Reduction of pulmonary toxicity of metal oxide nanoparticles by phosphonate-based surface passivation

Abstract

BackgroundThe wide application of engineered nanoparticles has induced increasing exposure to humans and environment, which led to substantial concerns on their biosafety. Some metal oxides (MOx) have shown severe toxicity in cells and animals, thus safe designs of MOx with reduced hazard potential are desired. Currently, there is a lack of a simple yet effective safe design approach for the toxic MOx. In this study, we determined the key physicochemical properties of MOx that lead to cytotoxicity and explored a safe design approach for toxic MOx by modifying their hazard properties.ResultsTHP-1 and BEAS-2B cells were exposed to 0–200 μg/mL MOx for 24 h, we found some toxic MOx including CoO, CuO, Ni2O3 and Co3O4, could induce reactive oxygen species (ROS) generation and cell death due to the toxic ion shedding and/or oxidative stress generation from the active surface of MOx internalized into lysosomes. We thus hypothesized that surface passivation could reduce or eliminate the toxicity of MOx. We experimented with a series of surface coating molecules and discovered that ethylenediamine tetra (methylene phosphonic acid) (EDTMP) could form stable hexadentate coordination with MOx. The coating layer can effectively reduce the surface activity of MOx with 85-99% decrease of oxidative potential, and 65-98% decrease of ion shedding. The EDTMP coated MOx show negligible ROS generation and cell death in THP-1 and BEAS-2B cells. The protective effect of EDTMP coating was further validated in mouse lungs exposed to 2 mg/kg MOx by oropharyngeal aspiration. After 40 h exposure, EDTMP coated MOx show significant decreases of neutrophil counts, lactate dehydrogenase (LDH) release, MCP-1, LIX and IL-6 in bronchoalveolar lavage fluid (BALF), compared to uncoated particles. The haematoxylin and eosin (H&E) staining results of lung tissue also show EDTMP coating could significantly reduce the pulmonary inflammation of MOx.ConclusionsThe surface reactivity of MOx including ion shedding and oxidative potential is the dominated physicochemical property that is responsible for the cytotoxicity induced by MOx. EDTMP coating could passivate the surface of MOx, reduce their cytotoxicity and pulmonary hazard effects. This coating would be an effective safe design approach for a broad spectrum of toxic MOx, which will facilitate the safe use of MOx in commercial nanoproducts.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-017-0193-5) contains supplementary material, which is available to authorized users.

Multi-hierarchical Profiling the Structure-Activity Relationships of Engineered Nanomaterials at Nano-Bio Interfaces

“…The DCF assay is based on a mechanism that nonfluorescent 2’,7’-dichlorodihydrofluorescein (H 2 DCF) could be converted to the highly fluorescent DCF by oxidation. This assay has been widely used to access the radicals or abiotic reactive oxygen species (ROS) generation on nanoparticle surface 6, 8 . Co 3 O 4 nanoparticles have been demonstrated to exhibit high surface reactivity in DCF assay and were used as a positive control 26 .…”

“…Our study successfully achieved tiered view of the nano-SARs of Fe 2 O 3 particles in THP-1 cells, providing substantial new insights for tailored design of ENMs by modifying their physicochemical properties to acquire desired bio-effects. This allows us to reduce the toxicities of some hazardous ENMs 7, 8, 28 , or enhance the effects of nanomedicine 5, 6, 39 . Besides of Fe 2 O 3 , the multi-hierarchical nano-SAR assessment method could be potentially extended to other ENMs.…”

“…These conditions were approved by the Chancellor’s Animal Research Committee at Soochow University and include standard operating procedures for animal housing (filter-topped cages; room temperature at 23 ± 2 °C; 60% relative humidity; 12 h light, 12 h dark cycle) and hygiene status (autoclaved food and acidified water). Animals were exposed by oropharyngeal aspiration as described by us 8 . Briefly, animals were anesthetized by intraperitoneal injection of ketamine (100 mg/kg)/xylazine (10 mg/kg) in a total volume of 100 μL.…”

“…2 , the in vitro structure-activity relationship (SAR) studies on ENMs have significantly promoted the development of nanobiotechnology 3-5 . In general, nano-SAR analyses have enabled the determination of the key physicochemical properties of ENMs that are responsible for evoking a target bio-effect in the organism 1, 6 , allowed bio-hazard ranking of various new ENMs 7 , and facilitated the engineering design of biocompatible materials by tailored functionalization 8 . However, current nano-SAR analyses only focus on the influence of a single property (size, charge, or surface charge, etc. )…”

Health concerns of various nanoparticles: A review of their in vitro and in vivo toxicity

“…Like metal NPs, the most important damage of TCL-SPION is inflammation [199]. Examples of these NPs are ZnO and CuO which have a damaging effect on the immune system in the lung tissue by increasing IL-1β; they also increase cytokines expression because they change pH in the tissue [200,201]. Other studies have reported the toxic effect of CeO2 and NiO NPs on lung tissue to be the expression of TNF-α in the lung cell-line [202].…”