Application of titanium dioxide (TiO2) nanoparticles in cancer therapies

Abstract

Cancer is one of the most common diseases all over the world; many people suffer from diverse types of cancer. However, currently there is no exact cure or therapy developed for cancer. On the other hand, nanoparticles are defined as microscopic particles that have dimensions less than 100?nm and they are known for their usage in health sciences and medicine, however a few harmful effects on different animal cells. Therefore, researchers began to use nanoparticles for cancer therapies and to develop new methods for much more effective therapies. Nanoparticles in cancer studies are commonly used in photodynamic therapy (PDT) and sonodynamic therapy (SDT) as a sensitising agent, in computed tomography imaging (CT) and radiation therapy as an enhancement agent, in dual-mode image contrast and enhancement therapy as an image contrast agent. Titanium dioxide nanoparticles (TiO₂ NPs) are known as commonly used nanoparticles in medical applications and hence in cancer studies. They are used in PDT, SDT and drug delivery systems. As cancer continues to affect people, new therapeutics and therapies will be developed and nanotechnology for this aim will be an important approach for the researchers.     

Tissue distribution and clearance of intravenously administered titanium dioxide (TiO2) nanoparticles

The organ-tissue distribution and clearance of Degussa P25 TiO₂ nanoparticles were determined after intravenous administration to rats (0.95 mg/kg bodyweight) using an inductively coupled plasma sector field mass spectrometer. The detection limits of Ti analysis, 0.54 and 1.4 ng/mL for blood and urine and 0.35–2.0 ng/g tissue for several organ tissues, enabled determination of tissue distribution and clearance for organs in which Ti content could not be previously determined due to low concentrations. Blood concentrations of TiO₂ were 420 and 19 ng/mL at 5 and 15 min after administration, which were equivalent of only 2.8% and 0.13% of the administration dose, respectively. At 6 h, 94%, 2.0%, 0.17%, 0.023%, 0.014% and 0.026% of administered TiO₂ was found in the liver, spleen, lung, kidney, heart and blood, respectively. Liver and spleen TiO₂ burden was significantly higher in the administration than control group (p < 0.01) and did not decrease up to 30 days after administration, while TiO₂ burden in the lung, kidney, heart and blood decreased over time. A two-step decay model was more suitable than a one-step decay model for the decay curves of pulmonary TiO₂ burden but did not improve fitting to the decay curves of kidney TiO₂ burden. No translocation to the brain was confirmed at a lower detection limit than was applied in previous studies. Ti content in faeces and urine in the TiO₂ administration group did not differ from that in the control group.     

Size influences the cytotoxicity of poly (lactic-co-glycolic acid) (PLGA) and titanium dioxide (TiO2) nanoparticles

The aim of this study is to uncover the size influence of poly (lactic-co-glycolic acid) (PLGA) and titanium dioxide (TiO₂) nanoparticles on their potential cytotoxicity. PLGA and TiO₂ nanoparticles of three different sizes were thoroughly characterized before in vitro cytotoxic tests which included viability, generation of reactive oxygen species (ROS), mitochondrial depolarization, integrity of plasma membrane, intracellular calcium influx and cytokine release. Size-dependent cytotoxic effect was observed in both RAW264.7 cells and BEAS-2B cells after cells were incubated with PLGA or TiO₂ nanoparticles for 24 h. Although PLGA nanoparticles did not trigger significantly lethal toxicity up to a concentration of 300 μg/ml, the TNF-α release after the stimulation of PLGA nanoparticles should not be ignored especially in clinical applications. Relatively more toxic TiO₂ nanoparticles triggered cell death, ROS generation, mitochondrial depolarization, plasma membrane damage, intracellular calcium concentration increase and size-dependent TNF-α release, especially at a concentration higher than 100 μg/ml. These cytotoxic effects could be due to the size-dependent interaction between nanoparticles and biomolecules, as smaller particles tend to adsorb more biomolecules. In summary, we demonstrated that the ability of protein adsorption could be an important paradigm to predict the in vitro cytotoxicity of nanoparticles, especially for low toxic nanomaterials such as PLGA and TiO₂ nanoparticles.     

Genotoxic and cytotoxic potential of titanium dioxide (TiO2) nanoparticles on fish cells in vitro

Intrinsic genotoxic and cytotoxic potential of titanium dioxide (TiO2) engineered nanoparticles (ENPs) were evaluated in a metabolically competent, established fish cell line derived from rainbow trout (Oncorhyncus mykiss) gonadal tissue (i.e. RTG-2 cells). Prior to evaluation of the toxic potential, mean size of the ENPs was determined using transmission electron microscopy (TEM). As a prerequisite, an extensive characterisation of the ENPs was carried out following sonication which enabled the synthesis of an efficient dosing strategy for the cells in which exposure in phosphate buffered saline (PBS) gave an optimal agglomeration effects compared to distilled water (H2O) and minimal essential media (MEM). Interaction of the ENPs with cells under scanning electron microscope (SEM) was also studied. The genotoxic and cytotoxic potential of the ENPs were determined either alone or in combination with ultraviolet radiation (i.e. UVA). Whilst genotoxic potential was determined by evaluating DNA strand breaks using single cell gel electrophoresis (SCGE) or the comet assay and induction of cytogenetic damage using cytokinesis-blocked micronucleus (MN) assay, cytotoxicity was determined by measuring the retention of supra vital stain, neutral red, by the lysosomes using the neutral red retention (NRR) assay. In addition, while performing the comet assay, lesion specific bacterial endonuclease, formamidopyrimidine DNA glycosylase (Fpg), which recognises oxidised purine bases, was used to determine oxidative DNA damage. The results suggested that the highest concentration of the ENPs (i.e. 50 microg ml(-1)) did not produce elevations in DNA damage over 4 h (comet assay), 24 h (modified comet assay) or 48 h (MN assay) exposures in the absence of UVA irradiation, although there was a significant reduction in lysosomal integrity over 24 h exposure (NRR assay). The induction of MN did not show any enhanced levels as a function of ENP concentration. A significantly increased level of strand breaks was observed in combination with UVA (3 kJ m(-2)). In general, the NRR assay suggested elevated levels of cytotoxicity when the UVA exposure was carried out with MEM compared to PBS, although both showed an increase when in combination with the highest concentration of ENPs (i.e. 50 microg ml(-1)). Overall, the study emphasises the need for adoption of an holistic approach while evaluating the potential toxic effects of ENPs in which appropriate measures should be taken to avoid agglomeration or aggregation to facilitate efficient cellular uptake to evaluate potential biological responses.     

Using physiologically based pharmacokinetic (PBPK) modeling for dietary risk assessment of titanium dioxide (TiO2) nanoparticles

Abstract

Nano-sized titanium dioxide particles (nano-TiO₂) can be found in a large number of foods and consumer products, such as cosmetics and toothpaste, thus, consumer exposure occurs via multiple sources, possibly involving different exposure routes. In order to determine the disposition of nano-TiO₂ particles that are taken up, a physiologically based pharmacokinetic (PBPK) model was developed. High priority was placed on limiting the number of parameters to match the number of underlying data points (hence to avoid overparameterization), but still reflecting available mechanistic information on the toxicokinetics of nano-TiO₂. To this end, the biodistribution of nano-TiO₂ was modeled based on their ability to cross the capillary wall of the organs and to be phagocytosed in the mononuclear phagocyte system (MPS). The model’s predictive power was evaluated by comparing simulated organ levels to experimentally assessed organ levels of independent in vivo studies. The results of our PBPK model indicate that: (1) within the application domain of the PBPK model from 15 to 150?nm, the size and crystalline structure of the particles had a minor influence on the biodistribution; and (2) at high internal exposure the particles agglomerate in vivo and are subsequently taken up by macrophages in the MPS. Furthermore, we also give an example on how the PBPK model may be used for risk assessment. For this purpose, the daily dietary intake of nano-TiO₂ was calculated for the German population. The PBPK model was then used to convert this chronic external exposure into internal titanium levels for each organ.     

Cytotoxic,genotoxic and the hemolytic effect of titanium dioxide (TiO2) nanoparticles on human erythrocyte and lymphocyte cells in vitro

With the increasing clinical use of titanium dioxide (TiO₂) nanoparticles, a better understanding of their safety in the blood stream is required. The present study evaluates the toxic effect of commercially available TiO₂ nanoparticles (~100 nm) using a battery of cytotoxic, genotoxic, hemolytic and morphological parameters. The cytotoxic effects of TiO₂ nanoparticles in human lymphocyte cells were studied with respect to membrane damage, mitochondrial function, metabolic activity and lysosomal membrane stability. Genotoxicity in lymphocyte cells was quantitated using a comet assay. The mode of cell death (apoptosis/necrosis) was evaluated using PI/Annexin V staining. TiO₂ nanoparticles were also evaluated for their hemolytic properties, osmotic fragility and interaction with hemoglobin. Human erythrocyte cells were studied for morphological alterations using atomic force microscopy (AFM). Results suggest that the particles could induce a significant reduction in mitochondrial dehydrogenase activity in human lymphocyte cells. Membrane integrity remained unaffected by nanoparticle treatment. DNA damage and apoptosis were induced by TiO₂ nanoparticles in a dose‐dependent manner. A study on human erythrocyte cells revealed a hemolytic property of TiO₂ nanoparticles characterized by spherocytosis and echinocytosis. Spectral analysis revealed a hemoglobin TiO₂ nanoparticle interaction. Our in vitro study results suggest that commercially available blood contacting nanoparticles (TiO₂ nanoparticle) should be carefully evaluated for their toxic potential. Copyright © 2013 John Wiley & Sons, Ltd.     

Beneficial effects of quercetin on oxidative stress in liver and kidney induced by titanium dioxide (TiO2) nanoparticles in rats

Abstract

TiO₂ nanoparticles used as vectors for the delivery of drugs have shown greater effectiveness. However, TiO₂ nanoparticles can cause oxidative stress in liver and kidney, so we analyzed if a previous or simultaneous quercetin treatment could counteract this in rats. Five groups of male Wistar rats (200–250?g) were included: (1) healthy controls, (2) TiO₂ group, (3) quercetin group, (4) preventive group: quercetin for 5 days prior to exposure of TiO₂, and (5) therapeutic group: TiO₂ (5?mg/kg, i.v.) plus quercetin single dose for 5 days (5?mg/kg/day, i.p.). Hepatic and renal function tests were made. Five animals from each group were sacrificed (0, 14 and 28 days), and liver and kidney tissue were obtained. Malondialdehyde (MDA), reduced/oxidized glutathione, and activity of glutathione peroxidase/reductase were measured, as well as the level of gene expression by q-PCR. There were no significant changes in serum ALT and AST activities. More damage was observed at 14 versus 28 days, because TiO₂ was excreted in urine. Quercetin indeed showed a renal protective effect by increasing glutathione reductase and peroxidase levels and reducing MDA levels. On the other hand, TiO₂ liver damage was less pronounced with quercetin as therapeutic treatment. TiO₂ induces significantly the glutathione reductase expression and it can be down-regulated by quercetin. Biochemical tests in serum and urine showed a better effect of quercetin administered in the therapeutic group. Care should be taken with the dose and time of administration of quercetin, because this antioxidant could also have a pro-oxidant effect.     

In vitro cytotoxicity and genotoxicity studies of titanium dioxide (TiO2) nanoparticles in Chinese hamster lung fibroblast cells

There are increasing safety concerns about the development and abundant use of nanoparticles. The unique physical and chemical characteristics of titanium dioxide (TiO₂) nanoparticles result in different chemical and biological activities compared to their larger micron-sized counterparts, and can subsequently play an important role in influencing toxicity. Therefore, our objective was to investigate the cytotoxicity and genotoxicity of commercially available TiO₂ nanoparticles with respect to their selected physicochemical properties, as well as the role of surface coating of these nanoparticles. While all types of tested TiO₂ samples decrease cell viability in a mass-based concentration- and size-dependent manner, the polyacrylate-coated nano-TiO₂ product was only cytotoxic at higher concentrations. A similar pattern of response was observed for induction of apoptosis/necrosis, and no DNA damage was detected in the polyacrylate-coated nano-TiO₂ model. Given the increasing production of TiO₂ nanoparticles, toxicological studies should take into account the physiochemical properties of these nanoparticles that may help researchers to develop new nanoparticles with minimum toxicity.     

Effects of titanium dioxide nanoparticles on human keratinocytes

Titanium dioxide (TiO₂) is a ubiquitous whitening compound widely used in topical products such as sunscreens, lotions and facial creams. The damaging health effects of TiO₂ inhalation has been widely studied in rats, mice and humans showing oxidative stress increase, DNA damage, cell death and inflammatory gene upregulation in lung and throat cells; however, the effects on skin cells from long-term topical use of various products remain largely unknown. In this study, we assessed the effect of specific TiO₂ nanoparticles (H₂TiO₇) on a human keratinocyte cell line (HaCaT). We performed a comparative analysis using three TiO₂ particles varying in size (Fine, Ultrafine and H₂TiO₇) and analyzed their effects on HaCaTs. There is a clear dose-dependent increase in superoxide production, caspase 8 and 9 activity, and apoptosis in HaCaTs after treatment with all three forms of TiO₂; however, there is no consistent effect on cell viability and proliferation with either of these TiO₂ particles. While there is data suggesting UV exposure can enhance the carcinogenic effects of TiO₂, we did not observe any significant effect of UV-C exposure combined with TiO₂ treatment on HaCaTs. Furthermore, TiO₂-treated cells showed minimal effects on VEGF upregulation and Wnt signaling pathway thereby showing no potential effect on angiogenesis and malignant transformation. Overall, we report here an increase in apoptosis, which may be caspase 8/Fas-dependent, and that the H₂TiO₇ nanoparticles, despite their smaller particle size, had no significant enhanced effect on HaCaT cells as compared to Fine and Ultrafine forms of TiO₂.     

Pulmonary response of rats exposed to titanium dioxide (TiO2) by inhalation for two years

Rats were exposed to TiO2 by inhalation exposure to concentrations of 0, 10, 50, and 250 mg/m3 for 6 hr/day, 5 days/week for 2 years. There were no abnormal clinical signs, body weight changes, or excess mortality in any exposed group. Exposed groups showed slight increases in the incidence of pneumonia, tracheitis, and rhinitis with squamous metaplasia in the anterior nasal cavity. The pulmonary response at 10 mg/m3 satisfied the biological criteria for a "nuisance dust." The lung reaction was characterized by dust-laden macrophage (dust cell) infiltration in the alveolar ducts and adjoining alveoli with hyperplasia of Type II pneumocytes. Rats at 50 and 250 mg/m3 exposure concentrations revealed a dose-dependent dust cell accumulation, a foamy macrophage response, Type II pneumocyte hyperplasia, alveolar proteinosis, alveolar bronchiolarization, cholesterol granulomas, focal pleurisy, and dust deposition in the tracheobronchial lymph nodes. Minute collagenized fibrosis occurred in the alveolar walls enclosing large dust cell aggregates. The pulmonary lesions with massive dust accumulation appeared to be the result of an overwhelmed lung clearance mechanism at 250 mg/m3 exposure. Bronchioloalveolar adenomas and cystic keratinizing squamous cell carcinomas occurred at 250 mg/m3 exposure, while no compound-related lung tumors were found in rats exposed to either 10 or 50 mg/m3. In addition to excessive dust loading in the lungs of rats exposed chronically at 250 mg/m3, the lung tumors were different from common human lung cancers in terms of tumor type, anatomic location, tumorigenesis, and were devoid of tumor metastasis. Therefore, the biological relevance of these lung tumors and other pulmonary lesions for man is negligible.     

ROS-mediated genotoxicity induced by titanium dioxide nanoparticles in human epidermal cells

Titanium dioxide nanoparticles (TiO₂ NPs) are among the top five NPs used in consumer products, paints and pharmaceutical preparations. Since, exposure to such nanoparticles is mainly through the skin and inhalation, the present study was conducted in the human epidermal cells (A431). A mild cytotoxic response of TiO₂ NPs was observed as evident by the MTT and NR uptake assays after 48 h of exposure. However, a statistically significant (p < 0.05) induction in the DNA damage was observed by the Fpg-modified Comet assay in cells exposed to 0.8 μg/ml TiO₂ NPs (2.20 ± 0.26 vs. control 1.24 ± 0.04) and higher concentrations for 6 h. A significant (p < 0.05) induction in micronucleus formation was also observed at the above concentration (14.67 ± 1.20 vs. control 9.33 ± 1.00). TiO₂ NPs elicited a significant (p < 0.05) reduction in glutathione (15.76%) with a concomitant increase in lipid hydroperoxide (60.51%; p < 0.05) and reactive oxygen species (ROS) generation (49.2%; p < 0.05) after 6 h exposure. Our data demonstrate that TiO₂ NPs have a mild cytotoxic potential. However, they induce ROS and oxidative stress leading to oxidative DNA damage and micronucleus formation, a probable mechanism of genotoxicity. This is perhaps the first study on human skin cells demonstrating the cytotoxic and genotoxic potential of TiO₂ NPs.     

Comprehensive assessment of nephrotoxicity of intravenously administered sodium-oleate-coated ultra-small superparamagnetic iron oxide (USPIO) and titanium dioxide (TiO2) nanoparticles in rats

As a main excretory organ, kidney is predisposed to direct/indirect injury. We addressed the potential nephrotoxic effects following expositions of healthy rats to nanoparticle (NP) loads relevant to humans in a situation of 100% bioavailability. Up to 4 weeks after administration, a single iv bolus of oleate-coated ultra-small superparamagnetic iron oxide NPs (in dose of 0.1%, 1.0% and 10.0% of LD50) or TiO₂ NPs (1.0% of LD50) did not elicit decline in renal function, damage to proximal tubules, alterations in: renal histology or expression of pro-inflammatory/pro-fibrotic genes, markers of systemic or local renal micro-inflammation or oxidative damage. Antioxidant enzyme activities in renal cortex, mildly elevated at 24 h, completely restored at later time points. Data obtained by multifaceted approach enable the prediction of human nephrotoxicity during preclinical studies, and may serve as comparison for alternative testing strategies using in vitro and in silico methods essential for the NP-nephrotoxicity risk assessment.     

Genotoxicity of titanium dioxide nanoparticles

Titanium dioxide nanoparticles (TiO₂-NPs, <100 nm) are increasingly being used in pharmaceuticals and cosmetics due to the unique properties derived from their small sizes. However, their large surface-area to mass ratio and high redox potential may negatively impact human health and the environment. TiO₂-NPs can cause inflammation, pulmonary damage, fibrosis, and lung tumors and they are possibly carcinogenic to humans. Because cancer is a disease involving mutation, there are a large number of studies on the genotoxicity of TiO₂-NPs. In this article, we review the results that have been reported in the literature, with a focus on data generated from the standard genotoxicity assays. The data include genotoxicity results from the Ames test, in vitro and in vivo Comet assay, in vitro and in vivo micronucleus assay, sister chromatid exchange assay, mammalian cell hypoxanthine-guanine phosphoribosyl transferase gene assay, the wing somatic mutation and recombination assay, and the mouse phosphatidylinositol glycan, class A gene assay. Inconsistent results have been found in these assays, with both positive and negative responses being reported. The in vitro systems for assessing the genotoxicity of TiO₂-NPs have generated a greater number of positive results than the in vivo systems, and tests for DNA and chromosome damage have produced more positive results than the assays measuring gene mutation. Nearly all tests for measuring the mutagenicity of TiO₂-NPs were negative. The current data indicate that the genotoxicity of TiO₂-NPs is mediated mainly through the generation of oxidative stress in cells.     

Oxidative stress pathways involved in cytotoxicity and genotoxicity of titanium dioxide (TiO2) nanoparticles on cells constitutive of alveolo-capillary barrier in vitro

The health risks of nanoparticles remain a serious concern given their prevalence from industrial and domestic use. The primary route of titanium dioxide nanoparticle exposure is inhalation. The extent to which nanoparticles contribute to cellular toxicity is known to associate induction of oxidative stress. To investigate this problem further, the effect of titanium dioxide nanoparticles was examined on cell lines representative of alveolo-capillary barrier.The present study showed that all nanoparticle-exposed cell lines displayed ROS generation. Macrophage-like THP-1 and HPMEC-ST1.6R microvascular cells were sensitive to endogenous redox changes and underwent apoptosis, but not alveolar epithelial A549 cells. Genotoxic potential of titanium dioxide nanoparticles was investigated using the activation of γH2AX, activation of DNA repair proteins and cell cycle arrest. In the sensitive cell lines, DNA damage was persistent and activation of DNA repair pathways was observed. Moreover, western blot analysis showed that specific pathways associated with cellular stress response were activated concomitantly with DNA repair or apoptosis.Nanoparticles-induced oxidative stress is finally signal transducer for further physiological effects including genotoxicity and cytotoxicity. Within activated pathways, HSP27 and SAPK/JNK proteins appeared as potential biomarkers of intracellular stress and of sensitivity to endogenous redox changes, respectively, enabling to predict cell behavior.     

Antioxidant imbalance and genotoxicity detected in fish induced by titanium dioxide nanoparticles (NpTiO2) and inorganic lead (PbII)

Titanium dioxide nanoparticles (NpTiO₂) are the most widely-used nanoparticle type and the adsorption of metals such as lead (PbII) onto their surface is a major source of concern to scientists. This study evaluated the effects of the associated exposure to both types of contaminant, i.e., lead (a known genotoxic metal) and NpTiO₂, in a freshwater fish (Astyanax serratus) through intraperitoneal injection for an acute assay of 96 h. The effects of this exposure were evaluated using the comet assay, DNA diffusion assay and piscine micronucleus test, as well as the quantification of antioxidant enzymes (SOD, CAT, and GST) and metallothioneins. Our findings indicate that co-exposure of PbII with NpTiO₂ can provoke ROS imbalances, leading to DNA damage in the blood and liver tissue of A. serratus, as well as modifying erythropoiesis in this species, inducing necrosis and changing the nuclear morphology of the erythrocytes.     

Toxicity assessment of six titanium dioxide nanoparticles in human epidermal keratinocytes

Purpose: The aim of this study was to evaluate and compare the toxicity of six different types of titanium dioxide (TiO₂) nanoparticles (NP) on human epidermal keratinocytes (HEK).

Materials and methods: Six TiO₂ NP (A (10?nm), A*(32?nm), B (27.5?nm), C (200?nm), C*(30–40?nm), and D*(200–400?nm)) were suspended in water or culture medium and characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS). In addition, these NP were assayed with cell viability, cytokine release and cellular uptake in HEK.

Results: TiO₂NP did not change in shape in the culture medium when visualized by TEM. There was an increase in agglomeration with all TiO₂NP in the medium when measured by DLS. Since TiO₂NP interfered with the CellTiter 96®AQueous One and MTT assays but had a minimal effect on alamar Blue (aB). The aB viability assay was selected to assess all six types of TiO₂NP and sample B had a statistically significant decrease in viability at 0.4?mg/ml. A slight increase in TNF-α was noted in sample A*, C, and D* at as low as 0.05?mg/ml. Sample A* and B at certain concentrations showed an increase in Interleukin (IL)-6. IL-10 and IL-1β release for all TiO₂NP were noted around the detection limit with no significant changes compared to control. A statistically significant decrease in IL-8 was noted for all TiO₂NP at the highest concentrations due to the adsorption of IL-8 by TiO₂. All TiO₂NP were localized within cytoplasmic vacuoles of HEK and the element Ti was detected by energy-dispersive x-ray spectroscopy analysis.

Conclusions: Based on cell viability, only sample B was slightly cytotoxic to HEK and samples B and A* have the potential to cause inflammation indicated by an increase in IL-6.     

Uniform titanium dioxide (TiO(2)) microcapsules prepared by glass membrane emulsification with subsequent solvent evaporation

Anatase-type titanium dioxide (TiO(2)) was encapsulated using an Shirasu porous glass (SPG) membrane emulsification technique and followed by solvent evaporation. The oil phase, consisting of fine#10; powder of anatase TiO(2), Disperbyk-180, the hydrophobic oil phase additive, and polymer wall solution, was pushed through the membrane pores into the aqueous phase of poly(vinyl alcohol) and sodium dodecyl sulfate to form the solid-in-oil-in water, (S/O)/W, emulsion droplets. Three types of styrene-based copolymer poly(styrene-co-acrylic acid) (PS-AA), poly(styrene-co-2-ethyl hexyl acrylate) (PS-2EHA) and poly(styrene-co-dimethyl aminoethylmethacrylate) (PS-DMAEMA) were used as an encapsulating shell. Uniform droplets were successfully obtained by modifying the oil phase using methyl laurate or hexadecanol as the oil phase additive, together with carefully monitoring the emulsification flow rate during the emulsification. The (S/O)/W emulsion was gently stirred in a sealed reactor, and evacuation of solvent started under moderate heating with increasing a vacuum intensity. Those uniform-sized TiO(2) microcapsules revealed fine porous morphologies on their surfaces as a result of a mild phase separation induced from the addition of the oil phase additive. The encapsulation efficiency was influenced by the stability of TiO(2) in the oil phase, the polymer wall employed, and the operational control of the glass membrane emulsification process. The membrane emulsification process could prepare the TiO(2) microcapsules with about approximately 6-8.5 wt% of encapsulation loadings. PS-AA and PS-2EHA copolymers provided better encapsulation efficiency compared to PS-DMAEMA. SPG membranes with 1.42, 2.8, 5.25, 7.0, or 9.5 microm were employed and 2-20 microm microcapsules were subsequently obtained.     

Inhalation exposure of nano-scaled titanium dioxide (TiO2) particles alters the inflammatory responses in asthmatic mice

Abstract

Context: Titanium dioxide (TiO₂) nanoparticles (NPs) are regarded as relatively non-toxic in concentrations occurring in occupational environments. Nevertheless, it is conceivable that adverse health effects may develop in sensitive populations such as individuals with respiratory diseases.

Objective: We investigated whether single or repeated exposure to TiO₂ could aggravate inflammatory responses in naïve mice and mice with ovalbumin (OVA)-induced airway inflammation.

Methods: Exposure to aerosolized TiO₂ was performed during OVA sensitization, before, or during the OVA challenge period. The effects on respiratory physiology, inflammatory cells in bronchoalveolar lavage (BAL) and inflammatory mediators in BAL and serum were assessed 24?h after the last OVA challenge or TiO₂ exposure.

Results: A single exposure of TiO₂ had a marked effect on responses in peripheral airways and increasing infiltration of neutrophils in airways of naïve animals. Marked aggravation of airway responses was also observed in animals with allergic disease provided that the single dose TiO₂ was given before allergen challenge. Repeated exposures to TiO₂ during sensitization diminished the OVA-induced airway eosinophilia and airway hyperresponsiveness but concomitant exposure to TiO₂ during the OVA challenge period resulted in neutrophilic airway inflammation and a decline in general health condition as indicated by the loss of body weight.

Conclusion: We conclude that inhalation of TiO₂ may aggravate respiratory diseases and that the adverse health effects are highly dependent on dose and timing of exposure. Our data imply that inhalation of NPs may increase the risk for individuals with allergic airway disease to develop symptoms of severe asthma.     

纳米活性炭,纳米二氧化硅和纳米二氧化钛对人胃肿瘤BGC-823细胞的毒性作用

目的探讨不同化学组成的纳米颗粒对人胃癌BGC-823细胞的毒性作用及其机制。方法分别以纳米活性炭(ACNP)、纳米二氧化硅(SiO2)和纳米二氧化钛(TiO2)100,200,400,800和1600mg·L-1悬液作用BGC-823细胞24,48和72h,MTT法检测细胞增殖,比色法检测乳酸脱氢酶(LDH)漏出量。ACNP100mg·L-1,纳米SiO2200mg·L-1,纳米TiO2200mg·L-1作用BGC-823细胞24h,透射电镜观察细胞形态及超微结构的影响。纳米SiO2和纳米TiO2100,200,400mg·L-1作用细胞24h后,AnnexinⅤ-FITC/PI双染法检测细胞凋亡。ACNP、纳米SiO2和纳米TiO2100,200mg·L-1作用细胞48h后,用PI染色法检测细胞周期。结果 ACNP,纳米SiO2和纳米TiO2均能明显抑制BGC-823细胞的增殖,作用72h后的IC50分别为874.2,676.2和883.5mg·L-1。与正常对照组相比,纳米SiO2100～800mg·L-1组LDH漏出量均显著升高,并呈浓度依赖性(r=0.9751,P<0.01),而纳米TiO2100mg·L-1作用细胞24h,LDH漏出量与对照组相比没有显著差异,但随着作用浓度增加和作用时间延长,各组LDH漏出量明显高于对照组(P<0.05)。ACNP100mg·L-1作用24h后,细胞出现细胞质浓缩、细胞核固缩和裂解。纳米SiO2200mg·L-1和纳米TiO2200mg·L-1作用24h后均出现细胞坏死。纳米颗粒ACNP,SiO2和TiO2作用组均可见纳米颗粒进入细胞及线粒体损伤。纳米SiO2100mg·L-1和纳米TiO2100mg·L-1作用24h,细胞坏死率与正常对照组(4.59±1.20)%相比显著升高(P<0.01),分别为(39.40±1.72)%和(14.12±0.90)%(P<0.05);细胞凋亡率与对照组相比没有显著差异。ACNP,纳米SiO2和纳米TiO2100和200mg·L-1作用细胞48h后,S期细胞增多,G0/G1期细胞减少,细胞碎片增多;ACNP组亚二倍体细胞增多。结论 ACNP、纳米SiO2和纳米TiO2能够抑制BGC-823细胞的增殖。ACNP可诱导细胞凋亡。纳米SiO2和纳米TiO2能损伤细胞膜,造成以细胞坏死为主的毒性损伤。