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ABSTRACT: Carbon nanotubes (CNTs) are exciting new materials that have been intensively researched and are becoming increasingly used in consumer products. With rapid growth in production and use of CNTs in many applications, there is the potential for emissions to the environment and thus research is needed to assess the risks associated with CNTs in the environment. Here we show that commercial CNTs differ in their stability, photoactivity, metal leachate, and toxicity to freshwater algae. The behavior between raw and purified variants of the CNTs differs considerably; for example purified CNTs are generally more photoactive, producing singlet oxygen and superoxide, while raw CNTs show little or no photoactivity. Residual metal catalysts differ based on synthesis method used to prepare CNTs and thus may be comprised of elements with varying degrees of toxic potential. Influenced by pH and other constituents of the natural waters, our work shows that metals can leach out from all the commercial CNTs studied, even purified versions, albeit at different levels in many natural waters. As much as 10% of the total residual nickel leached from a purified CNT after 72 h. Aqueous concentrations of molybdenum leached from a different purified CNT were nearly 0.060 mg L(-1) after 72 h. With little sample preparation, CNTs are dispersible in most freshwaters and stable for several days. Not all tested CNTs were toxic; for those CNTs that did induce toxicity we show that photoactivity, not metal leaching, contributes to the toxicity of commercial CNTs to freshwater algae, with growth rates significantly reduced by as much as 200%.
Water Research 04/2013; · 4.86 Impact Factor
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Ruibin Li,
Xiang Wang, Zhaoxia Ji,
Bingbing Sun,
Haiyuan Zhang,
Chong Hyun Chang,
Sijie Lin,
Huan Meng,
Yu-Pei Liao,
Meiying Wang,
Zongxi Li,
Angela A Hwang,
Tze-Bin Song,
Run Xu,
Yang Yang,
Jeffrey I Zink,
André E Nel,
Tian Xia
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ABSTRACT: Functionalized carbon nanotubes (f-CNTs) are being produced in increased volume because of the ease of dispersion and maintenance of the pristine material physicochemical properties when used in composite materials as well as for other commercial applications. However, the potential adverse effects of f-CNTs have not been quantitatively or systematically explored. In this study, we used a library of covalently functionalized multiwall carbon nanotubes (f-MWCNTs), established from the same starting material, to assess the impact of surface charge in a predictive toxicological model that relates the tubes' pro-inflammatory and pro-fibrogenic effects at cellular level to the development of pulmonary fibrosis. Carboxylate (COOH), polyethylene glycol (PEG), amine (NH2), sidewall amine (sw-NH2), and polyetherimide (PEI)-modified MWCNTs were successfully established from raw or as-prepared (AP-) MWCNTs and comprehensively characterized by TEM, XPS, FTIR, and DLS to obtain information about morphology, length, degree of functionalization, hydrodynamic size, and surface charge. Cellular screening in BEAS-2B and THP-1 cells showed that, compared to AP-MWCNTs, anionic functionalization (COOH and PEG) decreased the production of pro-fibrogenic cytokines and growth factors (including IL-1β, TGF-β1, and PDGF-AA), while neutral and weak cationic functionalization (NH2 and sw-NH2) showed intermediary effects. In contrast, the strongly cationic PEI-functionalized tubes induced robust biological effects. These differences could be attributed to differences in cellular uptake and NLRP3 inflammasome activation, which depends on the propensity toward lysosomal damage and cathepsin B release in macrophages. Moreover, the in vitro hazard ranking was validated by the pro-fibrogenic potential of the tubes in vivo. Compared to pristine MWCNTs, strong cationic PEI-MWCNTs induced significant lung fibrosis, while carboxylation significantly decreased the extent of pulmonary fibrosis. These results demonstrate that surface charge plays an important role in the structure-activity relationships that determine the pro-fibrogenic potential of f-CNTs in the lung.
ACS Nano 02/2013; · 10.77 Impact Factor
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Huan Meng,
Wilson X Mai,
Haiyuan Zhang,
Min Xue,
Tian Xia,
Sijie Lin,
Xiang Wang,
Yang Zhao, Zhaoxia Ji,
Jeffrey I Zink,
Andre E Nel
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ABSTRACT: We used a multifunctional mesoporous silica nanoparticle (MSNP) carrier to overcome doxorubicin (Dox) resistance in a multidrug resistant (MDR) human breast cancer xenograft by codelivering Dox and siRNA that targets the P-glycoprotein (Pgp) drug exporter. The Pgp siRNA selection from among a series of drug resistance targets was achieved by performing high throughput screening in a MDR breast cancer cell line, MCF-7/MDR. Following the establishment of a MCF-7/MDR xenograft model in nude mice, we demonstrated that a 50 nm MSNP, functionalized by a polyethyleneimine-polyethylene glycol (PEI-PEG) copolymer, provides protected delivery of stably bound Dox and Pgp siRNA to the tumor site. The effective biodistribution and reduced reticuloendothelial uptake, as a result of our nanocarrier design, allowed us to achieve an 8% enhanced permeability and retention effect at the tumor site. Compared to free Dox or the carrier loaded with either drug or siRNA alone, the dual delivery system resulted in synergistic inhibition of tumor growth in vivo. Analysis of multiple xenograft biopsies demonstrated significant Pgp knockdown at heterogeneous tumor sites that correspond to the regions where Dox was released intracellularly and induced apoptosis. We emphasize that the heterogeneity originates in the tumor microenvironment, which influences the vascular access, rather than heterogeneous Pgp expression in the MDR cells. Taken together, these data provide proof-of-principle testing of the use of a dual drug/siRNA nanocarrier to overcome Dox resistance in a xenograft. The study also provides the first detailed analysis of the impact of heterogeneity in the tumor microenvironment on the efficacy of siRNA delivery in vivo.
ACS Nano 01/2013; · 10.77 Impact Factor
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Sijie Lin,
Yan Zhao, Zhaoxia Ji,
Jason Ear,
Chong Hyun Chang,
Haiyuan Zhang,
Cecile Low-Kam,
Kristin Yamada,
Huan Meng,
Xiang Wang,
Rong Liu,
Suman Pokhrel,
Lutz Mädler,
Robert Damoiseaux,
Tian Xia,
Hilary A Godwin,
Shuo Lin,
André E Nel
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ABSTRACT: The zebrafish is emerging as a model organism for the safety assessment and hazard ranking of engineered nanomaterials. In this Communication, the implementation of a roboticized high-throughput screening (HTS) platform with automated image analysis is demonstrated to assess the impact of dissolvable oxide nanoparticles on embryo hatching. It is further demonstrated that this hatching interference is mechanistically linked to an effect on the metalloprotease, ZHE 1, which is responsible for degradation of the chorionic membrane. The data indicate that 4 of 24 metal oxide nanoparticles (CuO, ZnO, Cr(2) O(3) , and NiO) could interfere with embryo hatching by a chelator-sensitive mechanism that involves ligation of critical histidines in the ZHE1 center by the shed metal ions. A recombinant ZHE1 enzymatic assay is established to demonstrate that the dialysates from the same materials responsible for hatching interference also inhibit ZHE1 activity in a dose-dependent fashion. A peptide-based BLAST search identifies several additional aquatic species that express enzymes with homologous histidine-based catalytic centers, suggesting that the ZHE1 mechanistic paradigm could be used to predict the toxicity of a large number of oxide nanoparticles that pose a hazard to aquatic species.
Small 11/2012; · 8.35 Impact Factor
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ABSTRACT: Engineered nanomaterials (ENMs) continue to attract significant attention because they have novel physicochemical properties that can improve the functions of products that will benefit human lives. However, the physicochemical properties that make ENMs attractive could interact with biological systems and induce cascades of events that cause toxicological effects. Recently, there have been more studies suggesting inflammasome activation may play an important role in ENM-induced biological responses. Inflammasomes are a family of multiprotein complexes that are increasingly recognized as major mediators of the host immune system. Among these, NLRP3 inflammasome is the most studied that could directly interact with ENMs to generate inflammatory responses. In this review, the ENM physicochemical properties are linked to NLRP3 inflammasome activation. An understanding of the mechanisms of ENM-NLRP3 inflammasome interactions will provide us with strategies for safer nanomaterial design and therapy.
Small 11/2012; · 8.35 Impact Factor
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Tian Xia,
Davin Malasarn,
Sijie Lin, Zhaoxia Ji,
Haiyuan Zhang,
Robert J Miller,
Arturo A Keller,
Roger M Nisbet,
Barbara H Harthorn,
Hilary A Godwin,
Hunter S Lenihan,
Rong Liu,
Jorge Gardea-Torresdey,
Yoram Cohen,
Lutz Mädler,
Patricia A Holden,
Jeffrey I Zink,
Andre E Nel
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ABSTRACT: UC CEIN was established with funding from the US National Science Foundation and the US Environmental Protection Agency in 2008 with the mission to study the impact of nanotechnology on the environment, including the identification of hazard and exposure scenarios that take into consideration the unique physicochemical properties of engineered nanomaterials (ENMs). Since its inception, the Center has made great progress in assembling a multidisciplinary team to develop the scientific underpinnings, research, knowledge acquisition, education and outreach that is required for assessing the safe implementation of nanotechnology in the environment. In this essay, the development of the infrastructure, protocols, and decision-making tools that are required to effectively integrate complementary scientific disciplines allowing knowledge gathering in a complex study area that goes beyond the traditional safety and risk assessment protocols of the 20th century is outlined. UC CEIN's streamlined approach, premised on predictive hazard and exposure assessment methods, high-throughput discovery platforms and environmental decision-making tools that consider a wide range of nano/bio interfaces in terrestrial and aquatic ecosystems, demonstrates the implementation of a 21st-century approach to the safe implementation of nanotechnology in the environment.
Small 10/2012; · 8.35 Impact Factor
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Haiyuan Zhang,
Darren R Dunphy,
Xingmao Jiang,
Huan Meng,
Bingbing Sun,
Derrick Tarn,
Min Xue,
Xiang Wang,
Sijie Lin, Zhaoxia Ji,
Ruibin Li,
Fred L Garcia,
Jing Yang,
Martin L Kirk,
Tian Xia,
Jeffrey I Zink,
Andre Nel,
C Jeffrey Brinker
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ABSTRACT: We have developed structure/toxicity relationships for amorphous silica nanoparticles (NPs) synthesized through low-temperature colloidal (e.g., Stöber silica) or high-temperature pyrolysis (e.g., fumed silica) routes. Through combined spectroscopic and physical analyses, we have determined the state of aggregation, hydroxyl concentration, relative proportion of strained and unstrained siloxane rings, and potential to generate hydroxyl radicals for Stöber and fumed silica NPs with comparable primary particle sizes (16 nm in diameter). On the basis of erythrocyte hemolytic assays and assessment of the viability and ATP levels in epithelial and macrophage cells, we discovered for fumed silica an important toxicity relationship to postsynthesis thermal annealing or environmental exposure, whereas colloidal silicas were essentially nontoxic under identical treatment conditions. Specifically, we find for fumed silica a positive correlation of toxicity with hydroxyl concentration and its potential to generate reactive oxygen species (ROS) and cause red blood cell hemolysis. We propose fumed silica toxicity stems from its intrinsic population of strained three-membered rings (3MRs) along with its chainlike aggregation and hydroxyl content. Hydrogen-bonding and electrostatic interactions of the silanol surfaces of fumed silica aggregates with the extracellular plasma membrane cause membrane perturbations sensed by the Nalp3 inflammasome, whose subsequent activation leads to secretion of the cytokine IL-1β. Hydroxyl radicals generated by the strained 3MRs in fumed silica, but largely absent in colloidal silicas, may contribute to the inflammasome activation. Formation of colloidal silica into aggregates mimicking those of fumed silica had no effect on cell viability or hemolysis. This study emphasizes that not all amorphous silicas are created equal and that the unusual toxicity of fumed silica compared to that of colloidal silica derives from its framework and surface chemistry along with its fused chainlike morphology established by high-temperature synthesis (>1300 °C) and rapid thermal quenching.
Journal of the American Chemical Society 08/2012; 134(38):15790-804. · 9.91 Impact Factor
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ABSTRACT: To uncover the size influence of TiO(2) nanoparticles on their potential toxicity, the cytotoxicity of different-sized TiO(2) nanoparticles with and without photoactivation was tested. It was demonstrated that without photoactivation, TiO(2) nanoparticles were inert up to 100 μg/ml. On the contrary, with photoactivation, the toxicity of TiO(2) nanoparticles significantly increased, which correlated well with the specific surface area of the particles. Our results also suggest that the generation of hydroxyl radicals and reactive oxygen species (ROS)-mediated damage to the surface-adsorbed biomolecules could be the two major reasons for the cytotoxicity of TiO(2) nanoparticles after photoactivation. Higher ROS generation from smaller particles was detected under both biotic and abiotic conditions. Smaller particles could adsorb more proteins, which was confirmed by thermogravimetric analysis. To further investigate the influence of the generation of hydroxyl radicals and adsorption of protein, poly (ethylene-alt-maleic anhydride) (PEMA) and chitosan were used to coat TiO(2) nanoparticles. The results confirmed that surface coating of TiO(2) nanoparticles could reduce such toxicity after photoactivation, by hindering adsorption of biomolecules and generation of hydroxyl radical (·OH) during photoactivation.
Archive für Toxikologie 08/2012; · 4.67 Impact Factor
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ABSTRACT: The production of engineered nanomaterials (ENMs) is a sci-entific breakthrough in material design and the development of new consumer products. While the successful implementation of nanotechnology is important for the growth of the global economy, we also need to consider the possible environmental health and safety (EHS) impact as a result of the novel physicochemical properties that could generate hazardous biological outcomes. In order to assess ENM hazard, reliable and reproducible screening approaches are needed to test the basic materials as well as nanoenabled products. A platform is required to investigate the potentially endless number of biophysicochemical interactions at the nano/bio interface, in response to which we have developed a predictive toxicological approach. We define a predictive toxicological approach as the use of mechanisms-based high-throughput screening in vitro to make predictions about the physicochemical properties of ENMs that may lead to the generation of pathology or disease outcomes in vivo. The in vivo results are used to validate and improve the in vitro high-throughput screening (HTS) and to establish structure-activity relationships (SARs) that allow hazard ranking and modeling by an appropriate combination of in vitro and in vivo testing. This notion is in agreement with the landmark 2007 report from the US National Academy of Sciences, "Toxicity Testing in the 21st Century: A Vision and a Strategy" ( http://www.nap.edu/catalog.php?record_id=11970 ), which advocates increased efficiency of toxicity testing by transitioning from qualitative, descriptive animal testing to quantitative, mechanistic, and pathway-based toxicity testing in human cells or cell lines using high-throughput approaches. Accordingly, we have implemented HTS approaches to screen compositional and combinatorial ENM libraries to develop hazard ranking and structure-activity relationships that can be used for predicting in vivo injury outcomes. This predictive approach allows the bulk of the screening analysis and high-volume data generation to be carried out in vitro, following which limited, but critical, validation studies are carried out in animals or whole organisms. Risk reduction in the exposed human or environmental populations can then focus on limiting or avoiding exposures that trigger these toxicological responses as well as implementing safer design of potentially hazardous ENMs. In this Account, we review the tools required for establishing predictive toxicology paradigms to assess inhalation and environmental toxicological scenarios through the use of compositional and combinatorial ENM libraries, mechanism-based HTS assays, hazard ranking, and development of nano-SARs. We will discuss the major injury paradigms that have emerged based on specific ENM properties, as well as describing the safer design of ZnO nanoparticles based on characterization of dissolution chemistry as a major predictor of toxicity.
Accounts of Chemical Research 06/2012; · 21.64 Impact Factor
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ABSTRACT: While it has been shown that high aspect ratio nanomaterials like carbon nanotubes and TiO(2) nanowires can induce toxicity by acting as fiber-like substances that damage the lysosome, it is not clear what the critical lengths and aspect ratios are that induce this type of toxicity. To answer this question, we synthesized a series of cerium oxide (CeO(2)) nanorods and nanowires with precisely controlled lengths and aspect ratios. Both phosphate and chloride ions were shown to play critical roles in obtaining these high aspect ratio nanostructures. High-resolution TEM analysis shows that single-crystalline CeO(2) nanorods/nanowires were formed along the [211] direction by an "oriented attachment" mechanism, followed by Ostwald ripening. The successful creation of a comprehensive CeO(2) nanorod/nanowire combinatorial library allows, for the first time, the systematic study of the effect of aspect ratio on lysosomal damage, cytotoxicity, and IL-1β production by the human myeloid cell line (THP-1). This in vitro toxicity study demonstrated that, at lengths ≥200 nm and aspect ratios ≥22, CeO(2) nanorods induced progressive pro-inflammatory effects and cytotoxicity. The relatively low "critical" length and aspect ratio were associated with small nanorod/nanowire diameters (6-10 nm), which facilitates the formation of stacking bundles due to strong van der Waals and dipole-dipole attractions. Our results suggest that both length and diameter components of aspect ratio should be considered when addressing the cytotoxic effects of high aspect ratio materials.
ACS Nano 05/2012; 6(6):5366-80. · 10.77 Impact Factor
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Xiang Wang,
Tian Xia,
Matthew C Duch, Zhaoxia Ji,
Haiyuan Zhang,
Ruibin Li,
Bingbing Sun,
Sijie Lin,
Huan Meng,
Yu-Pei Liao,
Meiying Wang,
Tze-Bin Song,
Yang Yang,
Mark C Hersam,
André E Nel
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ABSTRACT: We compared the use of bovine serum albumin (BSA) and pluronic F108 (PF108) as dispersants for multiwalled carbon nanotubes (MWCNTs) in terms of tube stability as well as profibrogenic effects in vitro and in vivo. While BSA-dispersed tubes were a potent inducer of pulmonary fibrosis, PF108 coating protected the tubes from damaging the lysosomal membrane and initiating a sequence of cooperative cellular events that play a role in the pathogenesis of pulmonary fibrosis. Our results suggest that PF108 coating could serve as a safer design approach for MWCNTs.
Nano Letters 04/2012; 12(6):3050-61. · 13.20 Impact Factor
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Haiyuan Zhang, Zhaoxia Ji,
Tian Xia,
Huan Meng,
Cecile Low-Kam,
Rong Liu,
Suman Pokhrel,
Sijie Lin,
Xiang Wang,
Yu-Pei Liao,
Meiying Wang,
Linjiang Li,
Robert Rallo,
Robert Damoiseaux,
Donatello Telesca,
Lutz Mädler,
Yoram Cohen,
Jeffrey I Zink,
Andre E Nel
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ABSTRACT: We demonstrate for 24 metal oxide (MOx) nanoparticles that it is possible to use conduction band energy levels to delineate their toxicological potential at cellular and whole animal levels. Among the materials, the overlap of conduction band energy (E(c)) levels with the cellular redox potential (-4.12 to -4.84 eV) was strongly correlated to the ability of Co(3)O(4), Cr(2)O(3), Ni(2)O(3), Mn(2)O(3), and CoO nanoparticles to induce oxygen radicals, oxidative stress, and inflammation. This outcome is premised on permissible electron transfers from the biological redox couples that maintain the cellular redox equilibrium to the conduction band of the semiconductor particles. Both single-parameter cytotoxic as well as multi-parameter oxidative stress assays in cells showed excellent correlation to the generation of acute neutrophilic inflammation and cytokine responses in the lungs of C57 BL/6 mice. Co(3)O(4), Ni(2)O(3), Mn(2)O(3), and CoO nanoparticles could also oxidize cytochrome c as a representative redox couple involved in redox homeostasis. While CuO and ZnO generated oxidative stress and acute pulmonary inflammation that is not predicted by E(c) levels, the adverse biological effects of these materials could be explained by their solubility, as demonstrated by ICP-MS analysis. These results demonstrate that it is possible to predict the toxicity of a large series of MOx nanoparticles in the lung premised on semiconductor properties and an integrated in vitro/in vivo hazard ranking model premised on oxidative stress. This establishes a robust platform for modeling of MOx structure-activity relationships based on band gap energy levels and particle dissolution. This predictive toxicological paradigm is also of considerable importance for regulatory decision-making about this important class of engineered nanomaterials.
ACS Nano 04/2012; 6(5):4349-68. · 10.77 Impact Factor
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Saji George,
Sijie Lin, Zhaoxia Ji,
Courtney R Thomas,
LinJiang Li,
Mathew Mecklenburg,
Huan Meng,
Xiang Wang,
Haiyuan Zhang,
Tian Xia,
J Nathan Hohman,
Shuo Lin,
Jeffrey I Zink,
Paul S Weiss,
André E Nel
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ABSTRACT: We investigated and compared nanosize Ag spheres, plates, and wires in a fish gill epithelial cell line (RT-W1) and in zebrafish embryos to understand the mechanism of toxicity of an engineered nanomaterial raising considerable environmental concern. While most of the Ag nanoparticles induced N-acetyl cysteine sensitive oxidative stress effects in RT-W1, Ag nanoplates were considerably more toxic than other particle shapes. Interestingly, while Ag ion shedding and bioavailability failed to comprehensively explain the high toxicity of the nanoplates, cellular injury required direct particle contact, resulting in cell membrane lysis in RT-W1 as well as red blood cells (RBC). Ag nanoplates were also considerably more toxic in zebrafish embryos in spite of their lesser ability to shed Ag into the exposure medium. To elucidate the "surface reactivity" of Ag nanoplates, high-resolution transmission electron microscopy was performed and demonstrated a high level of crystal defects (stacking faults and point defects) on the nanoplate surfaces. Surface coating with cysteine was used to passivate the surface defects and demonstrated a reduction of toxicity in RT-W1 cells, RBC, and zebrafish embryos. This study demonstrates the important role of crystal defects in contributing to Ag nanoparticle toxicity in addition to the established roles of Ag ion shedding by Ag nanoparticles. The excellent correlation between the in vitro and in vivo toxicological assessment illustrates the utility of using a fish cell line in parallel with zebrafish embryos to perform a predictive environmental toxicological paradigm.
ACS Nano 04/2012; 6(5):3745-59. · 10.77 Impact Factor
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ABSTRACT: By exploiting a genome-wide collection of bacterial single-gene deletion mutants, we have studied the toxicological pathways of a 60-nm cationic (amino-functionalized) polystyrene nanomaterial (PS-NH(2)) in bacterial cells. The IC(50) of commercially available 60 nm PS-NH(2) was determined to be 158 μg/mL, the IC(5) is 108 μg/mL, and the IC(90) is 190 μg/mL for the parent E. coli strain of the gene deletion library. Over 4000 single nonessential gene deletion mutants of Escherichia coli were screened for the growth phenotype of each strain in the presence and absence of PS-NH(2). This revealed that genes clusters in the lipopolysaccharide biosynthetic pathway, outer membrane transport channels, ubiquinone biosynthetic pathways, flagellar movement, and DNA repair systems are all important to how this organism responds to cationic nanomaterials. These results, coupled with those from confirmatory assays described herein, suggest that the primary mechanisms of toxicity of the 60-nm PS-NH(2) nanomaterial in E. coli are destabilization of the outer membrane and production of reactive oxygen species. The methodology reported herein should prove generally useful for identifying pathways that are involved in how cells respond to a broad range of nanomaterials and for determining the mechanisms of cellular toxicity of different types of nanomaterials.
Environmental Science & Technology 12/2011; 46(4):2398-405. · 4.80 Impact Factor
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Xiang Wang,
Tian Xia,
Susana Addo Ntim, Zhaoxia Ji,
Sijie Lin,
Huan Meng,
Choong-Heui Chung,
Saji George,
Haiyuan Zhang,
Meiying Wang,
Ning Li,
Yang Yang,
Vincent Castranova,
Somenath Mitra,
James C Bonner,
André E Nel
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ABSTRACT: We developed a dispersal method for multiwalled carbon nanotubes (MWCNTs) that allows quantitative assessment of dispersion on profibrogenic responses in tissue culture cells and in mouse lung. We demonstrate that the dispersal of as-prepared (AP), purified (PD), and carboxylated (COOH) MWCNTs by bovine serum albumin (BSA) and dipalmitoylphosphatidylcholine (DPPC) influences TGF-β1, PDGF-AA, and IL-1β production in vitro and in vivo. These biomarkers were chosen based on their synergy in promoting fibrogenesis and cellular communication in the epithelial-mesenchymal cell trophic unit in the lung. The effect of dispersal was most noticeable in AP- and PD-MWCNTs, which are more hydrophobic and unstable in aqueous buffers than hydrophilic COOH-MWCNTs. Well-dispersed AP- and PD-MWCNTs were readily taken up by BEAS-2B, THP-1 cells, and alveolar macrophages (AM) and induced more prominent TGF-β1 and IL-1β production in vitro and TGF-β1, IL-1β, and PDGF-AA production in vivo than nondispersed tubes. Moreover, there was good agreement between the profibrogenic responses in vitro and in vivo as well as the ability of dispersed tubes to generate granulomatous inflammation and fibrosis in airways. Tube dispersal also elicited more robust IL-1β production in THP-1 cells. While COOH-MWCNTs were poorly taken up in BEAS-2B and induced little TGF-β1 production, they were bioprocessed by AM and induced less prominent collagen deposition at sites of nongranulomatous inflammation in the alveolar region. Taken together, these results indicate that the dispersal state of MWCNTs affects profibrogenic cellular responses that correlate with the extent of pulmonary fibrosis and are of potential use to predict pulmonary toxicity.
ACS Nano 11/2011; 5(12):9772-87. · 10.77 Impact Factor
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Sijie Lin,
Yan Zhao,
Tian Xia,
Huan Meng, Zhaoxia Ji,
Rong Liu,
Saji George,
Sijing Xiong,
Xiang Wang,
Haiyuan Zhang,
Suman Pokhrel,
Lutz Mädler,
Robert Damoiseaux,
Shuo Lin,
Andre E Nel
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ABSTRACT: Zebrafish is an aquatic organism that can be used for high content safety screening of engineered nanomaterials (ENMs). We demonstrate, for the first time, the use of high content bright-field and fluorescence-based imaging to compare the toxicological effect of transition metal oxide (CuO, ZnO, NiO, and Co(3)O(4)) nanoparticles in zebrafish embryos and larvae. High content bright-field imaging demonstrated potent and dose-dependent hatching interference in the embryos, with the exception of Co(3)O(4) which was relatively inert. We propose that the hatching interference was due to the shedding of Cu and Ni ions, compromising the activity of the hatching enzyme, ZHE1, similar to what we previously proposed for Zn(2+). This hypothesis is based on the presence of metal-sensitive histidines in the catalytic center of this enzyme. Co-introduction of a metal ion chelator, diethylene triamine pentaacetic acid (DTPA), reversed the hatching interference of Cu, Zn, and Ni. While neither the embryos nor larvae demonstrated morphological abnormalities, high content fluorescence-based imaging demonstrated that CuO, ZnO, and NiO could induce increased expression of the heat shock protein 70:enhanced green fluorescence protein (hsp70:eGFP) in transgenic zebrafish larvae. Induction of this response by CuO required a higher nanoparticle dose than the amount leading to hatching interference. This response was also DTPA-sensitive. We demonstrate that high content imaging of embryo development, morphological abnormalities, and HSP70 expression can be used for hazard ranking and determining the dose-response relationships leading to ENM effects on the development of the zebrafish embryo.
ACS Nano 08/2011; 5(9):7284-95. · 10.77 Impact Factor
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ABSTRACT: UV-light-induced electron-hole (e(-)/h(+)) pair generation with free radical production in TiO(2)-based nanoparticles is a major conceptual paradigm for biological injury. However, to date, this hypothesis has been difficult to experimentally verify due to the high energy of UV light that is intrinsically highly toxic to biological systems. Here, a versatile flame spray pyrolysis (FSP) synthetic process has been exploited to synthesize a library of iron-doped (0-10 wt%) TiO(2) nanoparticles. These particles have been tested for photoactivation-mediated cytotoxicity using near-visible light exposure. The reduction in TiO(2) band gap energy with incremental levels of Fe loading maintained the nanoparticle crystalline structure in spite of homogeneous Fe distribution (demonstrated by XRD, HRTEM, SAED, EFTEM, and EELS). Photochemical studies showed that band gap energy was reciprocally tuned proportional to the Fe content. The photo-oxidation capability of Fe-doped TiO(2) was found to increase during near-visible light exposure. Use of a macrophage cell line to evaluate cytotoxic and ROS production showed increased oxidant injury and cell death in parallel with a decrease in band gap energy. These findings demonstrate the importance of band gap energy in the phototoxic response of the cell to TiO(2) nanoparticles and reflect the potential of this material to generate adverse effects in humans and the environment during high-intensity light exposure.
Journal of the American Chemical Society 06/2011; 133(29):11270-8. · 9.91 Impact Factor
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ABSTRACT: A key challenge for improving the efficacy of passive drug delivery to tumor sites by a nanocarrier is to limit reticuloendothelial system uptake and to maximize the enhanced permeability and retention effect. We demonstrate that size reduction and surface functionalization of mesoporous silica nanoparticles (MSNP) with a polyethyleneimine-polyethylene glycol copolymer reduces particle opsonization while enhancing the passive delivery of monodispersed, 50 nm doxorubicin-laden MSNP to a human squamous carcinoma xenograft in nude mice after intravenous injection. Using near-infrared fluorescence imaging and elemental Si analysis, we demonstrate passive accumulation of ∼12% of the tail vein-injected particle load at the tumor site, where there is effective cellular uptake and the delivery of doxorubicin to KB-31 cells. This was accompanied by the induction of apoptosis and an enhanced rate of tumor shrinking compared to free doxorubicin. The improved drug delivery was accompanied by a significant reduction in systemic side effects such as animal weight loss as well as reduced liver and renal injury. These results demonstrate that it is possible to achieve effective passive tumor targeting by MSNP size reduction as well as by introducing steric hindrance and electrostatic repulsion through coating with a copolymer. Further endowment of this multifunctional drug delivery platform with targeting ligands and nanovalves may further enhance cell-specific targeting and on-demand release.
ACS Nano 05/2011; 5(5):4131-44. · 10.77 Impact Factor
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Huan Meng,
Sui Yang,
Zongxi Li,
Tian Xia,
Justin Chen, Zhaoxia Ji,
Haiyuan Zhang,
Xiang Wang,
Sijie Lin,
Connie Huang,
Z Hong Zhou,
Jeffrey I Zink,
Andre E Nel
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ABSTRACT: Although the aspect ratio (AR) of engineered nanomaterials (ENMs) is one of the key physicochemical parameters that could determine biological outcome, not much is understood about how AR contributes to shaping biological outcome. By using a mesoporous silica nanoparticle (MSNP) library that has been constructed to cover a range of different lengths, we could demonstrate that the AR of rod-shaped particles determines the rate and abundance of MSNP uptake by a macropinocytosis process in HeLa and A549 cancer cell lines. MSNPs with an AR of 2.1-2.5 were taken up in larger quantities compared to shorter or longer length rods by a process that is sensitive to amiloride, cytochalasin D, azide, and 4 °C inhibition. The rods with intermediary AR also induced the maximal number of filopodia, actin polymerization, and activation of small GTP-binding proteins (e.g., Rac1, CDC42) that involve assembly of the actin cytoskeleton and filopodia formation. When assessing the role of AR in the delivery of paclitaxel or camptothecin, the rods with AR 2.1-2.5 were clearly more efficient for drug delivery and generation of cytotoxic killing in HeLa cells. All considered, our data suggest an active sensoring mechanism by which HeLa and A549 cells are capable of detecting AR differences in MSNP to the extent that accelerated macropinocytosis can be used to achieve more efficient drug delivery.
ACS Nano 05/2011; 5(6):4434-47. · 10.77 Impact Factor
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ABSTRACT: A classification-based cytotoxicity nanostructure-activity relationship (nanoSAR) is presented based on a set of nine metal oxide nanoparticles to which transformed bronchial epithelial cells (BEAS-2B) were exposed over a range of concentrations (0.375-200 mg L(-1) ) and exposure times up to 24 h. The nanoSAR is developed using cytotoxicity data from a high-throughput screening assay that was processed to identify and label toxic (in terms of the propidium iodide uptake of BEAS-2B cells) versus nontoxic events relative to an unexposed control cell population. Starting with a set of fourteen intuitive but fundamental physicochemical nanoSAR input parameters, a number of models were identified which had a classification accuracy above 95%. The best-performing model had a 100% classification accuracy in both internal and external validations. This model is based on three descriptors: atomization energy of the metal oxide, period of the nanoparticle metal, and nanoparticle primary size, in addition to nanoparticle volume fraction (in solution). Notwithstanding the success of the present modeling approach with a relatively small nanoparticle library, it is important to recognize that a significantly larger data set would be needed in order to expand the applicability domain and increase the confidence and reliability of data-driven nanoSARs.
Small 03/2011; 7(8):1118-26. · 8.35 Impact Factor
