Despite increasing reports of using silica nanoparticles (SNPs) for controlled drug delivery applications, their long-term toxicity profile following intravenous administration remains unexplored. ...Herein, we investigated the acute (10-day) and subchronic (60-day and 180-day) toxicity of nonporous SNPs of approximately 50 nm (Stöber SNPs50) and approximately 500 nm in diameter (Stöber SNPs500), and mesoporous SNPs of approximately 500 nm in diameter (MSNPs500) upon single-dose intravenous injection into male and female immune-competent inbred BALB/c mice. The Maximum Tolerated Dose (MTD) of the particles was determined 10 days post-injection. The MTD of SNPs was administered and toxicity evaluated over 60 and 180 days. Results demonstrate that Stöber SNPs50 exhibit systemic toxicity with MTD of 103 ± 11 mg.kg−1 for female and 100 ± 6 mg.kg−1 for male mice, respectively. Toxicity was alleviated by increasing the size of the particles (Stöber SNPs500). MTD values of 303 ± 4 mg.kg−1 for female and 300 ± 13 mg.kg−1 for male were observed for Stöber SNPs500. Mesoporous SNPs500 showed considerable systemic sex-related toxicity, with MTDs ranging from 40 ± 2 mg.kg−1 to 95 ± 2 mg.kg−1 for male and female mice, respectively. Studies of SNPs showed blood toxicity as a function of physiochemical properties such as significant differences in the mean corpuscular hemoglobin (MCHC) and platelet number at day 10 and white blood cell count at day 60. Histological examination also showed size-, porosity- and time-dependent tissue toxicity. Stöber SNPs500 caused major toxic effects such as lung thrombosis, cardiac wall fibrosis and calcifications, brain infarctions with necrotizing inflammatory response, infiltrate, retinal injuries with calcification and focal gliosis, renal parenchymal damage and liver lobular inflammation dependent on the dose and time of exposure. However, tissue toxicity and accumulation of SNPs in liver observed at day 10 was greater than at day 60 and much greater than at day 180. In contrast, a dramatic increase in cytokine levels was observed at day 60. Despite the relatively high doses, SNPs did not cause subchronic toxicity at day 180 after single-dose intravenous injection. However, they showed distinct differences in the 60 day in vivo subchronic toxicity and inflammation profile as a function of surface area and size.
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This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).
This article has been retracted at the ...request of the corresponding author.
Subsequent to the publication of the article Journal of Controlled Release 311–312 (2019) 1–15, in follow up studies in 2021, the corresponding author's lab members noticed significant discrepancies in reproducibility of some of the results reported in this manuscript. A detailed investigation in the lab was launched, and by retrieving the raw data available at the core facility pertaining to this manuscript, the following discrepancies were discovered that provide the basis for this retraction. These discrepancies have been reported to the University of Utah Research Integrity and Compliance Office by the corresponding author. The co-authors have been made aware of these discrepancies and of the decision of the corresponding author to retract.
The corresponding author believes that the subject matter of this article, detailed analysis of the degradation of silica nanoparticles as a function of their physicochemical properties in relevant biological media in vitro, and in vivo, is significant. For successful utility of these particles in drug delivery applications their detailed biological fate needs to be examined. The significant discrepancies and lack of reproducibility of the reported data however is very unfortunate and the author hopes that this does not cast a doubt on the need for more detailed examination of the biological fate of silica nanoparticles in the future for their successful application in controlled release.
In Vitro Data (Fig. 3)
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Actual dissolution reaction volume was 2.5mL (confirmed by reviewing the lab notebook of the first author during the investigation) vs 3.5mL reported in the manuscript.
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Sample volume was not used in the calculation to convert Inductively Coupled Plasma Mass Spectrometry (ICPMS) data to mg of silicon retrieved which is needed to calculate % degradation (needed to multiply data by 0.1 due to 0.1mL sample volumes).
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Our investigation revealed a 20% “matrix effect with fluids” was communicated by ICPMS core facility person to the first author that was not addressed in the manuscript.
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All data is different when calculating % degradation, not just by a factor of 10 due to not calculating for the 100ml sample volume.
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Raw data during our investigation after publication, obtained from ICPMS facility, and not noted in the lab notebook, for day 28 of simulated lysosomal fluid (SLF) reveals n=1 and no data points for Stober100. In the manuscript however, error bars are shown for all particles at this time point and for the data for Stober100.
Intracellular Degradation (Fig. 5)
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Extremely high background with control causing negative % degradation for Disulfide Meso 100 from retrieved ICPMS data from core facility after publication, but manuscript shows ~1.25% degradation.
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All other calculated % degradation based on retrieved data from ICPMS facility during the investigation after publication, do not match reported data in the paper.
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Paper claims n=6, but raw data received from ICPMS facility during investigation (after publication) is clearly n=3.
In Vivo Degradation (Fig. 6)
ICPMS data retrieved during the investigation after publication for control mice showed extremely high background, and probably were not used in the calculations reported in this manuscript because it would have led to negative silicon contents for a few samples.
Urine ICPMS data from the core facility was not available during investigation after publication, and cannot be retrieved from the first author's lab notebook. Hence its validity cannot be ascertained.
There may be other discrepancies in the manuscript that have gone unnoticed. However, the Editor-in-Chief agrees that the above is significant enough to warrant retraction of the manuscript.
Polymer architecture can influence biodistribution and the mode of presentation of bioactive agents to cells. Herein delivery, loading efficiency, and mode of cellular entry of polymer conjugates of ...the photosensitizer Meso‐Tetra (4‐Carboxyphenyl) Porphyrine (MTCP) are examined when attached to hyperbranched amine terminated poly(amido amine) (PAMAM) dendrimer or random coil linear N‐(2‐hydroxypropyl)methacrylamide (HPMA) copolymer containing free amines in the side chains. The in vitro dark cytotoxicity and phototoxicity of MTCP and related conjugates are assessed on mouth epidermal carcinoma (KB) and human adenocarcinoma alveolar basal epithelial (A549) cells. Phototoxicity of polymeric conjugates increases by ≈100 and 4000 fold in KB and A549 cells compared with nonconjugated MTCP. The increase in phototoxicity activity is shown to result from increased rate of cellular uptake, whereas, cellular internalization of MTCP is negligible in comparison with the conjugated forms. The results of this study suggest the superiority of amine‐terminated HPMA copolymer versus PAMAM dendrimer under study for delivery of MTCP. Treatment with various pharmacological inhibitors of endocytosis shows that polymer architecture influences the mechanism of cellular uptake of the conjugated photosensitizer. Results show that polymeric conjugates of MTCP improve solubility, influence the route and the rate of cellular internalization, and drastically enhance the uptake of the photosensitizer.
The association of photosensitizers with polymeric carriers can improve solubility, influence the route and the rate of cellular internalization, and drastically enhance the uptake of the photosensitizer. Random coil HPMA copolymer‐MTCP has more chance for physical association with cell membrane than spherical hyperbranched PAMAM‐MTCP. Negatively charged MTCP might be taken up via lipid raft domain on the cell membrane surface.
This study was conducted to recover lignin from black liquor for synthesis of lignin-based polyurethane foam (LPUF). To do so, lignin was precipitated from black liquor through acid precipitation at ...different pH values. The precipitated lignin samples were characterized by mid-infrared spectroscopy (MIR), thermogravimetric analysis (TGA), proton nuclear magnetic resonance (1H-NMR), and ultraviolet–visible (UV–Vis) spectroscopy (UV–Vis) techniques. After that, lignin sample with higher purification and lower molecular weight was selected for preparation of lignin polyol. Then, microwave-assisted liquefaction was employed to liquefy lignin sample. The obtained lignin polyol was used successfully to synthesize LPUF samples in different 4, 4′-diphenylmethane diisocyanate (MDI) indexes. The effect of MDI index on properties of LPUF samples was investigated through MIR, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and compressive strength tests. The results demonstrated that MDI content could change morphology of the prepared LPUF samples and caused reduction of cell size and more regularity of cellular structure. Also, thermal and mechanical properties of LPUF samples were found to be influenced by MDI index.
A kraft lignin was liquefied in solution reagents such as polyethylene glycol (PEG) and glycerol under microwave heating. The effects of glycerol concentration, molecular weight of PEG and lignin ...mass were investigated on lignin liquefaction process through microwave irradiation. For this purpose, the prepared polyols were characterized by gel permeation chromatography, Fourier transform infrared spectroscopy, proton nuclear magnetic resonance and carbon-
13
nuclear magnetic resonance techniques. Further, the hydroxyl value (OHV) of polyols was determined by titration method. The results indicated that addition of glycerol increased liquefaction yield and OHV of polyols due to its role as co-solvent in liquefaction process and as a microwave absorber. Glycerol could be used up to 30 wt%, though the beneficial amount of glycerol was obtained as 20 wt%. In another run, it was observed that PEG with a molecular weight of 400 g/mol was an efficient solvent in liquefaction process, which introduced the highest amount of OHV in lignin polyol. A study on the effect of lignin mass was carried out with sufficient amount of glycerol and PEG400 as liquefaction reagents. The results revealed that with further increase in lignin/solvent weight ratio, the molecular weight of polyol increased while its OHV was reduced. Therefore, there was a limiting range in addition of lignin due to insufficient liquefaction solvent in causing enhanced condensation reaction during the liquefaction process. Finally, the polyol with sufficient amounts of testing components was nominated as an optimal polyol with the highest OHV (630 mg KOH/g) and suitable liquefaction yield.
Silica nanoparticles (SNPs) can cause abnormal spermatogenesis in male reproductive toxicity. However, the toxicity and toxicological mechanisms of SNPs in testosterone synthesis and secretion in ...Leydig cells are not well known. Therefore, this study aimed to determine the effect and molecular mechanism of low doses of SNPs in testosterone production in Leydig cells. For this, mouse primary Leydig cells (PLCs) were exposed to 100 nm Stöber nonporous spherical SNPs. We observed significant accumulation of SNPs in the cytoplasm of PLCs via transmission electron microscopy (TEM). CCK-8 and flow cytometry assays confirmed that low doses (50 and 100 μg/mL) of SNPs had no significant effect on cell viability and apoptosis, whereas high doses (more than 200 μg/mL) decreased cell viability and increased cell apoptosis in PLCs. Monodansylcadaverine (MDC) staining showed that SNPs caused the significant accumulation of autophagosomes in the cytoplasm of PLCs. SNPs activated autophagy by upregulating microtubule-associated protein light chain 3 (LC3-II) and BCL-2-interacting protein (BECLIN-1) levels, in addition to downregulating sequestosome 1 (SQSTM1/P62) level at low doses. In addition, low doses of SNPs enhanced testosterone secretion and increased steroidogenic acute regulatory protein (StAR) expression. SNPs combined with rapamycin (RAP), an autophagy activator, enhanced testosterone production and increased StAR expression, whereas SNPs combined with 3-methyladenine (3-MA) and chloroquine (CQ), autophagy inhibitors, had an opposite effect. Furthermore, BECLIN-1 depletion inhibited testosterone production and StAR expression. Altogether, our results demonstrate that low doses of SNPs enhanced testosterone secretion via the activation of autophagy in PLCs.
Silica nanoparticles (SiO
2
NPs) have potential utility in controlled release. Despite significant research in this area, there is a gap in the understanding of the correlation between SiO
2
NP ...physicochemical properties on the one hand and their degradation in solutions, in cells, and
in vivo
on the other. Here, we fabricated SiO
2
NPs with variations in size, porosity, density, and composition: 100 nm Stöber, 100 and 500 nm mesoporous, 100 nm disulfide-based mesoporous, and 100 nm disulfide-based hollow mesoporous. Degradation profiles over 28 days were investigated in simulated biological fluids and deionized water. Results show Meso 100, and 500 nanoparticles degraded faster at higher pH values. Results from macrophages indicate Meso 100 nanoparticles showed the highest degradation amount (~3.8%). Cytotoxicity evaluation of the particles in Human Aortal Endothelial Cells (HAECs) shows concentration-dependent toxicity for the particles. Results from CD-1 mice show ~53% of Meso 100 nanoparticles (25 mg kg
−1
) degraded and were detected in urine after seven days. It was shown nanoparticle porosity and composition as well as pH and ionic strength of the medium play the predominant roles for degradation of SiO
2
NPs. Based on histological evaluations, at the injected doses investigated, the particles did not show toxicity.
Inorganic nanoparticles provide the opportunity to localize bioactive agents to the target sites and protect them from degradation. In many cases, acute toxicities of inorganic nanoparticles used for ...delivery applications have been investigated. However, little information is available regarding the long-term toxicity of such materials. This review focuses on the importance of subchronic and chronic toxicity assessment of inorganic nanoparticles investigated for delivery applications. We have attempted to provide a comprehensive review of the available literature for chronic toxicity assessment of inorganic nanoparticles. Where possible correlations are made between particle composition, physiochemical properties, duration, frequency and route of administration, as well as the sex of animals, with tissue and blood toxicity, immunotoxicity and genotoxicity. A critical gap analysis is provided and important factors that need to be considered for long-term toxicology of inorganic nanoparticles are discussed.
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In the present study, lignin‐based polyurethane foam (LPUF) and hydrophobic silica LPUF (SLPUF) were synthesized using different concentrations of silica nanoparticles (SNP). The effect of SNP on the ...structure and properties of SLPUF samples was investigated and compared with LPUF through the scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT‐IR), thermogravimetric analysis (TGA), dynamic mechanical thermal analysis (DMTA), and compressive tests. The FT‐IR results showed changes in the H bonding interactions between the structures of SLPUF samples. Moreover, the SEM results indicated a decrease in the cell size of SLPUF samples. Incorporation of SNP improved the thermal stability of SLPUF samples while the compressive strength of SLPUF samples decreased in comparison with LPUF. Furthermore, the DMTA results revealed a decrease in the glass transition temperature from 90°C (LPUF) to around 52°C (SLPUF samples). This means that applying the hydrophobic SNP changes the foam type from a rigid foam to soft one. Therefore, significant changes were observed in the physical–chemical properties of the SLPUF samples compared to the LPUF.
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