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The Nanotox TSRTP has identified 3 major categories of nanomaterial (NM) properties that are hypothesized to govern human health and environmental impacts, and thus, are of the highest priority for the production, characterization, testing, and modification. These categories are (1) morphology and structure, (2) interfacial properties, and (3) physical-chemical reactivity. Physical morphology and chemical structure govern initial miscibility, stability, and reactivity of NMs in the suspending media of interest. These early interactions, ultimately, give rise to NM interfacial properties that control aggregation, transport, deposition, and partitioning behavior in aqueous media. Finally, the combination of bulk and interfacial NM properties define long-term stability, reactivity, and fate in biological and environmental systems. From these categories of NM properties, we have developed a preliminary list of reference NMs four our studies.
The nominated reference NMs (Table 1) should be considered a snapshot in time of those NMs in commerce or likely to be soon. This list should be considered a minimal base set, designed to facilitate ongoing studies focused on elucidating mechanisms of NM transport, fate, and toxicity. Our selections are designed to probe key NM properties across wide ranges of base material properties, in addition to an array of possible activities and reactivities induced by internal and external NM modifications. The combination of the base NMs and modifications results in a large "combinatorial library" of NM properties under investigation. Hence, we will evaluate the widest possible range of nanomaterial size, shape, flexibility, porosity, and aspect ratio across a broad phase space of reactive, insulating, conducting, and semi-conducting materials. Another motivation of the Nanotox program is to establish high-throughput synthesis, modification, and characterization methods for nominated NMs (Fig. 1).
For example, the combinatorial NM library includes nanoparticles, nanocrystals, nanotubes, nanobuds, nanowires, nanofibers, and nanoribbons comprised of carbonaceous, metallic, hybrid, and semi-conducting materialsMetal and metal oxide nanoparticles of different metals are being synthesized with finely controlled primary particle and aggregate particle sizes. Microporous nanocrystals are comprised of pure silica, alumino-silicate, and metal-organic frameworks giving rise to a wide array of surface chemistries, interfacial properties and dissolution, sorption-desorption, and catalytic potentials. Mesoporous silica nanoparticles synthesized with varied primary particle and pore sizes are also being studied. All nanomaterials will be further derivatized (after synthesis) to probe suspending media interactions, resulting interfacial properties, and nano-bio/geo interactions arising from (surface and bulk) chemical functionalities of biological and geological relevance.
It is likely that certain nanomaterials not on the list may become increasingly relevant over time and that certain nanomaterials currently on the list may have (over time) diminished practical relevance. With this in mind, the Nanotox TSRTP will consider revising the list of manufactured nanomaterials, as the need arises. In addition, some manufactured nanomaterials listed have variations that should be further considered. Also, the order in which the nanomaterials are listed does not indicate a priority.
Table 1. Preliminary nominations for nanomaterial combinatorial library
Base nanomaterial library
Carbonaceous materials
- Fullerene, graphene, and single/multi-walled CNT nanotubes, nanoribbons, nanofibers, and nanoparticles
- Manufactured carbon black nanoparticles and polystyrene nano-sphere standards
Metallic materials
- Noble metal (Au, Ag, Pt, Pd) and rare earth element (Ce, Nd, Sm, Eu, Yb) nanoparticles and nanwires
- Alloy (CdSe, PdPt, AuPd) and oxide (FexOyOHz, TiO2, SiO2, AlO3, ZnO, CeO) nanoparticles and nanorods
Nanostructured materials
- Dendrimers, dendrimer-metal complexes, and degradable polymer frameworks
- Zeolite (pure silica and alumino-silicate) and metal-organic (ZIFs, COPs) frameworks
- Inorganic-organic nanocomposite films (zeolite/metal/oxide/carbon-polymer mixed matrices)
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Nanomaterial derivatizations
Internal (bulk) compounds
- Sorbed gases of biological and geological relevance (e.g., CO2, N2, H2, O2)
- Doped metals in crystal frameworks (e.g., catalytic noble metals and alloys)
- Sorbed metals of biological and geological relevance (e.g., Cr6+, Cd2+, Ca2+, Na+, K+)
- Sorbed drug molecules (e.g., cancer agents, antibiotics, hormones)
External (surface) functionalities
- Type of linkage to NM (covalent, adsorbed, complexed, bioconjugatation)
- Structure of organic tether (aliphatic, alcohols, esters, ethers, aromatic, paraffinic, mixed)
- Terminal functional groups (amine, carboxyl, hydroxyl, thiol, phosphate, isocyanate)
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Fig.1. Combinatorial library of base and derivatzied NMs proposed for study within the Nanotox TSRTP.
Physical-chemical characterization studies
The Nanotox TSRTP will synthesize NMs for study, but all base NMs selected already have commercial analogs. Therefore, as part of the reference NM combinatorial library and online database we attempt to acquire the following NM identification parameters from MSDS sheets provided by commercial suppliers of the base NMs to be studied: nanomaterial name, CAS number, structural formula/molecular structure, composition of nanomaterial being tested (including degree of purity, known impurities or additives), basic morphology (e.g., spherical, aggregate, nanotube), description of surface chemistry (e.g., coating or modification), major commercial uses, known catalytic activity and electronic/photonic conductivity, plus method of production (e.g., precipitation, gas-phase, sol-gel).
Intrinsic NM morphological and structural properties to be characterized include: particle size (primary, aggregate); shape (aspect ratio, surface curvature, roughness); surface charge (density, ionization fraction, apparent pKa/pKb); pore structure (size distribution, surface area, crystallinity); chemical composition, especially impurities and coatings (bonding type, strength, chemical functionality); and electronic/phonic properties. Material properties will be evaluated using standard microscopic (SEM/TEM) and spectroscopic (FTIR/XPS/EDX) methods, gas sorption/desorption (BET), X-ray diffraction/scattering, and direct solution/surface titrations according to previously published methods. See Table 2 for characterization methods.
In addition, materials immersed in aqueous electrolytes also acquire charge through protonation, ion exchange, or specific adsorption. Acquired interfacial properties of nominated NMs and environmental materials (soil media, organics, colloids, microbes, and higher organisms) will be characterized systematically using multi-angle dynamic/static light scattering and differential mobility analyses (air/water mobility), contact angle titrations and tensiometry (interfacial tension, electron-donor/acceptor functionality), electro-kinetic (electrophoretic mobility, amphoteric behavior) and AFM (intermolecular force) measurements. Key interfacial forces between materials in aqueous media include van der Waals (nonpolar) and Lewis acid-base (polar) interactions.
Physical-chemical reactivity due to environmental stimuli (changes in redox, pH, ionic, and UV conditions) will be characterized using solution phase and interfacial studies, where NMs will be subjected to various environmental media and stimuli. In solution, ions will be measured using ICP-MS/AES, AA, UV spectroscopy, and other standard techniques; in addition, extra-cellular proteins will be screened for their enzymatic activity. Interfacial phenomena will be measured using an electrochemical quartz crystal microbalance (eQCM), which allows kinetic analysis of sub-nanogram levels at up to 100 measurements per second.
Table 2. Physical-chemical NM properties and associated analytical techniques
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Nanomaterial property
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Analytical techniques
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| Class 1: Morphology and structure
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Absolute particle size, shape, and size distribution
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TEM, SEM, AFM
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Aggregate size and fractal structure
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TEM, SAXS, SANS, DLS
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Pore size, porosity, and surface area
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BET, SAXS, SANS
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Crystallinity, framework structure, and crystal size
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XRD, Raman, SAXS, NMR
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Chemical composition
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Raman, NMR, EDAX, FTIR, XPS
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Elemental speciation
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Raman, XAS, NMR
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Elemental redox state
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SAXS, Mossbauer
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| Class 2: Interfacial properties
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Dispersed size and size distribution
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DLS, EMPS, AMPS, laser diffraction
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"Dustiness" or tendancy to aerosolize
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EMPS, AMPS
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Charge density, pKa, PZC, ionization fraction
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Direct titration in various suspending media
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Surface (zeta) potential and IEP
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EPM measurements in various suspending media
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Surface tension components (LW, y +, y-)
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Multiple probe liquid contact angle/tensiometry
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Roughness and chemical heterogeneity
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AFM, FTIR, XPS, NMR
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Class 3: Physical-chemical reactivity
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Water solubility
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Aqueous dissolution studies (varied pH, ORP, etc.)
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Hydrophobic partitioning
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Octanol-water partition coefficient, ATH
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Aggregation tendency and kinetics
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DLS, electroacoustic techniques, laser diffraction
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Deposition and adsorption kinetics
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QCM, DLS/EPM, DPI
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Photocatalytic activity
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UV absorption
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Acidity and redox potential
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pH, ORP, COD
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ROS generation
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ESR, spectrophotometric, DO
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Other relevant information (where available)
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Note: Techniques in bold indicate instrumentation that is currently available within Nanotx program facilities.
Legend: TEM = transmission electron microscopy; SEM = scanning electron microscopy; AFM = atomic force microscopy; SAXS = small angle X-ray scattering, SANS = small angle neutron scattering, BET = surface area and porosimetry; XRD = X-ray diffraction; NMR = nuclear magnetic resonance spectroscopy; EMPS = electrical mobility particle sizer; AMPS = aerodynamic mobility particle sizer; DLS = dynamic light scattering; EDAX = energy dispersive analysis of X-rays; FTIR = Fourier transform infrared spectroscopy; XPS = X-ray photoelectron spectroscopy; XAS = X-ray absorption spectroscopy; EPM = electro-phoretic mobility; QCM = quartz crystal microbalance; DPI = dual polarization interferometry; ORP = oxidation reduction potential; COD = chemical oxygen demand; ESR = electron spin resonance; DO = dissolved oxygen.
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| Key Scientific Questions to be addressed in the process of nomination, synthesis and characterization of nanoparticles |
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Key scientific question 1: How do systematic alterations to NM morphology influence environmental transport, fate, and toxicity? High-throughput synthesis methods are being developed for optimally preparing and characterizing metal and carbon based combinatorial libraries of nanoparticles, nanotubes, and nanowires with controlled size, shape, aspect ratio, connectivity, and topology. For example, the Lawrence Berekely National Laboratory's Molecular Foundry has already developed processes for synthesis of various nanoparticle morphologies including nanorods, tetrapods, and binary nanoparticle superlattices. They also have developed novel coatings for nanoparticles to control their interactions with environmental systems. Nanotox program researchers hope to extend existing synthetic approaches to create a combinatorial library of fullerene based materials ranging in aspect ratio from virtually spherical C-60 and metal NPs to high-aspect ratio carbon nanotubes and metal nanowires. In addition, the team will explore various combinations of CNTs with nanobuds, graphene nano-sheets, and carbon black NPs in rigorously controlled size-ranges.
Key scientific question 2: How do systematic alterations to NM pore structure, pore contents, and surface chemistry influence transport, fate, and toxicity? Mesoporous (~2-50 nm pores) and microporous (~0.2-2 nm pores) materials - collectively "nano-structured materials" - are being considered for use in catalysis, gas storage, CO2 sequestration, gas and liquid separations, and drug delivery applications. There is high probability that these materials will enter the environment or interact with environmental media in as-synthesized or modified forms (i.e., containing gases, chemicals, or catalysts). Recently, UCLA Chemistry Professor Omar Yaghi (and co-workers) established high-throughput synthesis of ZIFs and for evaluating CO2 sequestrationi. The Nanotox TSRTP team will extend these HTS methods for creation of microporous zeolite crystals comprised of pure silica, alumino-silicate, and metal organic frameworks (MOPs, ZIFs, and COFs), in addition to mesoporous silica nanoparticles (MSNs) as-synthesized and surface functionalized. Moreover, nanostructured materials will be prepared in pure form, doped with gases (O2, N2, and CO2), noble metals (Pt, Pd, Au, Ag), biologically relevant ions (Na+, K+, Ca2+, Cd2+, Ag+), biologically relevant molecules (drugs, nucleic acids, NOM molecules), and surface modified (internally and/or externally) with chemical functionalities indicated in Table 1.
Key scientific question 3: How do systematic alterations to NM surface chemical functionality influence transport, fate, and toxicity? Libraries of surface-functionalized nanoparticles based on the chemical schemes illustrated in Table 1. The surface hydroxyl groups of certain nanoparticles (titania, ceria, zinc, iron, and silica based oxides) can be functionalized with silane coupling agents containing various Y groups.ii The surface of noble metal and quantum dot nanoparticles can be coated with alkanethiols containing various Y groups.iii The surface functional group Y can in turn react with the target group Z using the listed crosslinker or catalyst and following the necessary reaction condition (Table 1). Any small molecules (alkanes, aromatic rings, charged groups) or large molecules (proteins, nucleotides) that contain the target group Z will then be covalently bonded to the surface of the nanoparticles. This will allow us to systematically synthesize large libraries of surface-functionalized particles for probing the influence of surface chemistry on environmental transport, fate, and toxicity for reference NMs with different morphologies and physical-chemical reactivities.
i R. Banerjee, A. Phan, B. Wang, C. Knobler, H. Furukawa, M. O'Keeffe, O. M. Yaghi, High-Throughput Synthesis of Zeolitic Imidazolate Frameworks and Application to CO2. Science, 2008, 319, 939-943.
iiStein, A.; Melde, B. J.; Schroden, R. C. Hybrid Inorganic-Organic Mesoporous Silicates - Nanoscopic Reactors Coming of Age. Adv. Mater. 2000, 12, 1403-1419; Wang, L.; Zhao, W.; O'Donoghue, M. B.; Tan, W. Fluorescent Nanoparticles for Multiplexed Bacteria Monitoring. Bioconjugate Chem. 2007, 18, 297-301; Torney, F.; Trewyn, B. G.; Lin, V. S.-Y.; Wang, K. Mesoporous Silica Nanoparticles Deliver DNA and Chemicals into Plants. Nat. Nanotech. 2007, 2, 295-300; Slowing, I.; Trewyn, B. G.; Lin, V. S.-Y. Effect of Surface Functionalization of MCM-41-Type Mesoporous Silica Nanoparticles on the Endocytosis by Human Cancer Cells. J. Am. Chem. Soc. 2006, 128, 14792-14793; Santra, S.; Yang, H.; Dutta, D.; Stanley, J. T.; Holloway, P. H.; Tan, W.; Moudgil, B. M.; Mericle, R. A. TAT Conjugated, FITC Doped Silica Nanoparticles for Bioimaging Applications. Chem. Commun. 2004, 2810-2811.
iiiHong, R.; Han, G.; Fernandez, J. M.; Kim, B. j.; Forbes, N. S.; Rotello, V. M. Glutathione-Mediated Delivery and Release Using Monolayer Protected Nanoparticle Carriers. J. Am. Chem. Soc. 2006, 128, 1078-1079; Hiramatsu, H.; Osterloh, F. E. A Simple Large-Scale Synthesis of Nearly Monodisperse Gold and Silver Nanoparticles with Adjustable Sizes and with Exchangeable Surfactants. Chem. Mater. 2004, 16, 2509-2511; Bakalova, R.; Ohba, H.; Zhelev, Z.; Nagase, T.; Jose, R.; Ishikawa, M.; Baba, Y. Quantum Dot anti-CD Conjugates: Are They Potential Photosensitizers or Potentiators of Classical Photosensitizing Agents in Photodynamic Therapy of Cancer? Nano Lett. 2004, 4, 1567-1573; Chan, W. C. W.; Nie, S. Quantum Dot Bioconjugates for Ultrasensitive Nonisotopic Detection. Science 1998, 281, 2016-2018 ; Liu, W.; Choi, H. S.; Zimmer, J. P.; Tanaka, E.; Frangioni, J. V.; Bawendi, M. Compact Cysteine-Coated CdSe(ZnCdS) Quantum Dots for in Vivo Applications. J. Am. Chem. Soc. 2007, 129, 14530-14531; Liu, W.; Howarth, M.; Greytak, A. B.; Zheng, Y.; Nocera, D. G.; Ting, A. Y.; Bawendi, M. G. Compact Biocompatible Quantum Dots Functionalized for Cellular Imaging. J. Am. Chem. Soc. 2008, 130, 1274-1284
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