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1.  Nanometer-long Ge-imogolite nanotubes cause sustained lung inflammation and fibrosis in rats 
Background
Ge-imogolites are short aluminogermanate tubular nanomaterials with attractive prospected industrial applications. In view of their nano-scale dimensions and high aspect ratio, they should be examined for their potential to cause respiratory toxicity. Here, we evaluated the respiratory biopersistence and lung toxicity of 2 samples of nanometer-long Ge-imogolites.
Methods
Rats were intra-tracheally instilled with single wall (SW, 70 nm length) or double wall (DW, 62 nm length) Ge-imogolites (0.02-2 mg/rat), as well as with crocidolite and the hard metal particles WC-Co, as positive controls. The biopersistence of Ge-imogolites and their localization in the lung were assessed by ICP-MS, X-ray fluorescence, absorption spectroscopy and computed micro-tomography. Acute inflammation and genotoxicity (micronuclei in isolated type II pneumocytes) was assessed 3 d post-exposure; chronic inflammation and fibrosis after 2 m.
Results
Cytotoxic and inflammatory responses were shown in bronchoalveolar lavage 3 d after instillation with Ge-imogolites. Sixty days after exposure, a persistent dose-dependent inflammation was still observed. Total lung collagen, reflected by hydroxyproline lung content, was increased after SW and DW Ge-imogolites. Histology revealed lung fibre reorganization and accumulation in granulomas with epithelioid cells and foamy macrophages and thickening of the alveolar walls. Overall, the inflammatory and fibrotic responses induced by SW and DW Ge-imogolites were more severe (on a mass dose basis) than those induced by crocidolite. A persistent fraction of Ge-imogolites (15% of initial dose) was mostly detected as intact structures in rat lungs 2 m after instillation and was localized in fibrotic alveolar areas. In vivo induction of micronuclei was significantly increased 3 d after SW and DW Ge-imogolite instillation at non-inflammatory doses, indicating the contribution of primary genotoxicity.
Conclusions
We showed that nm-long Ge-imogolites persist in the lung and promote genotoxicity, sustained inflammation and fibrosis, indicating that short high aspect ratio nanomaterials should not be considered as innocuous materials. Our data also suggest that Ge-imogolite structure and external surface determine their toxic activity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12989-014-0067-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12989-014-0067-z
PMCID: PMC4276264  PMID: 25497478
Lung; Inflammation; Fibrosis; Genotoxicity; Nanomaterial; Fibre; High aspect ratio; Biopersistence
2.  High-Aluminum-Affinity Silica Is a Nanoparticle That Seeds Secondary Aluminosilicate Formation 
PLoS ONE  2013;8(12):e84397.
Despite the importance and abundance of aluminosilicates throughout our natural surroundings, their formation at neutral pH is, surprisingly, a matter of considerable debate. From our experiments in dilute aluminum and silica containing solutions (pH ~ 7) we previously identified a silica polymer with an extraordinarily high affinity for aluminium ions (high-aluminum-affinity silica polymer, HSP). Here, further characterization shows that HSP is a colloid of approximately 2.4 nm in diameter with a mean specific surface area of about 1,000 m2 g-1 and it competes effectively with transferrin for Al(III) binding. Aluminum binding to HSP strongly inhibited its decomposition whilst the reaction rate constant for the formation of the β-silicomolybdic acid complex indicated a diameter between 3.6 and 4.1 nm for these aluminum-containing nanoparticles. Similarly, high resolution microscopic analysis of the air dried aluminum-containing silica colloid solution revealed 3.9 ± 1.3 nm sized crystalline Al-rich silica nanoparticles (ASP) with an estimated Al:Si ratio of between 2 and 3 which is close to the range of secondary aluminosilicates such as imogolite. Thus the high-aluminum-affinity silica polymer is a nanoparticle that seeds early aluminosilicate formation through highly competitive binding of Al(III) ions. In niche environments, especially in vivo, this may serve as an alternative mechanism to polyhydroxy Al(III) species binding monomeric silica to form early phase, non-toxic aluminosilicates.
doi:10.1371/journal.pone.0084397
PMCID: PMC3862809  PMID: 24349573
3.  Lipid Bilayers Covalently Anchored to Carbon Nanotubes 
Langmuir  2012;28(21):8174-8182.
The unique physical and electrical properties of carbon nanotubes make them an exciting material for applications in various fields such as bioelectronics and biosensing. Due to the poor water solubility of carbon nanotubes, functionalization for such applications has been a challenge. Of particular need are functionalization methods for integrating carbon nanotubes with biomolecules and constructing novel hybrid nanostructures for bionanoelectronic applications. We present a novel method for the fabrication of dispersible, biocompatible carbon nanotube-based materials. Multi-walled carbon nanotubes (MWCNTs) are covalently modified with primary amine-bearing phospholipids in a carbodiimide-activated reaction. These modified carbon nanotubes have good dispersibility in nonpolar solvents. Fourier transform infrared (FTIR) spectroscopy shows peaks attributable to the formation of amide bonds between lipids and the nanotube surface. Simple sonication of lipid-modified nanotubes with other lipid molecules leads to the formation of a uniform lipid bilayer coating the nanotubes. These bilayer-coated nanotubes are highly dispersible and stable in aqueous solution. Confocal fluorescence microscopy shows labeled lipids on the surface of bilayer-modified nanotubes. Transmission electron microscopy (TEM) shows the morphology of dispersed bilayer-coated MWCNTs. Fluorescence quenching of lipid-coated MWCNTs confirms the bilayer configuration of the lipids on the nanotube surface and fluorescence anisotropy measurements show that the bilayer is fluid above the gel-to-liquid transition temperature. The membrane protein α-hemolysin spontaneously inserts into the MWCNT-supported bilayer, confirming the biomimetic membrane structure. These biomimetic nanostructures are a promising platform for the integration of carbon nanotube-based materials with biomolecules.
doi:10.1021/la301094h
PMCID: PMC3378680  PMID: 22568448
4.  Tungsten Disulfide Nanotubes Reinforced Biodegradable Polymers for Bone Tissue Engineering 
Acta biomaterialia  2013;9(9):8365-8373.
In this study, we have investigated the efficacy of inorganic nanotubes as reinforcing agents to improve the mechanical properties of poly(propylene fumarate) (PPF) composites as a function of nanomaterial loading concentration (0.01-0.2 wt%). Tungsten disulfide nanotubes (WSNTs) were used as reinforcing agents in the experimental groups. Single- and multi- walled carbon nanotubes (SWCNTs and MWCNTs) were used as positive controls, and crosslinked PPF composites were used as baseline control. Mechanical testing (compression and three-point bending) shows a significant enhancement (up to 28-190%) in the mechanical properties (compressive modulus, compressive yield strength, flexural modulus, and flexural yield strength) of WSNT reinforced PPF nanocomposites compared to the baseline control. In comparison to positive controls, at various concentrations, significant improvements in the mechanical properties of WSNT nanocomposites were also observed. In general, the inorganic nanotubes (WSNTs) showed a better (up to 127%) or equivalent mechanical reinforcement compared to carbon nanotubes (SWCNTs and MWCNTs). Sol fraction analysis showed significant increases in the crosslinking density of PPF in the presence of WSNTs (0.01-0.2 wt%). Transmission electron microscopy (TEM) analysis on thin sections of crosslinked nanocomposites showed the presence of WSNTs as individual nanotubes in the PPF matrix, whereas SWCNTs and MWCNTs existed as micron sized aggregates. The trend in the surface area of nanostructures obtained by BET surface area analysis was SWCNTs > MWCNTs > WSNTs. The BET surface area analysis, TEM analysis, and sol fraction analysis results taken together suggest that chemical composition (inorganic vs. carbon nanomaterials), presence of functional groups (such as sulfide and oxysulfide), and individual dispersion of the nanomaterials in the polymer matrix (absence of aggregation of the reinforcing agent) are the key parameters affecting the mechanical properties of nanostructure-reinforced PPF composites, and the reason for the observed increases in the mechanical properties compared to the baseline and positive controls.
doi:10.1016/j.actbio.2013.05.018
PMCID: PMC3732565  PMID: 23727293
polymer nanocomposites; carbon nanotubes; tungsten nanotubes; mechanical properties; bone tissue engineering
5.  Antibacterial activity and cytotoxicity of multi-walled carbon nanotubes decorated with silver nanoparticles 
Recently, various nanoscale materials, including silver (Ag) nanoparticles, have been actively studied for their capacity to effectively prevent bacterial growth. A critical challenge is to enhance the antibacterial properties of nanomaterials while maintaining their biocompatibility. The conjugation of multiple nanomaterials with different dimensions, such as spherical nanoparticles and high-aspect-ratio nanotubes, may increase the target-specific antibacterial capacity of the consequent nanostructure while retaining an optimal biocompatibility. In this study, multi-walled carbon nanotubes (MWCNTs) were treated with a mixture of acids and decorated with Ag nanoparticles via a chemical reduction of Ag cations by ethanol solution. The synthesized Ag-MWCNT complexes were characterized by transmission electron microscopy, X-ray diffractometry, and energy-dispersive X-ray spectroscopy. The antibacterial function of Ag-MWCNTs was evaluated against Methylobacterium spp. and Sphingomonas spp. In addition, the biocompatibility of Ag-MWCNTs was evaluated using both mouse liver hepatocytes (AML 12) and human peripheral blood mononuclear cells. Finally, we determined the minimum amount of Ag-MWCNTs required for a biocompatible yet effective antibacterial treatment modality. We report that 30 μg/mL of Ag-MWCNTs confers antibacterial functionality while maintaining minimal cytotoxicity toward both human and animal cells. The results reported herein would be beneficial for researchers interested in the efficient preparation of hybrid nanostructures and in determining the minimum amount of Ag-MWCNTs necessary to effectively hinder the growth of bacteria.
doi:10.2147/IJN.S69561
PMCID: PMC4200021  PMID: 25336943
antimicrobial; nanoconstructs; toxicity
6.  Dual effects and mechanism of TiO2 nanotube arrays in reducing bacterial colonization and enhancing C3H10T1/2 cell adhesion 
Competition occurs between the osteoblasts in regional microenvironments and pathogens introduced during surgery, on the surface of bone implants, such as joint prostheses. The aim of this study was to modulate bacterial and osteoblast adhesion on implant surfaces by using a nanotube array. Titanium oxide (TiO2) nanotube arrays, 30 nm or 80 nm in diameter, were prepared by a two-step anodization on titanium substrates. Mechanically polished and acid-etched titanium samples were also prepared to serve as control groups. The standard strains of Staphylococcus epidermidis (S. epidermidis, American Type Culture Collection [ATCC]35984) and mouse C3H10T1/2 cell lines with osteogenic potential were used to evaluate the different responses to the nanotube arrays, in bacteria and eukaryotic cells. We found that the initial adhesion and colonization of S. epidermidis on the surface of the TiO2 nanotube arrays were significantly reduced and that the adhesion of C3H10T1/2 cells on the surface of the TiO2 nanotube arrays was significantly enhanced when compared with the control samples. Based on a surface analysis of all four groups, we observed increased surface roughness, decreased water contact angles, and an enhanced concentration of oxygen and fluorine atoms on the TiO2 nanotube surface. We conclude that the TiO2 nanotube surface can reduce bacterial colonization and enhance C3H10T1/2 cell adhesion; multiple physical and chemical properties of the TiO2 nanotube surface may contribute to these dual effects.
doi:10.2147/IJN.S48084
PMCID: PMC3747852  PMID: 23983463
bacterial adhesion; titanium implant; surface modification
7.  Revealing the Adsorption Mechanisms of Nitroxides on Ultrapure, Metallicity-Sorted Carbon Nanotubes 
ACS Nano  2014;8(2):1375-1383.
Carbon nanotubes are a natural choice as gas sensor components given their high surface to volume ratio, electronic properties, and capability to mediate chemical reactions. However, a realistic assessment of the interaction of the tube wall and the adsorption processes during gas phase reactions has always been elusive. Making use of ultraclean single-walled carbon nanotubes, we have followed the adsorption kinetics of NO2 and found a physisorption mechanism. Additionally, the adsorption reaction directly depends on the metallic character of the samples. Franck–Condon satellites, hitherto undetected in nanotube–NOx systems, were resolved in the N 1s X-ray absorption signal, revealing a weak chemisorption, which is intrinsically related to NO dimer molecules. This has allowed us to identify that an additional signal observed in the higher binding energy region of the core level C 1s photoemission signal is due to the C=O species of ketene groups formed as reaction byproducts . This has been supported by density functional theory calculations. These results pave the way toward the optimization of nanotube-based sensors with tailored sensitivity and selectivity to different species at room temperature.
doi:10.1021/nn405114z
PMCID: PMC3936481  PMID: 24404865
carbon nanotube sensors; X-ray absorption; physisorption; chemisorption; photoemission
8.  Biodurability of Single-Walled Carbon Nanotubes Depends on Surface Functionalization 
Carbon  2010;48(7):1961-1969.
Recent research has led to increased concern about the potential adverse human health impacts of carbon nanotubes, and further work is needed to better characterize those risks and develop risk management strategies. One of the most important determinants of the chronic pathogenic potential of a respirable fiber is its biological durability, which affects the long-term dose retained in the lungs, or biopersistence. The present article characterizes the biodurability of single-walled carbon nanotubes using an in vitro assay simulating the phagolysosome. Biodurability is observed to depend on the chemistry of nanotube surface functionalization. Single-walled nanotubes with carboxylated surfaces are unique in their ability to undergo 90-day degradation in a phagolysosomal simulant leading to length reduction and accumulation of ultrafine solid carbonaceous debris. Unmodified, ozone-treated, and aryl-sulfonated tubes do not degrade under these conditions. We attribute the difference to the unique chemistry of acid carboxylation, which not only introduces COOH surface groups, but also causes collateral damage to the tubular graphenic backbone in the form of neighboring active sites that provide points of attack for further oxidative degradation. These results suggest the strategic use of surface carboxylation in nanotube applications where biodegradation may improve safety or add function.
doi:10.1016/j.carbon.2010.02.002
PMCID: PMC2844903  PMID: 20352066
9.  Rapid Isolation of Viable Circulating Tumor Cells from Patient Blood Samples 
Circulating tumor cells (CTC) are cells that disseminate from a primary tumor throughout the circulatory system and that can ultimately form secondary tumors at distant sites. CTC count can be used to follow disease progression based on the correlation between CTC concentration in blood and disease severity1. As a treatment tool, CTC could be studied in the laboratory to develop personalized therapies. To this end, CTC isolation must cause no cellular damage, and contamination by other cell types, particularly leukocytes, must be avoided as much as possible2. Many of the current techniques, including the sole FDA-approved device for CTC enumeration, destroy CTC as part of the isolation process (for more information see Ref. 2). A microfluidic device to capture viable CTC is described, consisting of a surface functionalized with E-selectin glycoprotein in addition to antibodies against epithelial markers3. To enhance device performance a nanoparticle coating was applied consisting of halloysite nanotubes, an aluminosilicate nanoparticle harvested from clay4. The E-selectin molecules provide a means to capture fast moving CTC that are pumped through the device, lending an advantage over alternative microfluidic devices wherein longer processing times are necessary to provide target cells with sufficient time to interact with a surface. The antibodies to epithelial targets provide CTC-specificity to the device, as well as provide a readily adjustable parameter to tune isolation. Finally, the halloysite nanotube coating allows significantly enhanced isolation compared to other techniques by helping to capture fast moving cells, providing increased surface area for protein adsorption, and repelling contaminating leukocytes3,4. This device is produced by a straightforward technique using off-the-shelf materials, and has been successfully used to capture cancer cells from the blood of metastatic cancer patients. Captured cells are maintained for up to 15 days in culture following isolation, and these samples typically consist of >50% viable primary cancer cells from each patient. This device has been used to capture viable CTC from both diluted whole blood and buffy coat samples. Ultimately, we present a technique with functionality in a clinical setting to develop personalized cancer therapies.
doi:10.3791/4248
PMCID: PMC3471307  PMID: 22733259
Bioengineering;  Issue 64;  Biomedical Engineering;  Cancer Biology;  Circulating tumor cells;  metastasis;  selectin;  nanotechnology;  halloysite nanotubes;  cell isolation;  cancer
10.  Gold Nanopopcorn Attached Single-Walled Carbon Nanotube Hybrid for Rapid Detection and Killing of Bacteria 
We report a strategy to fabricate a rapid and stable surface-enhanced Raman scattering (SERS)-based hybrid nanomaterial using gold nanopopcorns attached single-walled carbon nanotubes (AuNP@f3-SWCNTs) for label-free detection and photothermal killing of bacteria. Herein, previously ester-functionalized single-walled carbon nanotubes (f1-SWCNTs) undergo 1,3-dipolar cycloaddition reaction with in-situ generated nitrile imine under Microwave (MW) irradiation to form a doubly ester terminated SWCNTs cycloadduct (f2-SWCNTs). The ester terminals are further modified with 4-aminothiophenol (4-ATP) under MW-irradiation to form thiol-terminated SWCNTs templates (f3-SWCNTs) that allow gold nanopopcorns (AuNPs) to covalently and uniformly attach at a minimum inter-particle distance thus yielding a hybrid nanomaterial (AuNP@f3-SWCNT) with good aqueous stability and abundant ‘hotspots’. Consequently, monoclonal E. coli antibody-conjugated bioassays fabricated with our AuNP@f3-SWCNT substrates (mAb-AuNP@f3-SWCNT) rapidly detect E. coli in water with good selectivity and impressive SERS sensitivity. The detection limit of E. coli 49979, selected as a model to establish proof of principle, was found to be 1.0×102 CFU/mL. Furthermore, the AuNP@f3-SWCNT hybrid nanomaterial offers impressive photothermal pathogen killing effects. The synergy-type enhancement effect arising from the inherent noble properties of the respective components of the hybrid nanomaterial indicate that our AuNP@f3-SWCNT has the potential for further application in multiplex detection in samples.
doi:10.1039/C4TB01195C
PMCID: PMC4234150  PMID: 25414794
11.  Self-assembly of carbon nanotubes and antibodies on tumours for targeted, amplified delivery 
Nature nanotechnology  2013;8(10):763-771.
Single-walled carbon nanotubes (SWNTs) can deliver imaging agents or drugs to tumours and offer significant advantages over approaches based on antibodies or other nanomaterials. In particular, the nanotubes can carry a substantial amount of cargo (100 times more than a monoclonal antibody), but can still be rapidly eliminated from circulation by renal filtration, like a small molecule, due to their high aspect ratio. Here we show that SWNTs can target tumours in a two-step approach in which nanotubes modified with morpholino oligonucleotide sequences bind to cancer cells that have been pre-targeted with antibodies modified with oligonucleotide strands complementary to those on the nanotubes. The nanotubes can carry fluorophores or radioisotopes, and were shown to selectively bind to cancer cells in vitro and in tumour-bearing xenografted mice. The binding process is also found to lead to antigen capping and internalization of the antibody/nanotube complexes. The nanotube conjugates were labelled with both alpha-particle and gamma-ray emitting isotopes, at high specific activities. Conjugates labelled with alpha-particle generating 225Ac were found to clear rapidly, thus mitigating radioisotope toxicity, and were shown to be therapeutically effective in vivo.
doi:10.1038/nnano.2013.190
PMCID: PMC3798027  PMID: 24077028
12.  Conducting-Polymer Nanotubes Improve Electrical Properties, Mechanical Adhesion, Neural Attachment, and Neurite Outgrowth of Neural Electrodes 
An in vitro comparison of conducting-polymer nanotubes of poly(3,4-ethylenedioxythiophene) (PEDOT) and poly(pyrrole) (PPy) and to their film counterparts is reported. Impedance, charge-capacity density (CCD), tendency towards delamination, and neurite outgrowth are compared. For the same deposition charge density, PPy films and nanotubes grow relatively faster vertically, while PEDOT films and nanotubes grow more laterally. For the same deposition charge density (1.44 C cm–2), PPy nanotubes and PEDOT nanotubes have lower impedance (19.5 ± 2.1 kΩ for PPy nanotubes and 2.5 ± 1.4 kΩ for PEDOT nanotubes at 1 kHz) and higher CCD (184 ± 5.3 mC cm–2 for PPy nanotubes and 392 ± 6.2 mC cm–2 for PEDOT nanotubes) compared to their film counterparts. However, PEDOT nanotubes decrease the impedance of neural-electrode sites by about two orders of magnitude (bare iridium 468.8 ± 13.3 kΩ at 1 kHz) and increase capacity of charge density by about three orders of magnitude (bare iridium 0.1 ± 0.5 mC cm–2). During cyclic voltammetry measurements, both PPy and PEDOT nanotubes remain adherent on the surface of the silicon dioxide while PPy and PEDOT films delaminate. In experiments of primary neurons with conducting-polymer nanotubes, cultured dorsal root ganglion explants remain more intact and exhibit longer neurites (1400 ± 95 μm for PPy nanotubes and 2100 ± 150 μm for PEDOT nanotubes) than their film counterparts. These findings suggest that conducting-polymer nanotubes may improve the long-term function of neural microelectrodes.
doi:10.1002/smll.200901868
PMCID: PMC3045566  PMID: 20077424
bioelectronics; conducting polymers; nanotubes; neural electrodes; neurite
13.  Monitoring Transport Across Modified Nanoporous Alumina Membranes 
Sensors (Basel, Switzerland)  2007;7(11):2942-2952.
This paper describes the use of several characterization methods to examine alumina nanotubule membranes that have been modified with specific silanes. The function of these silanes is to alter the transport properties through the membrane by changing the local environment inside the alumina nanotube. The presence of alkyl groups, either long (C18) or short and branched (isopropyl) hydrocarbon chains, on these silanes significantly decreases the rate of transport of permeant molecules through membranes containing alumina nanotubes as monitored via absorbance spectroscopy. The presence of an ionic surfactant can alter the polarity of these modified nanotubes, which correlates to an increased transport of ions. Fluorescent spectroscopy is also utilized to enhance the sensitivity of detecting these permeant molecules. Confirmation of the alkylsilane attachment to the alumina membrane is achieved with traditional infrared spectroscopy, which can also examine the lifetime of the modified membrane. The physical parameters of these silane-modified porous alumina membranes are studied via scanning electron microscopy. The alumina nanotubes are not physically closed off or capped by the silanes that are attached to the alumina surfaces.
PMCID: PMC3965222
Porous alumina membranes; sensors; nanotubes; silanization; membrane modification; spectroscopy
14.  Computational Design of a Carbon Nanotube Fluorofullerene Biosensor 
Sensors (Basel, Switzerland)  2012;12(10):13720-13735.
Carbon nanotubes offer exciting opportunities for devising highly-sensitive detectors of specific molecules in biology and the environment. Detection limits as low as 10−11 M have already been achieved using nanotube-based sensors. We propose the design of a biosensor comprised of functionalized carbon nanotube pores embedded in a silicon-nitride or other membrane, fluorofullerene-Fragment antigen-binding (Fab fragment) conjugates, and polymer beads with complementary Fab fragments. We show by using molecular and stochastic dynamics that conduction through the (9, 9) exohydrogenated carbon nanotubes is 20 times larger than through the Ion Channel Switch ICS™ biosensor, and fluorofullerenes block the nanotube entrance with a dissociation constant as low as 37 pM. Under normal operating conditions and in the absence of analyte, fluorofullerenes block the nanotube pores and the polymer beads float around in the reservoir. When analyte is injected into the reservoir the Fab fragments attached to the fluorofullerene and polymer bead crosslink to the analyte. The drag of the much larger polymer bead then acts to pull the fluorofullerene from the nanotube entrance, thereby allowing the flow of monovalent cations across the membrane. Assuming a tight seal is formed between the two reservoirs, such a biosensor would be able to detect one channel opening and thus one molecule of analyte making it a highly sensitive detection design.
doi:10.3390/s121013720
PMCID: PMC3545589  PMID: 23202018
carbon nanotube; biosensor; fluorofullerene; molecular dynamics; distributional molecular dynamics; proof-of-concept
15.  Analytical modeling of glucose biosensors based on carbon nanotubes 
In recent years, carbon nanotubes have received widespread attention as promising carbon-based nanoelectronic devices. Due to their exceptional physical, chemical, and electrical properties, namely a high surface-to-volume ratio, their enhanced electron transfer properties, and their high thermal conductivity, carbon nanotubes can be used effectively as electrochemical sensors. The integration of carbon nanotubes with a functional group provides a good and solid support for the immobilization of enzymes. The determination of glucose levels using biosensors, particularly in the medical diagnostics and food industries, is gaining mass appeal. Glucose biosensors detect the glucose molecule by catalyzing glucose to gluconic acid and hydrogen peroxide in the presence of oxygen. This action provides high accuracy and a quick detection rate. In this paper, a single-wall carbon nanotube field-effect transistor biosensor for glucose detection is analytically modeled. In the proposed model, the glucose concentration is presented as a function of gate voltage. Subsequently, the proposed model is compared with existing experimental data. A good consensus between the model and the experimental data is reported. The simulated data demonstrate that the analytical model can be employed with an electrochemical glucose sensor to predict the behavior of the sensing mechanism in biosensors.
doi:10.1186/1556-276X-9-33
PMCID: PMC3898395  PMID: 24428818
Carbon nanotube; SWCNT FET; Glucose detection; Biosensor; Analytical model; I-V characteristics; PBS; Glucose oxide
16.  Carbon Nanotubes: Artificial Nanomaterials to Engineer Single Neurons and Neuronal Networks 
ACS Chemical Neuroscience  2012;3(8):611-618.
In the past decade, nanotechnology applications to the nervous system have often involved the study and the use of novel nanomaterials to improve the diagnosis and therapy of neurological diseases. In the field of nanomedicine, carbon nanotubes are evaluated as promising materials for diverse therapeutic and diagnostic applications. Besides, carbon nanotubes are increasingly employed in basic neuroscience approaches, and they have been used in the design of neuronal interfaces or in that of scaffolds promoting neuronal growth in vitro. Ultimately, carbon nanotubes are thought to hold the potential for the development of innovative neurological implants. In this framework, it is particularly relevant to document the impact of interfacing such materials with nerve cells. Carbon nanotubes were shown, when modified with biologically active compounds or functionalized in order to alter their charge, to affect neurite outgrowth and branching. Notably, purified carbon nanotubes used as scaffolds can promote the formation of nanotube–neuron hybrid networks, able per se to affect neuron integrative abilities, network connectivity, and synaptic plasticity. We focus this review on our work over several years directed to investigate the ability of carbon nanotube platforms in providing a new tool for nongenetic manipulations of neuronal performance and network signaling.
doi:10.1021/cn300048q
PMCID: PMC3419456  PMID: 22896805
Carbon nanotubes; nanotechnology; cultured neuronal network; synapse; short-term plasticity; patch clamp recordings
17.  Characterization and in vitro studies of the anticancer effect of oxidized carbon nanotubes functionalized with betulinic acid 
Among the array of nanomaterials, carbon nanotubes have shown great potential as drug carriers in the field of nanomedicine, owing to their attractive physicochemical structure, which facilitates functionalization of therapeutic molecules onto their external walls or being encapsulated inside the tubes. The aim of this preliminary study was to formulate betulinic acid (BA), a poorly water-soluble drug, in oxidized multiwalled carbon nanotubes (MWCNT-COOH) for enhanced delivery efficiency into cancer cells with reduced cytotoxicity. The synthesized MWCNT-BA nanocomposite was characterized using ultraviolet-visible, Fourier transform infrared, thermogravimetric analysis, powder X-ray diffraction, and field emission scanning electron microscopy techniques. The loading of BA in MWCNT-COOH nanocarrier was estimated to be about 14.5%–14.8% (w/w), as determined by ultraviolet-visible and thermogravimetric analysis. Fourier transform infrared study shows that the peaks of the resulting MWCNT-BA nanocomposite correlate to the characteristic functional groups of BA and MWCNT-COOH. The powder X-ray diffraction results confirmed that the tubular structures of MWCNT-COOH were not affected by the drug loading mechanism of BA. The release profiles demonstrated that approximately 98% of BA could be released within 22 hours by phosphate-buffered saline solution at pH 7.4 compared with about 22% within 24 hours at pH 4.8. The biocompatibility studies revealed that MWCNT-BA at concentrations <50μg/mL expressed no cytotoxicity effects for mouse embryo fibroblast cells after 72 hours of treatment. The anticancer activity of MWCNT-BA was observed to be more sensitive to human lung cancer cell line when compared with human liver cancer cell line, with half maximal inhibitory concentration values of 2.7 and 11.0μg/mL, respectively. Our findings form a fundamental platform for further investigation of the MWCNT-BA formulation against different types of cancer cells.
doi:10.2147/DDDT.S70650
PMCID: PMC4242135  PMID: 25429205
multiwalled carbon nanotubes (MWCNTs); drug delivery; controlled release; cytotoxicity; A549 cell line; HepG2 cell line
18.  Advances in NO2 sensing with individual single-walled carbon nanotube transistors 
Summary
The charge carrier transport in carbon nanotubes is highly sensitive to certain molecules attached to their surface. This property has generated interest for their application in sensing gases, chemicals and biomolecules. With over a decade of research, a clearer picture of the interactions between the carbon nanotube and its surroundings has been achieved. In this review, we intend to summarize the current knowledge on this topic, focusing not only on the effect of adsorbates but also the effect of dielectric charge traps on the electrical transport in single-walled carbon nanotube transistors that are to be used in sensing applications. Recently, contact-passivated, open-channel individual single-walled carbon nanotube field-effect transistors have been shown to be operational at room temperature with ultra-low power consumption. Sensor recovery within minutes through UV illumination or self-heating has been shown. Improvements in fabrication processes aimed at reducing the impact of charge traps have reduced the hysteresis, drift and low-frequency noise in carbon nanotube transistors. While open challenges such as large-scale fabrication, selectivity tuning and noise reduction still remain, these results demonstrate considerable progress in transforming the promise of carbon nanotube properties into functional ultra-low power, highly sensitive gas sensors.
doi:10.3762/bjnano.5.227
PMCID: PMC4273237  PMID: 25551046
carbon nanotube field-effect transistors (CNFETs); cross-sensitivity; functionalization; gas sensors; hysteresis; low power; selectivity; self-heating; single walled carbon nanotubes
19.  Carbon Nanotubes in Biology and Medicine: In vitro and in vivo Detection, Imaging and Drug Delivery 
Nano research  2009;2(2):85-120.
Carbon nanotubes exhibit many unique intrinsic physical and chemical properties and have been intensively explored for biological and biomedical applications in the past few years. In this comprehensive review, we summarize the main results from our and other groups in this field and clarify that surface functionalization is critical to the behavior of carbon nanotubes in biological systems. Ultrasensitive detection of biological species with carbon nanotubes can be realized after surface passivation to inhibit the non-specific binding of biomolecules on the hydrophobic nanotube surface. Electrical nanosensors based on nanotubes provide a label-free approach to biological detection. Surface-enhanced Raman spectroscopy of carbon nanotubes opens up a method of protein microarray with detection sensitivity down to 1 fmol/L. In vitro and in vivo toxicity studies reveal that highly water soluble and serum stable nanotubes are biocompatible, nontoxic, and potentially useful for biomedical applications. In vivo biodistributions vary with the functionalization and possibly also size of nanotubes, with a tendency to accumulate in the reticuloendothelial system (RES), including the liver and spleen, after intravenous administration. If well functionalized, nanotubes may be excreted mainly through the biliary pathway in feces. Carbon nanotube-based drug delivery has shown promise in various In vitro and in vivo experiments including delivery of small interfering RNA (siRNA), paclitaxel and doxorubicin. Moreover, single-walled carbon nanotubes with various interesting intrinsic optical properties have been used as novel photoluminescence, Raman, and photoacoustic contrast agents for imaging of cells and animals. Further multidisciplinary explorations in this field may bring new opportunities in the realm of biomedicine.
doi:10.1007/s12274-009-9009-8
PMCID: PMC2824900  PMID: 20174481
Carbon nanotubes; biomedical applications; surface functionalization; biosensor; drug delivery; biomedical imaging
20.  Delivery of small interfering RNAs in human cervical cancer cells by polyethylenimine-functionalized carbon nanotubes 
Nanoscale Research Letters  2013;8(1):267.
Carbon nanotubes are capable of penetrating the cell membrane and are widely considered as potential carriers for gene or drug delivery. Because the C-C and C=C bonds in carbon nanotubes are nonpolar, functionalization is required for carbon nanotubes to interact with genes or drugs as well as to improve their biocompatibility. In this study, polyethylenimine (PEI)-functionalized single-wall (PEI-NH-SWNTs) and multiwall carbon nanotubes (PEI-NH-MWNTs) were produced by direct amination method. PEI functionalization increased the positive charge on the surface of SWNTs and MWNTs, allowing carbon nanotubes to interact electrostatically with the negatively charged small interfering RNAs (siRNAs) and to serve as nonviral gene delivery reagents. PEI-NH-MWNTs and PEI-NH-SWNTs had a better solubility in water than pristine carbon nanotubes, and further removal of large aggregates by centrifugation produced a stable suspension of reduced particle size and improved homogeneity and dispersity. The amount of grafted PEI estimated by thermogravimetric analysis was 5.08% (w/w) and 5.28% (w/w) for PEI-NH-SWNTs and PEI-NH-MWNTs, respectively. For the assessment of cytotoxicity, various concentrations of PEI-NH-SWNTs and PEI-NH-MWNTs were incubated with human cervical cancer cells, HeLa-S3, for 48 h. PEI-NH-SWNTs and PEI-NH-MWNTs induced cell deaths in a dose-dependent manner but were less cytotoxic compared to pure PEI. As determined by electrophoretic mobility shift assay, siRNAs directed against glyceraldehyde-3-phosphate dehydrogenase (siGAPDH) were completely associated with PEI-NH-SWNTs or PEI-NH-MWNTs at a PEI-NH-SWNT/siGAPDH or PEI-NH-MWNT/siGAPDH mass ratio of 80:1 or 160:1, respectively. Furthermore, PEI-NH-SWNTs and PEI-NH-MWNTs successfully delivered siGAPDH into HeLa-S3 cells at PEI-NH-SWNT/siGAPDH and PEI-NH-MWNT/siGAPDH mass ratios of 1:1 to 20:1, resulting in suppression of the mRNA level of GAPDH to an extent similar to that of DharmaFECT, a common transfection reagent for siRNAs. Our results indicate that the PEI-NH-SWNTs and PEI-NH-MWNTs produced in this study are capable of delivering siRNAs into HeLa-S3 cells to suppress gene expression and may therefore be considered as novel nonviral gene delivery reagents.
doi:10.1186/1556-276X-8-267
PMCID: PMC3683344  PMID: 23742156
SWNTs; MWNTs; PEI; Small interfering RNA; Gene delivery
21.  Color Detection Using Chromophore-Nanotube Hybrid Devices 
Nano Letters  2009;9(3):1028-1033.
We present a nanoscale color detector based on a single-walled carbon nanotube functionalized with azobenzene chromophores, where the chromophores serve as photoabsorbers and the nanotube as the electronic read-out. By synthesizing chromophores with specific absorption windows in the visible spectrum and anchoring them to the nanotube surface, we demonstrate the controlled detection of visible light of low intensity in narrow ranges of wavelengths. Our measurements suggest that upon photoabsorption, the chromophores isomerize from the ground state trans configuration to the excited state cis configuration, accompanied by a large change in dipole moment, changing the electrostatic environment of the nanotube. All-electron ab initio calculations are used to study the chromophore-nanotube hybrids and show that the chromophores bind strongly to the nanotubes without disturbing the electronic structure of either species. Calculated values of the dipole moments support the notion of dipole changes as the optical detection mechanism.
doi:10.1021/nl8032922
PMCID: PMC3258674  PMID: 19206226
22.  A 3-dimensional in vitro model of epithelioid granulomas induced by high aspect ratio nanomaterials 
Background
The most common causes of granulomatous inflammation are persistent pathogens and poorly-degradable irritating materials. A characteristic pathological reaction to intratracheal instillation, pharyngeal aspiration, or inhalation of carbon nanotubes is formation of epithelioid granulomas accompanied by interstitial fibrosis in the lungs. In the mesothelium, a similar response is induced by high aspect ratio nanomaterials, including asbestos fibers, following intraperitoneal injection. This asbestos-like behaviour of some engineered nanomaterials is a concern for their potential adverse health effects in the lungs and mesothelium. We hypothesize that high aspect ratio nanomaterials will induce epithelioid granulomas in nonadherent macrophages in 3D cultures.
Results
Carbon black particles (Printex 90) and crocidolite asbestos fibers were used as well-characterized reference materials and compared with three commercial samples of multiwalled carbon nanotubes (MWCNTs). Doses were identified in 2D and 3D cultures in order to minimize acute toxicity and to reflect realistic occupational exposures in humans and in previous inhalation studies in rodents. Under serum-free conditions, exposure of nonadherent primary murine bone marrow-derived macrophages to 0.5 μg/ml (0.38 μg/cm2) of crocidolite asbestos fibers or MWCNTs, but not carbon black, induced macrophage differentiation into epithelioid cells and formation of stable aggregates with the characteristic morphology of granulomas. Formation of multinucleated giant cells was also induced by asbestos fibers or MWCNTs in this 3D in vitro model. After 7-14 days, macrophages exposed to high aspect ratio nanomaterials co-expressed proinflammatory (M1) as well as profibrotic (M2) phenotypic markers.
Conclusions
Induction of epithelioid granulomas appears to correlate with high aspect ratio and complex 3D structure of carbon nanotubes, not with their iron content or surface area. This model offers a time- and cost-effective platform to evaluate the potential of engineered high aspect ratio nanomaterials, including carbon nanotubes, nanofibers, nanorods and metallic nanowires, to induce granulomas following inhalation.
doi:10.1186/1743-8977-8-17
PMCID: PMC3120675  PMID: 21592387
23.  Non-Covalent Functionalization of Carbon Nanotubes by Fluorescein-Polyethylene Glycol: Supramolecular Conjugates with pH Dependent Absorbance and Fluorescence 
We report the use of fluorescein-polyethylene glycol (Fluor-PEG) to non-covalently functionalize single-walled carbon nanotubes (SWNTs) for obtaining aqueous-soluble nanotube conjugates (Fluor-PEG/SWNT) and simultaneously affording fluorescence labels to nanotubes. We find serendipitously that fluorescein, a widely used fluorophore, can strongly adsorb onto the sidewall of the SWNTs likely via π-stacking, and the hydrophilic PEG chain imparts high aqueous solubility. Interaction between fluorescein and SWNT is pH dependent; it weakens as the pH is increased, causing the Fluor-PEG/SWNT conjugate to be less stable at high pHs. Fluorescein molecules bound to SWNTs exhibit interesting pH dependent optical absorbance and fluorescence properties that are distinct from free molecules, as a result of pH dependent interactions with SWNT sidewalls. Fluorescence emission from fluorescein adsorbed on SWNT is quenched by ~67%, but remains sufficient and useful as a fluorescent label. The utility of Fluor-PEG/SWNT as a simultaneous fluorescent marker and an intracellular transporter is demonstrated by uptake of Fluor-PEG/SWNT by mammalian cells and detection of fluorescence inside the cells. Raman detection of SWNTs in the cells is also carried out and used to prove the co-localization of fluorescein and SWNT.
doi:10.1021/ja068684j
PMCID: PMC4161124  PMID: 17284037
24.  Nanotubes Functionalized with Lipids and Natural Amino Acid Dendrimers: A new strategy to create nanomaterials for delivering systemic RNAi 
Bioconjugate chemistry  2010;21(1):56.
Single-walled carbon nanotubes (SWNT) have unique electronic, mechanical, and structural properties as well as chemical stability that make them ideal nanomaterials for applications in materials science and medicine. Here we report the design and creation of a novel strategy for functionalizing SWNT to systemically silence a target gene in mice by delivering siRNA at doses <1 mg/Kg. SWNT were functionalized with lipids and natural amino acid-based dendrimers (TOT) and complexed to siRNA. Our model study of the silencing efficiency of the TOT-siRNA complex showed that in mice injected at 0.96 mg/kg, an endogenous gene for apoliproprotein B (ApoB) was silenced in liver, plasma levels of ApoB decreased, and total plasma cholesterol decreased. TOT-siRNA treatment was non-toxic and did not induce an immune response. Most (80%) of the RNA trigger molecules assembled with TOT were cleared from the body 48 h after injection, suggesting that the nanotubes did not cause siRNA aggregation or inhibit biodegradation and drug clearance in vivo. These results provide the first evidence that nanotubes can be functionalized with lipids and amino acids to systemically deliver siRNA. This new technology cannot only be used for systemic RNAi, but may also be used to deliver other drugs in vivo.
doi:10.1021/bc900296z
PMCID: PMC2814541  PMID: 19957956
RNAi; nanotubes; siRNA delivery; chemically modified siRNA; therapeutic silencing
25.  Effect of metal catalyzed oxidation in recombinant viral protein assemblies 
Background
Protein assemblies, such as virus-like particles, have increasing importance as vaccines, delivery vehicles and nanomaterials. However, their use requires stable assemblies. An important cause of loss of stability in proteins is oxidation, which can occur during their production, purification and storage. Despite its importance, very few studies have investigated the effect of oxidation in protein assemblies and their structural units. In this work, we investigated the role of in vitro oxidation in the assembly and stability of rotavirus VP6, a polymorphic protein.
Results
The susceptibility to oxidation of VP6 assembled into nanotubes (VP6NT) and unassembled VP6 (VP6U) was determined and compared to bovine serum albumin (BSA) as control. VP6 was more resistant to oxidation than BSA, as determined by measuring protein degradation and carbonyl content. It was found that assembly protected VP6 from in vitro metal-catalyzed oxidation. Oxidation provoked protein aggregation and VP6NT fragmentation, as evidenced by dynamic light scattering and transmission electron microscopy. Oxidative damage of VP6 correlated with a decrease of its center of fluorescence spectral mass. The in vitro assembly efficiency of VP6U into VP6NT decreased as the oxidant concentration increased.
Conclusions
Oxidation caused carbonylation, quenching, and destruction of aromatic amino acids and aggregation of VP6 in its assembled and unassembled forms. Such modifications affected protein functionality, including its ability to assemble. That assembly protected VP6 from oxidation shows that exposure of susceptible amino acids to the solvent increases their damage, and therefore the protein surface area that is exposed to the solvent is determinant of its susceptibility to oxidation. The inability of oxidized VP6 to assemble into nanotubes highlights the importance of avoiding this modification during the production of proteins that self-assemble. This is the first time that the role of oxidation in protein assembly is studied, evidencing that oxidation should be minimized during the production process if VP6 nanotubes are required.
doi:10.1186/1475-2859-13-25
PMCID: PMC3928578  PMID: 24533452
Protein oxidation; Carbonylation; Virus-like particles; Viral protein assemblies; Assembly efficiency

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