Route-dependent systemic and local immune effects following exposure to solutions prepared from titanium dioxide nanoparticles

Abstract

Nanoparticle titanium dioxide (nano-TiO₂) is a white pigment widely used in foods, sunscreens, and other cosmetic products. However, it remains unclear whether exposure to nano-TiO₂ results in immunosuppressive effects or induces a contact hypersensitivity response. To address these data gaps, studies were conducted with the hypothesis that nano-TiO₂ exposure could alter immune responses. After 28 days of oral gavage, nano-TiO₂ (1.25–250?mg/kg in 0.5% methylcellulose) produced no significant effects on innate, humoral, or cell-mediated immune functions in female B6C3F1 mice. Furthermore, there were no effects on the weights of selected organs (spleen, thymus, liver, lung, and kidneys with adrenals). Following dermal exposure on the ears for 3 days, nano-TiO₂ (2.5–10% w/v in 4:1 acetone:olive oil) did not affect auricular lymph node cell proliferation, although an irritancy response was observed following treatment with 5% and 10% nano-TiO₂. Dermal sensitization (2.5–10%) on the back and subsequent challenge (10%) on the right ear with nano-TiO₂ produced no significant effects on percentage ear swelling in the Mouse Ear Swelling Test (MEST). However, when nano-TiO₂ was injected subcutaneously along the mid-line on top of the head at 125–250?mg/kg (in 0.5% methylcellulose), significant increases in auricular lymph node cell proliferation resulted. These results demonstrate that immune effects of nano-TiO₂ exposure are route-of-exposure dependent, and they suggest that irritancy and/or potential hypersensitivity responses may occur following parenteral exposure or dermal administration of nano-TiO₂ to compromised skin.     

Nanoparticles for targeted delivery of antioxidant enzymes to the brain after cerebral ischemia and reperfusion injury

Stroke is one of the major causes of death and disability in the United States. After cerebral ischemia and reperfusion injury, the generation of reactive oxygen species (ROS) and reactive nitrogen species may contribute to the disease process through alterations in the structure of DNA, RNA, proteins, and lipids. We generated various nanoparticles (liposomes, polybutylcyanoacrylate (PBCA), or poly(lactide-co-glycolide) (PLGA)) that contained active superoxide dismutase (SOD) enzyme (4,000 to 20,000 U/kg) in the mouse model of cerebral ischemia and reperfusion injury to determine the impact of these molecules. In addition, the nanoparticles were untagged or tagged with nonselective antibodies or antibodies directed against the N-methyl-𝒟-aspartate (NMDA) receptor 1. The nanoparticles containing SOD protected primary neurons in vitro from oxygen-glucose deprivation (OGD) and limited the extent of apoptosis. The nanoparticles showed protection against ischemia and reperfusion injury when applied after injury with a 50% to 60% reduction in infarct volume, reduced inflammatory markers, and improved behavior in vivo. The targeted nanoparticles not only showed enhanced protection but also showed localization to the CA regions of the hippocampus. Nanoparticles alone were not effective in reducing infarct volume. These studies show that targeted nanoparticles containing protective factors may be viable candidates for the treatment of stroke.     

Silver nanoparticles inhaled during pregnancy reach and affect the placenta and the foetus

Recently, interest for the potential impact of consumer-relevant engineered nanoparticles on pregnancy has dramatically increased. This study investigates whether inhaled silver nanoparticles (AgNPs) reach and cross mouse placental barrier and induce adverse effects. Apart from their relevance for the growing use in consumer products and biomedical applications, AgNPs are selected since they can be unequivocally identified in tissues. Pregnant mouse females are exposed during the first 15 days of gestation by nose-only inhalation to a freshly produced aerosol of 18–20?nm AgNPs for either 1 or 4?h, at a particle number concentration of 3.80?×?107 part./cm^?3 and at a mass concentration of 640?μg/m³. AgNPs are identified and quantitated in maternal tissues, placentas and foetuses by transmission electron microscopy coupled with energy-dispersive X-ray spectroscopy and single-particle inductively coupled plasma mass spectrometry. Inhalation of AgNPs results in increased number of resorbed foetuses associated with reduced oestrogen plasma levels, in the 4?h/day exposed mothers. Increased expression of pregnancy-relevant inflammatory cytokines is also detected in the placentas of both groups. These results prove that NPs are able to reach and cross the mouse placenta and suggest that precaution should be taken with respect to acute exposure to nanoparticles during pregnancy.     

Antibacterial activity and biofilm inhibition by surface modified titanium alloy medical implants following application of silver,titanium dioxide and hydroxyapatite nanocoatings

One of the most common causes of implant failure is peri-implantitis, which is caused by bacterial biofilm formation on the surfaces of dental implants. Modification of the surface nanotopography has been suggested to affect bacterial adherence to implants. Silver nanoparticles are also known for their antibacterial properties. In this study, titanium alloy implants were surface modified following silver plating, anodisation and sintering techniques to create a combination of silver, titanium dioxide and hydroxyapatite (HA) nanocoatings. Their antibacterial performance was quantitatively assessed by measuring the growth of Streptococcus sanguinis, proportion of live/dead cells and lactate production by the microbes over 24?h. Application of a dual layered silver–HA nanocoating to the surface of implants successfully inhibited bacterial growth in the surrounding media (100% mortality), whereas the formation of bacterial biofilm on the implant surfaces was reduced by 97.5%. Uncoated controls and titanium dioxide nanocoatings showed no antibacterial effect. Both silver and HA nanocoatings were found to be very stable in biological fluids with material loss, as a result of dissolution, to be less than 0.07% for the silver nanocoatings after 24?h in a modified Krebs-Ringer bicarbonate buffer. No dissolution was detected for the HA nanocoatings. Thus, application of a dual layered silver–HA nanocoating to titanium alloy implants creates a surface with antibiofilm properties without compromising the HA biocompatibility required for successful osseointegration and accelerated bone healing.     

Quantitative biokinetics of titanium dioxide nanoparticles after intratracheal instillation in rats: Part 3

The biokinetics of a size-selected fraction (70?nm median size) of commercially available and ⁴⁸V-radiolabeled [⁴⁸V]TiO₂ nanoparticles has been investigated in healthy adult female Wistar-Kyoto rats at retention time-points of 1?h, 4?h, 24?h, 7?d and 28?d after intratracheal instillation of a single dose of an aqueous [⁴⁸V]TiO₂-nanoparticle suspension. A completely balanced quantitative biodistribution in all organs and tissues was obtained by applying typical [⁴⁸V]TiO₂-nanoparticle doses in the range of 40–240?μg·kg^?1 bodyweight and making use of the high sensitivity of the radiotracer technique. The [⁴⁸V]TiO₂-nanoparticle content was corrected for residual blood retained in organs and tissues after exsanguination and for ⁴⁸V-ions not bound to TiO₂-nanoparticles. About 4% of the initial peripheral lung dose passed through the air-blood-barrier after 1?h and were retained mainly in the carcass (4%); 0.3% after 28?d. Highest organ fractions of [⁴⁸V]TiO₂-nanoparticles present in liver and kidneys remained constant (0.03%). [⁴⁸V]TiO₂-nanoparticles which entered across the gut epithelium following fast and long-term clearance from the lungs via larynx increased from 5 to 20% of all translocated/absorbed [⁴⁸V]TiO₂-nanoparticles. This contribution may account for 1/5 of the nanoparticle retention in some organs. After normalizing the fractions of retained [⁴⁸V]TiO₂-nanoparticles to the fraction that reached systemic circulation, the biodistribution was compared with the biodistributions determined after IV-injection (Part 1) and gavage (GAV) (Part 2). The biokinetics patterns after IT-instillation and GAV were similar but both were distinctly different from the pattern after intravenous injection disproving the latter to be a suitable surrogate of the former applications. Considering that chronic occupational inhalation of relatively biopersistent TiO₂-particles (including nanoparticles) and accumulation in secondary organs may pose long-term health risks, this issue should be scrutinized more comprehensively.     

The elemental changes occurring in the rat liver after exposure to PEG-coated iron oxide nanoparticles: total reflection x-ray fluorescence (TXRF) spectroscopy study

The main goal of this study was to evaluate in vivo effects of low dose of PEG-coated magnetic iron oxide nanoparticles (IONPs) on the rat liver. The IONPs was intravenously injected into rats at a dose equaled to 0.03?mg of Fe per 1?kg of an animal body weight. The elemental composition of liver tissue in rats subjected to IONPs action and controls were compared. Moreover, in order to determine the dynamics of nanoparticles (NPs) induced elemental changes, the tissues taken from animals 2?hours, 24?hours, and 7?days from IONPs injection were examined. The analysis of subtle elemental anomalies occurring as a result of IONPs action required application of highly sensitive analytical method. The total reflection X-ray fluorescence spectroscopy perfectly meets such requirements and therefore it was used in this study. The obtained results showed increasing trend of Fe level within liver occurring 2?hours from IONPs injection. One day after NPs administration, the liver Fe content presented the baseline level what suggests only the short-term accumulation of nanoparticles in the organ. The Ca, Cu, and Zn levels changed significantly as a result of NPs action. Moreover, the anomalies in their accumulation were still observed 7?days after IONPs injection. The level of Cu decreased while those of Ca and Zn increased in the liver of NPs-treated animals. The reduced liver Cu, followed by elevated serum level of this element, might be related in triggering the mechanisms responsible for Fe metabolism in the organism.