Toxicity Of Mesoporous Silica Nanoparticles Research Articles

Shape and Shear Stress Impact on the Toxicity of Mesoporous Silica Nanoparticles: In Vitro and In Vivo Evidence.

Mesoporous silica nanoparticles (MSNs) are widely used in the biomedical field because of their unique and excellent properties. However, the potential toxicity of different shaped MSNs via injection has not been fully studied. This study aims to systematically explore the impact of shape and shear stress on the toxicity of MSNs after injection. An in vitro blood flow model was developed to investigate the cytotoxicity and the underlying mechanisms of spherical MSNs (S-MSN) and rodlike MSNs (R-MSN) in human umbilical vein endothelial cells (HUVECs). The results suggested that the interactions between MSNs and HUVECs under the physiological flow conditions were significantly different from that under static conditions. Whether under static or flow conditions, R-MSN showed better cellular uptake and less oxidative damage than S-MSN. The main mechanism of cytotoxicity induced by R-MSN was due to shear stress-dependent mechanical damage of the cell membrane, while the toxicity of S-MSN was attributed to mechanical damage and oxidative damage. The addition of fetal bovine serum (FBS) alleviated the toxicity of S-MSN by reducing cellular uptake and oxidative stress under static and flow conditions. Moreover, the in vivo results showed that both S-MSN and R-MSN caused cardiovascular toxicity in zebrafish and mouse models due to the high shear stress, especially in the heart. S-MSN led to severe oxidative damage at the accumulation site, such as liver, spleen, and lung in mice, while R-MSN did not cause significant oxidative stress. The results of in vitro blood flow and in vivo models indicated that particle shape and shear stress are crucial to the biosafety of MSNs, providing new evidence for the toxicity mechanisms of the injected MSNs.

Antibacterial toxicity of mesoporous silica nanoparticles with functional decoration of specific organic moieties

Mesoporous silica nanoparticles (MSNs) are generally considered as biocompatible nanocarriers for biomedical applications; however, no study has provided conclusive evidence regarding the antimicrobial toxicity of MSNs. Here, we systematically evaluated the toxicity of MSNs against Escherichia coli (E. coli) by investigating not only the removal rate of cetyltrimethyl ammonium bromide (CTAB) from the MSNs, but also functional decorations of specific organic moieties such as polydopamine (PDA) and graphene oxide (GO). The mortality of E coli was strongly dependent on the residual CTAB that was not completely removed from the MSNs by acid etching process. On the other hand, for the removal of CTAB from the MSNs the reduced etching time and increased H2O content in the etchant increased the survival of E. coli, probably because of the reduction of bioactive H+ ions that inhibit bacterial growth. Notably, PDA-coated and GO-wrapped MSNs demonstrated the higher toxicity than the pristine MSNs, because of the strong interplay of antibacterial activity of functional decoration (PDA and GO). This study provides a useful guideline for the design of biocompatible MSNs for biomedical applications.

Subacute toxicity of mesoporous silica nanoparticles to the intestinal tract and the underlying mechanism

The biological safety of mesoporous silica nanoparticles (MSNs) has gradually attracted attention. However, few studies of their toxicity to the intestine and mechanism are available. In this study, their primary structures were characterized, and their subacute toxicity to mice was investigated. After 2 weeks of intragastric administration of MSNs, they significantly enhanced serum ALP, ALT, AST and TNF-α levels and caused infiltration of inflammatory cells in the spleen and intestines. MSNs induced intestinal oxidative stress and colonic epithelial cell apoptosis in mice. Intestinal epithelial cells exhibited mitochondrial ridge rupture and membrane potential decrease after MSN treatment. Additionally, MSNs increased ROS and NLRP3 levels and inhibited expression of the autophagy proteins LC3-II and Beclin1. MSNs significantly changed the intestinal flora diversity in mice, especially for harmful bacteria, leading to intestinal microecology imbalance. Meanwhile, MSNs influenced the expression of metabolites, which were involved in a range of metabolic pathways, including pyrimidine metabolism, central carbon metabolism in cancer, protein digestion and absorption, mineral absorption, ABC transport and purine metabolism. These results indicated that the subacute toxicity of mesoporous silicon was mainly caused by intestinal damage. Thus, our research provides additional evidence about the safe dosage of MSNs in the clinical and food industries.

Cellular Toxicity of Mesoporous Silica Nanoparticle in SHSY5Y and BMMNCs Cell.

Mesoporous silica nanoparticles (MSNs) are emerging as one of the new and promising nanomaterials for biomedical applications, but enough investigation has not been done in the field of the biocompatibility of MSNs in vitro condition. The present study aims to investigate the toxicity of mesoporous silica nanoparticles in BM-MNCs and SHSY5Y Cell. The synthesis of MSN was performed and it was characterized for its size by SEM and XRD. The cellular toxicity of MSN was investigated by MTT assay as well as LDH assay in BMMNCs and SHSY5Y Cell. In this article, cellular toxicity of mesoporous silica has been targeted keeping in view the size, toxicity, dose administered and in vitro toxicity. In the present study, mesoporous silica was synthesized and characterized for its size via SEM and XRD as 123.05 nM. The antibacterial test via disc diffusion assay was performed and no significant antimicrobial effect was found at low dose i. e less than 150 uM. The in vitro toxicity of MSN in bone marrow mononuclear cells and SHSY5Y cell was investigated in a time and dose-dependent manner. These results also confirmed no significant toxic effect at a low dose while at the higher doses, toxicity was observed. Altogether, this article illuminates mesoporous silica as safe nanoparticle at low doses for drug delivery. The present finding will help researchers to develop and target MSN nanoparticlebased therapeutics for several applications in biological science.

Cardiac and pulmonary toxicity of mesoporous silica nanoparticles is associated with excessive ROS production and redox imbalance in Wistar rats

Mesoporous silica nanoparticles (MSNs) represent one of the most promising drug delivery systems. MSNs have attracted considerable attention in recent years both in industry and biomedicine due to their unique properties. Thus, evaluation of the toxic effects of MSNs is necessary before the biomedical and clinical applications. We investigated the in vivo effect of MSNs on the production of reactive oxygen species (ROS), antioxidant defenses and histology of the heart and lung. Rats received 25, 50, 100 and 200 mg/kg body weight of synthesized MSNs intraperitoneally for 30 days and samples were collected for analysis. MSNs induced significant increase in serum cardiac function markers, tumor necrosis factor alpha and lipids. MSNs-induced rats exhibited anemia, thrombocytopenia, leukocytosis, significantly increased ROS, malondialdehyde and nitric oxide, and declined antioxidant defenses in the heart and lung of rats. In addition, MSNs induced histological alterations in the heart and lung of rats. In conclusion, our results demonstrated that MSNs induce cardiotoxicity and pulmonary toxicity via excessive generation of ROS, suppressed antioxidants, inflammation and histological alterations. Further investigations are recommended to understand the molecular mechanism underlying the toxic effects of MSNs and to improve the performance of nanomedicine.

Transient Receptor Potential Ion Channel-Dependent Toxicity of Silica Nanoparticles and Poly(amido amine) Dendrimers.

Fundamental to the design and development of nanoparticles for applications in nanomedicine is a detailed understanding of their biologic fate and potential toxic effects. Transient receptor potential (TRP) ion channels are a large superfamily of cation channels with varied physiologic functions. This superfamily is classified into six related subfamilies: TRP canonical, TRP vanilloid (TRPV), TRP melastatin (TRPM), TRP ankyrin (TRPA), TRP polycystin, and TRP mucolipin. TRPA1, TRPM2, and TRPM8 are nonselective Ca2+-permeable cation channels which regulate calcium pathways under oxidative stress, whereas TRPV4 can be activated by oxidative, osmotic, and thermal stress as well as different fatty acid metabolites. Using a series of well characterized silica nanoparticles with variations in size (approximately 50-350 nm in diameter) and porosity, as well as cationic and anionic poly(amido amine) (PAMAM) dendrimers of similar size, we examined the toxicity of these nanoparticles to human embryonic kidney-293 cells overexpressing different TRP channels. The data show that the toxicity of mesoporous silica nanoparticles was influenced by expression of the TRPA1 and TRPM2 channels, whereas the toxicity of smaller nonporous silica nanoparticles was only affected by TRPM8. Additionally, TRPA1 and TRPM2 played a role in the cytotoxicity of cationic dendrimers, but not anionic dendrimers. TRPV4 did not seem to play a significant role in silica nanoparticle or PAMAM toxicity.

Molecular Elucidation of Biological Response to Mesoporous Silica Nanoparticles in Vitro and in Vivo.

Biomedical applications of mesoporous silica nanoparticles (MSNs) require efficient cellular uptake and low toxicity. The purpose of this study is to investigate the cellular uptake and toxicity of MSNs with different sizes and charges (50, 100, and 250 nm with a positive surface charge and 100 nm with a negative surface charge) exposed to human monocyte-derived macrophages, lung epithelium BEAS-2B cells, and mice using genome-wide gene expression analysis and cellular/animal-level end point tests. We found that MSNs can be taken up into cells through endocytosis in a charge- and size-dependent manner, with positively charged and larger MSNs being more easily taken up into the cells by recruiting more types of endocytotic pathways for more cellular uptake. Moreover, the cytotoxicity of MSNs could be correlated with the amount of MSNs taken up by cells, which positively correlates to the particle size and dosage. Therefore, only positively charged and larger MSNs (≥100 nm) during higher treatment doses (≥500 μg mL-1) resulted in a sufficient accumulation of internalized MSNs in cells to induce significant release of reactive oxygen species (ROS) and oxidative stress, inflammatory gene upregulation through NF-κB and AP-1, and eventually autophagy-mediated necrotic cell death. Furthermore, genome-wide gene expression analysis could reflect the above in vitro cellular damages and corresponding in vivo injuries in mice, indicating that specific gene expression footprints may be used for assessing the safety of nanoparticles. The present finding provides some insights into the rational design of effective MSN-based drug/gene delivery systems and biomedical applications.

Biodistribution, excretion, and toxicity of mesoporous silica nanoparticles after oral administration depend on their shape

Mesoporous silica nanoparticles (MSNs) have been proven to be effective drug carriers for oral delivery. However, little attention has been paid to their in vivo biodistribution and toxicity after oral administration. The effect of particle shape on their in vivo behavior is also unknown. In this study, we systematically studied the acute toxicity and biodistribution of three types of MSNs with aspect ratios (ARs) of 1, 1.75 and 5 after oral administration. The effect of particle shape as a key physicochemical parameter of MSNs was discussed. With the increase of AR, MSNs showed decreased in vivo biodegradation, systematic absorption and excretion, especially decreased liver distribution and urinal excretion. During the period of urinal excretion, MSNs induced a shape-dependent renal damage including hemorrhage, vascular congestion and renal tubular necrosis. These findings will enrich the knowledge to rationally engineer bionanomaterials, and bring new insights into nanotoxicity. From the Clinical EditorAdvances in nanotechnology have resulted in improvement in drug delivery, of which mesoporous silica nanoparticles have been used as carriers for oral drugs. Nonetheless, studies on their absorption, distribution, metabolism, excretion (ADME) and toxicity still need to be performed. In this article, authors evaluated the effects of particle size and shape on in vivo behavior. The findings would shine light on future design of future drug delivery systems.

Synthesis and Physicochemical Characterization of Mesoporous SiO2 Nanoparticles

There exists a knowledge gap in understanding potential toxicity of mesoporous silica nanoparticles. A critical step in assessing toxicity of these particles is to have a wide size range with different chemistries and physicochemical properties. There are several challenges when synthesizing mesoporous silica nanoparticles over a wide range of sizes including (1) nonuniform synthesis protocols using the same starting materials, (2) the low material yield in a single batch synthesis (especially for particles below 60–70 nm), and (3) morphological instability during surfactant removal process and surface modifications. In this study, we synthesized a library of mesoporous silica nanoparticles with approximate particle sizes of 25, 70, 100, 170, and 600 nm. Surfaces of the silica nanoparticles were modified with hydrophilic‐CH2–(CH2)2–COOH and relatively hydrophobic‐CH2–(CH2)10–COOH functional groups. All silica nanoparticles were analysed for morphology, surface functionality, surface area/pore volume, surface organic content, and dispersion characteristics in liquid media. Our analysis revealed the synthesis of a spectrum of monodisperse bare and surface modified mesoporous silica nanoparticles with a narrow particle size distribution and devoid of cocontaminants critical for toxicity studies. Complete physicochemical characterization of these synthetic mesoporous silica nanoparticles will permit systematic toxicology studies for investigation of structure‐activity relationships.

The absorption, distribution, excretion and toxicity of mesoporous silica nanoparticles in mice following different exposure routes

Mesoporous silica nanoparticles (MSNs) are emerging as one of the promising nanomaterials for biomedical applications, but the nanomaterials–body interaction exposed by different administration routes remained poorly understood. In the present study, a systematic investigation of the absorption, distribution, excretion and toxicity of silica nanoparticles (SNs) with the average size of 110 nm after four different exposure routes including intravenous, hypodermic, intramuscular injection and oral administration to mice were achieved. The results showed that a fraction of the SNs administrated by the intramuscular and hypodermic injection could cross different biological barriers into the liver but with a low absorption rate. Exposing by oral administration, SNs were absorbed into the intestinal tract and persisted in the liver. And SNs administrated by intravenous injection were mainly present in the liver and spleen. In addition, SNs could cause inflammatory response around the injection sites after intramuscular and hypodermic injection. It was also found that SNs were mainly excreted through urine and feces after different exposure routes. This study will be helpful for selecting the appropriate exposed routes for the development of nanomaterials-based drug delivery system for biomedical applications.