Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis

The study of ordered mesoporous silica materials has exploded since their discovery by Mobil researchers 20 years ago. The ability to make uniformly sized, porous, and dispersible nanoparticles using colloidal chemistry and evaporation-induced self-assembly has led to many applications of mesoporous silica nanoparticles (MSNPs) as "nanocarriers" for delivery of drugs and other cargos to cells. The exceptionally high surface area of MSNPs, often exceeding 1000 m²/g, and the ability to independently modify pore size and surface chemistry, enables the loading of diverse cargos and cargo combinations at levels exceeding those of other common drug delivery carriers such as liposomes or polymer conjugates. This is because noncovalent electrostatic, hydrogen-bonding, and van der Waals interactions of the cargo with the MSNP internal surface cause preferential adsorption of cargo to the MSNP, allowing loading capacities to surpass the solubility limit of a solution or that achievable by osmotic gradient loading. The ability to independently modify the MSNP surface and interior makes possible engineered biofunctionality and biocompatibility. In this Account, we detail our recent efforts to develop MSNPs as biocompatible nanocarriers (Figure 1 ) that simultaneously display multiple functions including (1) high visibility/contrast in multiple imaging modalities, (2) dispersibility, (3) binding specificity to a particular target tissue or cell type, (4) ability to load and deliver large concentrations of diverse cargos, and (5) triggered or controlled release of cargo. Toward function 1, we chemically conjugated fluorescent dyes or incorporated magnetic nanoparticles to enable in vivo optical or magnetic resonance imaging. For function 2, we have made MSNPs with polymer coatings, charged groups, or supported lipid bilayers, which decrease aggregation and improve stability in saline solutions. For functions 3 and 4, we have enhanced passive bioaccumulation via the enhanced permeability and retention effect by modifying the MSNP surfaces with positively charged polymers. We have also chemically attached ligands to MSNPs that selectively bind to receptors overexpressed in cancer cells. We have used encapsulation of MSNPs within reconfigurable supported lipid bilayers to develop new classes of responsive nanocarriers that actively interact with the target cell. Toward function 4, we exploit the high surface area and tailorable surface chemistry of MSNPs to retain hydrophobic drugs. Finally, for function 5, we have engineered dynamic behaviors by incorporating molecular machines within or at the entrances of MSNP pores and by using ligands, polymers, or lipid bilayers. These provide a means to seal-in and retain cargo and to direct MSNP interactions with and internalization by target cells. Application of MSNPs as nanocarriers requires biocompatibility and low toxicity. Here the intrinsic porosity of the MSNP surface reduces the extent of hydrogen bonding or electrostatic interactions with cell membranes as does surface coating with polymers or lipid bilayers. Furthermore, the high surface area and low extent of condensation of the MSNP siloxane framework promote a high rate of dissolution into soluble silicic acid species, which are found to be nontoxic. Potential toxicity is further mitigated by the high drug capacity of MSNPs, which greatly reduces needed dosages compared with other nanocarriers. We anticipate that future generations of MSNPs incorporating molecular machines and encapsulated by membrane-like lipid bilayers will achieve a new level of controlled cellular interactions.

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Mesoporous Silica Nanoparticle Nanocarriers: Biofunctionality and Biocompatibility

Asbestos is a commercial term for a group of fibrous minerals often associated with the development of pulmonary interstitial fibrosis (asbestosis), lung cancer, and malignant mesothelioma in occupationally exposed individuals. The pathogenicity of different forms of asbestos varies--long, thin amphibole fibers are most pathogenic, particularly in the induction of mesothelioma. Available data do not support the concept that low-level exposure to asbestos is a health hazard in buildings and schools. The concentration of asbestos fibers in air, type of asbestos, and size of fibers must be considered in evaluation of potential health risks.

https://science.sciencemag.org/content/sci/247/4940/294.full.pdf

Asbestos: scientific developments and implications for public policy.

Silica nanoparticles (SNPs) are produced on an industrial scale and are an addition to a growing number of commercial products. SNPs also have great potential for a variety of diagnostic and therapeutic applications in medicine. Contrary to the well-studied crystalline micron-sized silica, relatively little information exists on the toxicity of its amorphous and nano-size forms. Because nanoparticles possess novel properties, kinetics and unusual bioactivity, their potential biological effects may differ greatly from those of micron-size bulk materials. In this review, we summarize the physico-chemical properties of the different nano-sized silica materials that can affect their interaction with biological systems, with a specific emphasis on inhalation exposure. We discuss recent in vitro and in vivo investigations into the toxicity of nanosilica, both crystalline and amorphous. Most of the in vitro studies of SNPs report results of cellular uptake, size- and dose-dependent cytotoxicity, increased reactive oxygen species levels and pro-inflammatory stimulation. Evidence from a limited number of in vivo studies demonstrates largely reversible lung inflammation, granuloma formation and focal emphysema, with no progressive lung fibrosis. Clearly, more research with standardized materials is needed to enable comparison of experimental data for the different forms of nanosilicas and to establish which physico-chemical properties are responsible for the observed toxicity of SNPs.

/pdf/the-nanosilica-hazard-another-variable-entity-20k22g6ml1.pdf

The nanosilica hazard: another variable entity

Phyllosilicates, and among them clay minerals, are of great interest not only for the scientific community but also for their potential applications in many novel and advanced areas. However, the correct application of these minerals requires a thorough knowledge of their crystal chemical properties. This chapter provides crystal chemical and structural details related to phyllosilicates and describes the fundamental features leading to their different behaviour in different natural or technical processes, as also detailed in other chapters of this book. Phyllosilicates, described in this chapter, are minerals of the (i) kaolin-serpentine group (e.g. kaolinite, dickite, nacrite, halloysite, hisingerite, lizardite, antigorite, chrysotile, amesite, carlosturanite, greenalite); (ii) talc and pyrophyllite group (e.g. pyrophyllite, ferripyrophyllite); (iii) mica group, with particular focus to illite; (iv) smectite group (e.g. montmorillonite, beidellite, nontronite, saponite, hectorite, sauconite); (v) vermiculite group; (vi) chlorite group; (vii) some 2:1 layer silicates involving a discontinuous octahedral sheet and a modulated tetrahedral sheet such as kalifersite, palygorskite and sepiolite; (viii) allophane and imogolite and (ix) mixed layer structures with particular focus on illite-smectite.

Structure and Mineralogy of Clay Minerals

Formation of hydroxyl radicals, in relatively large quantities, by oxygen reduction due to the surface activity of asbestos in a cell-free system is demonstrated, using electron spin resonance and a spin trapping agent. The quantity of OH• produced (in general, above 1014 mg−1 for a Canadian chrysotile) is a function of activation or passivation of the electron donor surface sites of the minerals. The role of these radicals in oxidative stress in relation to the toxic properties of these minerals is discussed.

Formation of oxy radicals by oxygen reduction arising from the surface activity of asbestos

Nine synthetic Na-saponites with charge densities varying between 0.33 and 1.0 have been prepared. Their swelling properties and structural organization in water, ethylene glycol and glycerol show discontinuities in the physico-chemical behaviour of these samples. The layer charge densities caused changes in swelling properties and structural organization of the minerals. These changes also depended upon the nature of the solvation liquid and the interlayer cation involved. Electron diffraction patterns of the Ba-saponites showed no abnormal diffusion making honeycomb- like patterns between Bragg reflections. The results indicate criteria for estimating the layer charge of tetrahedrally substituted trioctahedral 2/1 phyllosilicates. There is no upper limit until x = 1 for the layer charge x which is specific to the smectite-group. Consequentb,, the changes in the swelling properties observed when x = 0.5-0.6 and x = 0.8-0.9 come from the modifications of the interlayer structure, which are mainly a function of cation-liquid and silicate layer-liquid interactions. Consequently, there is an overlap between the saponite and the vermi- culite mineral groups.

Synthesis and swelling properties of saponites with increasing layer charge

Cytotoxic and transforming effects of silica particles with different surface properties in Syrian hamster embryo (SHE) cells

Saponites and vermiculites may assume at least 11 ordered or semi-ordered layer stacking sequences. For a given relative humidity, the layer stacking type assumed is a function of the nature of the interlayer cation, the layer charge density, the mean size of the particles, and the di- or trioctahedral character of the sheets. For each interlayer cation, a succession of layer stacking types can be observed as relative humidity increases. For high relative humidity, some particular layer stacking types exist, but only for low-charge minerals. No other differences have been found for saponites and vermiculites in each successive layer stacking type. The degree of order that these layer stacking types imply is probably due to the existence of electrostatic bonds between hydrated interlayer cations and surface oxygens of the substituted tetrahedra. For octahedrally substituted 2:1 phyllosilicates, however, the disorder of the layer stacking sequences is related to a highly delocalized distribution of negative charges on the surface oxygens of the layers. A study of the superstructures detected in saponites and vermiculites indicates that the interlayer cations tend to be located as far as possible from one another. The superstructures exist only with some cations and some layer stacking types and if the layer charge density is compatible with the charge produced by the cation distribution in this kind of superstructure.

Parameters influencing layer stacking types in saponite and vermiculite: a review

According to certain hypotheses, the production of oxygen radicals within the biological medium (the phenomenon of oxidative stress) may play an important role in fibrosis and in certain steps of carcinogenesis. The mineral fibres of various materials are capable of participating in this phenomenon, owing to the reducing nature of their surface activity, so that OH. radicals can be produced from oxygen in 3 steps. The surface activity of inorganic materials which are insoluble or only very slightly soluble is due to the presence of electron donor active sites, generally linked to Fe2+ ions found in the neighbourhood of the surface. In biological systems, these sites may emerge on the surface as a result of the partial dissolution of the particle, the action of a biological reducing agent, the phenomenon of deposition on the surfaces or cation exchange. We have explored the reducing properties of the surfaces of a certain number of mineral fibres, in aqueous buffer medium, by electron paramagnetic resonance (EPR) measurement of the adduct with the radical-trapping agent 5,5'-dimethyl-l-pyrrolidine-N-oxide (DMPO), produced from the radicals initially formed (OH. or R.). We have found certain fibres to be highly effective in producing radicals from dissolved oxygen (Canadian chrysotile, nemalite, freshly ground amphiboles) while others have little effect. The reducing activity of certain fibres may be markedly increased by prior treatment in the presence of a ferrous salt (as in the case of erionite) or by the addition of glutathione to the reaction medium (as in the case of UICC crocidolite). It is suggested that the carcinogenic activity of certain inorganic materials at the pulmonary level is the result of their surface reducing properties. These reducing properties may either be present at the time of inhalation or acquired in the biological medium. This hypothesis is not in conflict with the observation of the role of the dimensional characteristics of fibres in mesothelioma.

Henri Pezerat

Papers

Formation of oxy radicals by oxygen reduction arising from the surface activity of asbestos

Synthesis and swelling properties of saponites with increasing layer charge

Cytotoxic and transforming effects of silica particles with different surface properties in Syrian hamster embryo (SHE) cells

Parameters influencing layer stacking types in saponite and vermiculite: a review

Production of oxygen radicals by the reduction of oxygen arising from the surface activity of mineral fibres.