "CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety" established jointly by National Center for Nanoscience and Technology(NCNST) and Institute of High Energy Physics of Chinese Academy of Sciences(IHEP of CAS) was the first professional laboratory focusing on the biological effects and safety of nanomaterials in China.Scientists in this laboratory have done many in-depth studies of the relationship between the physical-chemical properties and biological responses of nanomaterials.They found several factors which affected the biological effects of carbon nanotubes significantly,such as nanoparticle-Crona,metal impurities,surface,size,shape and so on.They have also established multiple models for hazard recognition and risk assessment.Nanomaterials/nanoparticles(NMs/NPs) are exposed to human beings mostly through four routes,i.e.,oral intake,skin contact,inhalation,and intravenous injection.Upon entering the body,NMs/NPs are quickly distributed into specific organs and then metabolized primarily by the liver.The final excretion of NMs/NPs usually occurs in the liver and kidney in the form of urine and feces.In general,the most important issues regarding the absorption,distribution,metabolism and excretion(ADME) processes of NMs/NPs include:(1) Where do and how much NMs/NPs get in(via absorption)?(2) Where do and how much NMs/NPs go(via distribution)?(3) How much,when do,and what form of NMs/NPs remain intact(via metabolism)?(4) Where do,how much,and what form of NMs/NPs stay in the system(via excretion)? At various stages of the ADME processes,the challenges for in vivo analysis of NMs/NPs may become largely different.Important analytical methods to resolve the analytical challenges for each absorption,distribution,metabolism and excretion(ADME) process are summarized.The state-of-the art techniques with high sensitivity and high resolution suitable for safety evaluation have been developed to ensure the sustainable development of nanotechnology,such as inductively coupled plasma mass spectrometry(ICPMS),inductively coupled plasma optical emission spectrometry(ICP-OES),nuclear analysis such as neutron activation analysis(NAA),laser ablation inductively coupled plasma mass spectrometry(LAICPMS),secondary ion mass spectrometry(SIMS),synchrotron radiation X-ray fluorescence spectroscopy(SRXRF),X-ray absorption spectroscopy(XAS),X-ray fluorescence spectroscopy(XRF),scanning transmission X-ray microscopy(STXM),transmission X-ray microscopy(TXM) and so on.In this review,we summarize these research progresses in recent years.
引文
1 Xu L,Liang H W,Yang Y,et al.Stability and reactivity:Positive and negative aspects for nanoparticle processing.Chem Rev,2018,118:3209-3250
2 Service R F.Nanomaterials show signs of toxicity.Science,2003,300:243
3 Zhao Y L,Nalwa S H.Nanotoxicology:Interactions of Nanomaterials with Biological Systems.USA,California:American Scientific Publishers,2007
4 Zhao Y L.Nano-biological Effects(in Chinese).Beijing:Science Press,2009,2010[赵宇亮.纳米生物效应系列.北京:科学出版社,2009,2010]
5 Chen C Y,Chen R,Bai R,et al.Guidelines for Monitoring Exposure to Nanoparticles in Production and Workplace(in Chinese).Beijing:Science Press,2015[陈春英,陈瑞,白茹,等.生产与工作场所纳米颗粒暴露监测指南.北京:科学出版社,2015]
6 Cai R,Chen C Y.Protein corona in vivo:Dynamic complement proteins-mediated opsonization and immune modulation.Sci Bull,2017,62:976-977
7 Ge C C,Du J F,Zhao L N,et al.Binding of blood proteins to carbon nanotubes reduces cytotoxicity.Proc Natl Acad Sci USA,2011,108:16968-16973
8 Liu Y,Zhao Y L,Sun B Y,et al.Understanding the toxicity of carbon nanotubes.Acc Chem Res,2013,46:702-713
9 Monopoli M P,Aberg C,Salvati A,et al.Biomolecular coronas provide the biological identity of nanosized materials.Nat Nanotechnol,2012,7:779-786
10 Riehemann K.Nanotoxicity:How the body develops a way to reduce the toxicity of carbon nanotubes.Small,2012,8:1970-1972
11 Wang X Y,Wang M Z,Lei R,et al.Chiral surface of nanoparticles determines the orientation of adsorbed transferrin and its interaction with receptors.ACS Nano,2017,11:4606-4616
12 Wang X Y,Wang X F,Wang M Z,et al.Probing adsorption behaviors of BSA onto chiral surfaces of nanoparticles.Small,2018,14:e1703982
13 Ge C C,Li Y,Yin J J,et al.The contributions of metal impurities and tube structure to the toxicity of carbon nanotube materials.NPGAsia Mater,2012,4:e32
14 Meng L,Jiang A H,Chen R,et al.Inhibitory effects of multiwall carbon nanotubes with high iron impurity on viability and neuronal differentiation in cultured PC12 cells.Toxicology,2013,313:49-58
15 Ge C,Meng L,Xu L,et al.Acute pulmonary and moderate cardiovascular responses of spontaneously hypertensive rats after exposure to single-wall carbon nanotubes.Nanotoxicology,2012,6:526-542
16 Wang J,Bai R,Yang R,et al.Size-and surface chemistry-dependent pharmacokinetics and tumor accumulation of engineered gold nanoparticles after intravenous administration.Metallomics,2015,7:516-524
17 Xu L G,Liu Y,Chen Z Y,et al.Surface-engineered gold nanorods:Promising DNA vaccine adjuvant for HIV-1 treatment.Nano Lett,2012,12:2003-2012
18 Qiu Y,Liu Y,Wang L M,et al.Surface chemistry and aspect ratio mediated cellular uptake of Au nanorods.Biomaterials,2010,31:7606-7619
19 Wang L M,Liu Y,Li W,et al.Selective targeting of gold nanorods at the mitochondria of cancer cells:Implications for cancer therapy.Nano Lett,2011,11:772-780
20 Liu Y X,Li W,Lao F,et al.Intracellular dynamics of cationic and anionic polystyrene nanoparticles without direct interaction with mitotic spindle and chromosomes.Biomaterials,2011,32:8291-8303
21 Li Y,Liu Y,Fu Y,et al.The triggering of apoptosis in macrophages by pristine graphene through the MAPK and TGF-beta signaling pathways.Biomaterials,2012,33:402-411
22 Zhou H J,Zhao K,Li W,et al.The interactions between pristine graphene and macrophages and the production of cytokines/chemokines via TLR-and NF-kappa B-related signaling pathways.Biomaterials,2012,33:6933-6942
23 Chong Y,Ge C C,Fang G,et al.Light-enhanced antibacterial activity of graphene oxide,mainly via accelerated electron transfer.Environ Sci Technol,2017,51:10154-10161
24 Fratoddi I,Venditti I,Cametti C,et al.How toxic are gold nanoparticles?The state-of-the-art.Nano Res,2015,8:1771-1799
25 Dykman L A,Khlebtsov N G.Uptake of engineered gold nanoparticles into mammalian cells.Chem Rev,2014,114:1258-1288
26 Gruber J,Fong S,Chen C B,et al.Mitochondria-targeted antioxidants and metabolic modulators as pharmacological interventions to slow ageing.Biotechnol Adv,2013,31:563-592
27 Webb J A,Bardhan R.Emerging advances in nanomedicine with engineered gold nanostructures.Nanoscale,2014,6:2502-2530
28 Behzadi S,Serpooshan V,Tao W,et al.Cellular uptake of nanoparticles:Journey inside the cell.Chem Soc Rev,2017,46:4218-4244
29 Zhao F,Zhao Y,Liu Y,et al.Cellular uptake,intracellular trafficking,and cytotoxicity of nanomaterials.Small,2011,7:1322-1337
30 Meng L,Chen R,Jiang A H,et al.Short multiwall carbon nanotubes promote neuronal differentiation of PC12 cells via up-regulation of the neurotrophin signaling pathway.Small,2013,9:1786-1798
31 Wang P,Nie X,Wang Y,et al.Multiwall Carbon nanotubes mediate macrophage activation and promote pulmonary fibrosis through TGF-beta/smad signaling pathway.Small,2013,9:3799-3811
32 Wang P,Wang Y,Nie X,et al.Multiwall carbon nanotubes directly promote fibroblast-myofibroblast and epithelial-mesenchymal transitions through the activation of the TGF-beta/smad signaling pathway.Small,2015,11:446-455
33 Wang J,Xie Y D,Wang L M,et al.In vivo pharmacokinetic features and biodistribution of star and rod shaped gold nanoparticles by multispectral optoacoustic tomography.RSC Adv,2015,5:7529-7538
34 Fang G,Li W F,Shen X M,et al.Differential Pd-nanocrystal facets demonstrate distinct antibacterial activity against Gram-positive and Gram-negative bacteria.Nat Commun,2018,9:129
35 Jiang X,Miclaus T,Wang L,et al.Fast intracellular dissolution and persistent cellular uptake of silver nanoparticles in CHO-K1 cells:Implication for cytotoxicity.Nanotoxicology,2015,9:181-189
36 Wang L M,Zhang T L,Li P Y,et al.Use of synchrotron radiation-analytical techniques to reveal chemical origin of silver-nanoparticle cytotoxicity.ACS Nano,2015,9:6532-6547
37 Wang L M,Li Y F,Zhou L J,et al.Characterization of gold nanorods in vivo by integrated analytical techniques:Their uptake,retention,and chemical forms.Anal Bioanal Chem,2010,396:1105-1114
38 Jiang X M,Wu Y,Gray P,et al.Influence of gastrointestinal environment on free radical generation of silver nanoparticles and implications for their cytotoxicity.NanoImpact,2018,10:144
39 Jiang X M,Wang L M,Ji Y L,et al.Interference of steroidogenesis by gold nanorod core/silver shell nanostructures:Implications for reproductive toxicity of silver nanomaterials.Small,2017,13:1602855
40 Wang J X,Chen C Y,Liu Y,et al.Potential neurological lesion after nasal instillation of TiO2 nanoparticles in the anatase and rutile crystal phases.Toxicol Lett,2008,183:72-80
41 Wang J X,Liu Y,Jiao F,et al.Time-dependent translocation and potential impairment on central nervous system by intranasally instilled TiO2 nanoparticles.Toxicology,2008,254:82-90
42 Qu Y,Li W,Zhou Y L,et al.Full assessment of fate and physiological behavior of quantum dots utilizing caenorhabditis elegans as a model organism.Nano Lett,2011,11:3174-3183
43 Cong W S,Wang P,Qu Y,et al.Evaluation of the influence of fullerenol on aging and stress resistance using Caenorhabditis elegans.Biomaterials,2015,42:78v86
44 Dong J L,Shang Y D,Inthavong K,et al.Comparative numerical modeling of inhaled nanoparticle deposition in human and rat nasal cavities.Toxicol Sci,2016,152:284-296
45 Tian L,Shang Y,Chen R,et al.A combined experimental and numerical study on upper airway dosimetry of inhaled nanoparticles from an electrical discharge machine shop.Part Fibre Toxicol,2017,14:24
46 Le T C,Yin H,Chen R,et al.An experimental and computational approach to the development of ZnO nanoparticles that are safe by design.Small,2016,12:3568-3577
47 Chen R,Qiao J,Bai R,et al.Intelligent testing strategy and analytical techniques for the safety assessment of nanomaterials.Anal Bioanal Chem,2018,410:6051-6066
48 Chen R,Zhao L,Bai R,et al.Silver nanoparticles induced oxidative and endoplasmic reticulum stresses in mouse tissues:Implications for the development of acute toxicity after intravenous administration.Toxicol Res UK,2016,5:602-608
49 Chen R,Huo L L,Shi X F,et al.Endoplasmic reticulum stress induced by zinc oxide nanoparticles is an earlier biomarker for nanotoxicological evaluation.ACS Nano,2014,8:2562-2574
50 Zhang L,Bai R,Liu Y,et al.The dose-dependent toxicological effects and potential perturbation on the neurotransmitter secretion in brain following intranasal instillation of copper nanoparticles.Nanotoxicology,2012,6:562-575
51 Huo L L,Chen R,Zhao L,et al.Silver nanoparticles activate endoplasmic reticulum stress signaling pathway in cell and mouse models:The role in toxicity evaluation.Biomaterials,2015,61:307-315
52 Chen R,Zhang L L,Ge C C,et al.Subchronic toxicity and cardiovascular responses in spontaneously hypertensive rats after exposure to multiwalled carbon nanotubes by intratracheal instillation.Chem Res Toxicol,2015,28:440-450
53 Chen Z Y,Liu Y,Sun B Y,et al.Polyhydroxylated metallofullerenols stimulate IL-1 beta secretion of macrophage through TLRs/MyD88/NF-kappa B pathway and NLRP3 inflammasome activation.Small,2014,10:2362-2372
54 Chen Z J,Wang Y,Ba T,et al.Genotoxic evaluation of titanium dioxide nanoparticles in vivo and in vitro.Toxicol Lett,2014,226:314-319
55 Wang L M,Yan L,Liu J,et al.Quantification of nanomaterial/nanomedicine trafficking in vivo.Anal Chem,2018,90:589-614
56 Liu J,Wang P,Zhang X,et al.Rapid degradation and high renal clearance of Cu3BiS3 nanodots for efficient cancer diagnosis and photothermal therapy in vivo.ACS Nano,2016,10:4587-4598
57 He X,Pan Y Y,Zhang J Z,et al.Quantifying the total ionic release from nanoparticles after particle-cell contact.Environ Pollut,2015,196:194-200
58 Cao M J,Wang P Y,Kou Y,et al.Gadolinium(III)-chelated silica nanospheres integrating chemotherapy and photothermal therapy for cancer treatment and magnetic resonance imaging.ACS Appl Mater Interfaces,2015,7:25014-25023
59 Wang J,Liu J,Liu Y,et al.Gd-Hybridized plasmonic au-nanocomposites enhanced tumor-interior drug permeability in multimodal imaging-guided therapy.Adv Mater,2016,28:8950-8958
60 Yao S K,Fan J D,Chen Z Y,et al.Three-dimensional ultrastructural imaging reveals the nanoscale architecture of mammalian cells.IUCRJ,2018,5:141-149
61 Wang L M,Li J Y,Pan J,et al.Revealing the binding structure of the protein corona on gold nanorods using synchrotron radiation-based techniques:Understanding the reduced damage in cell membranes.J Am Chem Soc,2013,135:17359-17368
62 Porcaro F,Roudeau S,Carmona A,et al.Advances in element speciation analysis of biomedical samples using synchrotron-based techniques.Trac-Trend Anal Chem,2017,1:1-20
2 Service R F.Nanomaterials show signs of toxicity.Science,2003,300:243
3 Zhao Y L,Nalwa S H.Nanotoxicology:Interactions of Nanomaterials with Biological Systems.USA,California:American Scientific Publishers,2007
4 Zhao Y L.Nano-biological Effects(in Chinese).Beijing:Science Press,2009,2010[赵宇亮.纳米生物效应系列.北京:科学出版社,2009,2010]
5 Chen C Y,Chen R,Bai R,et al.Guidelines for Monitoring Exposure to Nanoparticles in Production and Workplace(in Chinese).Beijing:Science Press,2015[陈春英,陈瑞,白茹,等.生产与工作场所纳米颗粒暴露监测指南.北京:科学出版社,2015]
6 Cai R,Chen C Y.Protein corona in vivo:Dynamic complement proteins-mediated opsonization and immune modulation.Sci Bull,2017,62:976-977
7 Ge C C,Du J F,Zhao L N,et al.Binding of blood proteins to carbon nanotubes reduces cytotoxicity.Proc Natl Acad Sci USA,2011,108:16968-16973
8 Liu Y,Zhao Y L,Sun B Y,et al.Understanding the toxicity of carbon nanotubes.Acc Chem Res,2013,46:702-713
9 Monopoli M P,Aberg C,Salvati A,et al.Biomolecular coronas provide the biological identity of nanosized materials.Nat Nanotechnol,2012,7:779-786
10 Riehemann K.Nanotoxicity:How the body develops a way to reduce the toxicity of carbon nanotubes.Small,2012,8:1970-1972
11 Wang X Y,Wang M Z,Lei R,et al.Chiral surface of nanoparticles determines the orientation of adsorbed transferrin and its interaction with receptors.ACS Nano,2017,11:4606-4616
12 Wang X Y,Wang X F,Wang M Z,et al.Probing adsorption behaviors of BSA onto chiral surfaces of nanoparticles.Small,2018,14:e1703982
13 Ge C C,Li Y,Yin J J,et al.The contributions of metal impurities and tube structure to the toxicity of carbon nanotube materials.NPGAsia Mater,2012,4:e32
14 Meng L,Jiang A H,Chen R,et al.Inhibitory effects of multiwall carbon nanotubes with high iron impurity on viability and neuronal differentiation in cultured PC12 cells.Toxicology,2013,313:49-58
15 Ge C,Meng L,Xu L,et al.Acute pulmonary and moderate cardiovascular responses of spontaneously hypertensive rats after exposure to single-wall carbon nanotubes.Nanotoxicology,2012,6:526-542
16 Wang J,Bai R,Yang R,et al.Size-and surface chemistry-dependent pharmacokinetics and tumor accumulation of engineered gold nanoparticles after intravenous administration.Metallomics,2015,7:516-524
17 Xu L G,Liu Y,Chen Z Y,et al.Surface-engineered gold nanorods:Promising DNA vaccine adjuvant for HIV-1 treatment.Nano Lett,2012,12:2003-2012
18 Qiu Y,Liu Y,Wang L M,et al.Surface chemistry and aspect ratio mediated cellular uptake of Au nanorods.Biomaterials,2010,31:7606-7619
19 Wang L M,Liu Y,Li W,et al.Selective targeting of gold nanorods at the mitochondria of cancer cells:Implications for cancer therapy.Nano Lett,2011,11:772-780
20 Liu Y X,Li W,Lao F,et al.Intracellular dynamics of cationic and anionic polystyrene nanoparticles without direct interaction with mitotic spindle and chromosomes.Biomaterials,2011,32:8291-8303
21 Li Y,Liu Y,Fu Y,et al.The triggering of apoptosis in macrophages by pristine graphene through the MAPK and TGF-beta signaling pathways.Biomaterials,2012,33:402-411
22 Zhou H J,Zhao K,Li W,et al.The interactions between pristine graphene and macrophages and the production of cytokines/chemokines via TLR-and NF-kappa B-related signaling pathways.Biomaterials,2012,33:6933-6942
23 Chong Y,Ge C C,Fang G,et al.Light-enhanced antibacterial activity of graphene oxide,mainly via accelerated electron transfer.Environ Sci Technol,2017,51:10154-10161
24 Fratoddi I,Venditti I,Cametti C,et al.How toxic are gold nanoparticles?The state-of-the-art.Nano Res,2015,8:1771-1799
25 Dykman L A,Khlebtsov N G.Uptake of engineered gold nanoparticles into mammalian cells.Chem Rev,2014,114:1258-1288
26 Gruber J,Fong S,Chen C B,et al.Mitochondria-targeted antioxidants and metabolic modulators as pharmacological interventions to slow ageing.Biotechnol Adv,2013,31:563-592
27 Webb J A,Bardhan R.Emerging advances in nanomedicine with engineered gold nanostructures.Nanoscale,2014,6:2502-2530
28 Behzadi S,Serpooshan V,Tao W,et al.Cellular uptake of nanoparticles:Journey inside the cell.Chem Soc Rev,2017,46:4218-4244
29 Zhao F,Zhao Y,Liu Y,et al.Cellular uptake,intracellular trafficking,and cytotoxicity of nanomaterials.Small,2011,7:1322-1337
30 Meng L,Chen R,Jiang A H,et al.Short multiwall carbon nanotubes promote neuronal differentiation of PC12 cells via up-regulation of the neurotrophin signaling pathway.Small,2013,9:1786-1798
31 Wang P,Nie X,Wang Y,et al.Multiwall Carbon nanotubes mediate macrophage activation and promote pulmonary fibrosis through TGF-beta/smad signaling pathway.Small,2013,9:3799-3811
32 Wang P,Wang Y,Nie X,et al.Multiwall carbon nanotubes directly promote fibroblast-myofibroblast and epithelial-mesenchymal transitions through the activation of the TGF-beta/smad signaling pathway.Small,2015,11:446-455
33 Wang J,Xie Y D,Wang L M,et al.In vivo pharmacokinetic features and biodistribution of star and rod shaped gold nanoparticles by multispectral optoacoustic tomography.RSC Adv,2015,5:7529-7538
34 Fang G,Li W F,Shen X M,et al.Differential Pd-nanocrystal facets demonstrate distinct antibacterial activity against Gram-positive and Gram-negative bacteria.Nat Commun,2018,9:129
35 Jiang X,Miclaus T,Wang L,et al.Fast intracellular dissolution and persistent cellular uptake of silver nanoparticles in CHO-K1 cells:Implication for cytotoxicity.Nanotoxicology,2015,9:181-189
36 Wang L M,Zhang T L,Li P Y,et al.Use of synchrotron radiation-analytical techniques to reveal chemical origin of silver-nanoparticle cytotoxicity.ACS Nano,2015,9:6532-6547
37 Wang L M,Li Y F,Zhou L J,et al.Characterization of gold nanorods in vivo by integrated analytical techniques:Their uptake,retention,and chemical forms.Anal Bioanal Chem,2010,396:1105-1114
38 Jiang X M,Wu Y,Gray P,et al.Influence of gastrointestinal environment on free radical generation of silver nanoparticles and implications for their cytotoxicity.NanoImpact,2018,10:144
39 Jiang X M,Wang L M,Ji Y L,et al.Interference of steroidogenesis by gold nanorod core/silver shell nanostructures:Implications for reproductive toxicity of silver nanomaterials.Small,2017,13:1602855
40 Wang J X,Chen C Y,Liu Y,et al.Potential neurological lesion after nasal instillation of TiO2 nanoparticles in the anatase and rutile crystal phases.Toxicol Lett,2008,183:72-80
41 Wang J X,Liu Y,Jiao F,et al.Time-dependent translocation and potential impairment on central nervous system by intranasally instilled TiO2 nanoparticles.Toxicology,2008,254:82-90
42 Qu Y,Li W,Zhou Y L,et al.Full assessment of fate and physiological behavior of quantum dots utilizing caenorhabditis elegans as a model organism.Nano Lett,2011,11:3174-3183
43 Cong W S,Wang P,Qu Y,et al.Evaluation of the influence of fullerenol on aging and stress resistance using Caenorhabditis elegans.Biomaterials,2015,42:78v86
44 Dong J L,Shang Y D,Inthavong K,et al.Comparative numerical modeling of inhaled nanoparticle deposition in human and rat nasal cavities.Toxicol Sci,2016,152:284-296
45 Tian L,Shang Y,Chen R,et al.A combined experimental and numerical study on upper airway dosimetry of inhaled nanoparticles from an electrical discharge machine shop.Part Fibre Toxicol,2017,14:24
46 Le T C,Yin H,Chen R,et al.An experimental and computational approach to the development of ZnO nanoparticles that are safe by design.Small,2016,12:3568-3577
47 Chen R,Qiao J,Bai R,et al.Intelligent testing strategy and analytical techniques for the safety assessment of nanomaterials.Anal Bioanal Chem,2018,410:6051-6066
48 Chen R,Zhao L,Bai R,et al.Silver nanoparticles induced oxidative and endoplasmic reticulum stresses in mouse tissues:Implications for the development of acute toxicity after intravenous administration.Toxicol Res UK,2016,5:602-608
49 Chen R,Huo L L,Shi X F,et al.Endoplasmic reticulum stress induced by zinc oxide nanoparticles is an earlier biomarker for nanotoxicological evaluation.ACS Nano,2014,8:2562-2574
50 Zhang L,Bai R,Liu Y,et al.The dose-dependent toxicological effects and potential perturbation on the neurotransmitter secretion in brain following intranasal instillation of copper nanoparticles.Nanotoxicology,2012,6:562-575
51 Huo L L,Chen R,Zhao L,et al.Silver nanoparticles activate endoplasmic reticulum stress signaling pathway in cell and mouse models:The role in toxicity evaluation.Biomaterials,2015,61:307-315
52 Chen R,Zhang L L,Ge C C,et al.Subchronic toxicity and cardiovascular responses in spontaneously hypertensive rats after exposure to multiwalled carbon nanotubes by intratracheal instillation.Chem Res Toxicol,2015,28:440-450
53 Chen Z Y,Liu Y,Sun B Y,et al.Polyhydroxylated metallofullerenols stimulate IL-1 beta secretion of macrophage through TLRs/MyD88/NF-kappa B pathway and NLRP3 inflammasome activation.Small,2014,10:2362-2372
54 Chen Z J,Wang Y,Ba T,et al.Genotoxic evaluation of titanium dioxide nanoparticles in vivo and in vitro.Toxicol Lett,2014,226:314-319
55 Wang L M,Yan L,Liu J,et al.Quantification of nanomaterial/nanomedicine trafficking in vivo.Anal Chem,2018,90:589-614
56 Liu J,Wang P,Zhang X,et al.Rapid degradation and high renal clearance of Cu3BiS3 nanodots for efficient cancer diagnosis and photothermal therapy in vivo.ACS Nano,2016,10:4587-4598
57 He X,Pan Y Y,Zhang J Z,et al.Quantifying the total ionic release from nanoparticles after particle-cell contact.Environ Pollut,2015,196:194-200
58 Cao M J,Wang P Y,Kou Y,et al.Gadolinium(III)-chelated silica nanospheres integrating chemotherapy and photothermal therapy for cancer treatment and magnetic resonance imaging.ACS Appl Mater Interfaces,2015,7:25014-25023
59 Wang J,Liu J,Liu Y,et al.Gd-Hybridized plasmonic au-nanocomposites enhanced tumor-interior drug permeability in multimodal imaging-guided therapy.Adv Mater,2016,28:8950-8958
60 Yao S K,Fan J D,Chen Z Y,et al.Three-dimensional ultrastructural imaging reveals the nanoscale architecture of mammalian cells.IUCRJ,2018,5:141-149
61 Wang L M,Li J Y,Pan J,et al.Revealing the binding structure of the protein corona on gold nanorods using synchrotron radiation-based techniques:Understanding the reduced damage in cell membranes.J Am Chem Soc,2013,135:17359-17368
62 Porcaro F,Roudeau S,Carmona A,et al.Advances in element speciation analysis of biomedical samples using synchrotron-based techniques.Trac-Trend Anal Chem,2017,1:1-20
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