Evaluation of silica nanoparticle toxicity after topical exposure for 90 days

Park

Jeong

et al. 2017

Nonporous silica nanoparticles (SiNPs) have potential as promising carriers for ophthalmic drugs. However, the in vivo safety of ocular topical SiNPs remains unclear. This study investigated the in vivo safety of oral and ocular topical applications of 100 nm-sized SiNPs in Sprague-Dawley rats. The rats were divided into the following four groups: low-dose oral administration (total 100 mg/kg of SiNPs mixed with food for one week), high-dose oral administration (total 1000 mg/kg of SiNPs mixed with food for one week), ocular topical administration (10 mg/ml concentration, one drop, applied to the right eyes four times a day for one month), or a negative control (no SiNP treatment). The rats were observed for 12 weeks to investigate any signs of general or ocular toxicity. During the observation period, no differences were observed in the body weights, food and water intakes, behaviors and abnormal symptoms of the four groups. No animal deaths occurred. After 12 weeks, hematologic, blood biochemical parameters and ophthalmic examinations revealed no abnormal findings in any of the animals. The lack of toxicity of the SiNPs was further verified in autopsy findings of brain, liver, lung, spleen, heart, kidneys, intestine, eyeballs, and ovaries or testes.

Section: Introductionmentioning

confidence: 99%

An Evaluation of the in vivo Safety of Nonporous Silica Nanoparticles: Ocular Topical Administration versus Oral Administration

Park

Jeong

et al. 2017

“…Studies have focused on their unique physical and chemical characteristics as well as the potential adverse effects arising from these properties. Among the many kinds of these nanomaterials, silica (SiO 2 ) nanoparticles (NPs) have great promise for applications in biosensors, DNA delivery, sunscreen lotions, and cancer therapy 1 2 . Despite many efforts to understand the potential hazardous effects of silica NPs, including oxidative stress and pro-inflammatory responses in rodents and RAW264.7 cells 3 , autophagy and endothelial dysfunction via the PI3K/Akt/mTOR signaling pathway 4 , acute inflammation and hepatocyte necrosis through neutrophil-mediated liver injury 5 , as well as apoptosis and changes of the cell cycle in HaCaT cells 6 , there is still a lack of clear understanding of the cytotoxic effects of silica NPs on components of the immune system that provide the first line of defense, such as neutrophils, monocytes, and macrophages.…”

mentioning

confidence: 99%

A dual role of transient receptor potential melastatin 2 channel in cytotoxicity induced by silica nanoparticles

Jiang

et al. 2015

Silica nanoparticles (NPs) have remarkable applications. However, accumulating evidence suggests NPs can cause cellular toxicity by inducing ROS production and increasing intracellular Ca2+ ([Ca2+]i), but the underlying molecular mechanism is largely unknown. Transient receptor potential melastatin 2 (TRPM2) channel is known to be a cellular redox potential sensor that provides an important pathway for increasing the [Ca2+]i under oxidative stress. In this study, we examined the role of TRPM2 channel in silica NPs-induced oxidative stress and cell death. By quantitation of cell viability, ROS production, [Ca2+]i, and protein identification, we showed that TRPM2 channel is required for ROS production and Ca2+ increase induced by silica NPs through regulating NADPH oxidase activity in HEK293 cells. Strikingly, HEK293 cells expressing low levels of TRPM2 were more susceptible to silica NPs than those expressing high levels of TRPM2. Macrophages from young mice showed significantly lower TRPM2 expression than those from senescent mice and had significantly lower viability after silica NPs exposure than those from senescent ones. Taken together, these findings demonstrate for the first time that TRPM2 channel acts as an oxidative stress sensor that plays a dual role in silica NPs-induced cytotoxicity by differentially regulating the NADPH oxidase activity and ROS generation.

“…The crystalline form of silica is toxic to alveolar cells and can induce irreversible pulmonary silicosis 23 , 24 . Conversely, amorphous silica, such as nonporous silica particle, is considered relatively biologically safe because of its biodegradability 25 – 27 . Biodegradation and clearance are essential for biomedical use of nanoparticles because chronic accumulation of nanoparticles in human bodies can lead to serious long term complications.…”

Section: Discussionmentioning

confidence: 99%

Safety of Nonporous Silica Nanoparticles in Human Corneal Endothelial Cells

Park

et al. 2017

Nonporous silica nanoparticles (SiNPs) are promising drug carrier platforms for intraocular drug delivery. In this study, we investigated the safety of three different sizes of SiNPs (50, 100, and 150 nm) in a human corneal endothelial cell (HCEC) line, B4G12. The HCECs were exposed to different concentrations (0, 25, 50, and 100 µg/ml) of three sizes of SiNPs for up to 48 h. Cellular viability, autophagy, lactate dehydrogenase (LDH) assay, and mammalian target of rapamycin (mTOR) pathway activation were evaluated. Intracellular distribution of the SiNPs was evaluated with transmission electron microscopy (TEM). TEM revealed that the SiNPs were up-taken by the HCECs inside cytoplasmic vacuoles. No mitochondrial structural damage was observed. Both cellular viability and LDH level remained unchanged with up to 100 µg/mL of SiNP treatment. Autophagy showed a significant dose-dependent activation with 50, 100, and 150 nm SiNPs. However, the mTOR activation remained unchanged. Human corneal tissue culture with 100 µg/ml concentrations of SiNPs for 72 h revealed no significant endothelial toxicity. In vivo corneal safety of the SiNPs (0.05 ml intracameral injection, 200 mg/ml concentration) was also verified in rabbit models. These findings suggested that 50, 100, and 150 nm SiNPs did not induce acute significant cytotoxicity in corneal endothelial cells at concentrations up to 100 µg/mL. However, long-term toxicity of SiNPs remains unknown.