Original Article
Assessment of in vivo systemic toxicity and biodistribution of iron-doped silica nanoshells

https://doi.org/10.1016/j.nano.2016.10.018Get rights and content

Abstract

Silica nanoparticles are an emerging class of biomaterials which may be used as diagnostic and therapeutic tools for biomedical applications. In particular, hollow silica nanoshells are attractive due to their hollow core. Approximately 70% of a 500 nm nanoshell is hollow, therefore more particles can be administered on a mg/kg basis compared to solid nanoparticles. Additionally, their nanoporous shell permits influx/efflux of gases and small molecules. Since the size, shape, and composition of a nanoparticle can dramatically alter its toxicity and biodistribution, the toxicology of these nanomaterials was assessed. A single dose toxicity study was performed in vivo to assess the toxicity of 500 nm iron-doped silica nanoshells at clinically relevant doses of 10-20 mg/kg. This study showed that only a trace amount of silica was detected in the body 10 weeks post-administration. The hematology, biochemistry and pathological results show that the nanoshells exhibit no acute or chronic toxicity in mice.

Graphical Abstract

Many studies have evaluated the toxicity of various silica nanoparticle formulations. The size, shape, morphology, charge, and surface properties of a nanoparticle can dramatically affect its biodistribution and toxicology. In the present study, 500 nm hollow silica nanoshells showed no acute or chronic toxicity in mice after intravenous administration. In addition, the nanoshells were retained mostly by the liver and were undetectable after 10 weeks. Incorporation of iron altered the biodistribution of SiO2 nanoshells.

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Section snippets

Materials

Tetramethyl orthosilicate (TMOS) was purchased from Sigma Aldrich Corp (St. Louis, Missouri). 500 nm amino-polystyrene beads were acquired from Polysciences Inc. (Warrington, Pennsylvania). Iron (III) ethoxide was acquired from Gelest Inc. (Morrisville, Pennsylvania). Potassium hydroxide was purchased from Fischer-Scientific (Pittsburg, Pennsylvania). 500 mM aqueous KOH was obtained by dissolving the KOH pellets in Milli-Q water. Nitric acid (HNO3) was provided by EMD (Billerica, Massachusetts)

Characterization of nanoshells

The SiO2 and Fe-SiO2 nanoshells were hollow and spherical in shape with an average diameter of 497 nm ± 13 and 455 nm ± 14, respectively, as shown by SEM and TEM in Figure 1. The images show that the SiO2 and Fe-SiO2 nanoshells are fairly uniform in size with no visible holes, cracks, or other deformations. The diameters and shell thicknesses of nanoshells were determined by using TEM images. The incorporation of iron does not greatly affect the shell thickness or morphology compared to pure SiO2

Discussion

The kidney is capable of removing molecules from the blood by filtering particles through the glomerular capillary wall, also known as glomerular filtration. Renal filtration depends on surface charge and size, where molecules with a hydrodynamic diameter greater than 8 nm are typically not capable of glomerular filtration and therefore are not excreted via the renal system33, 34; however, some studies have suggested that particles larger than 8 nm can be excreted through the urine.4

Acknowledgment

The authors thank the Cancer Center Microscopy Core Facility at UCSD and the UCSD Histology and Immunohistochemistry core facility.

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    This research was supported by National Institutes of Health IMAT1R33CA177449-01A1 and the National Institutes of Health Cross Training Translation Cancer Researchers in Nanotechnology (CRIN) Support (National Institutes of Health Grant No. 3 R25 CA 153915-03S1). Individual student funding was provided by the NCI Research Supplements to Promote Diversity in Health Related Research Fellowship (National Institutes of Health Grant No. 1R33CA177449-01A1). The authors thank Dr. K. Pestonjamasp and the rest of the Cancer Center Microscopy Core Facility at UCSD (NCI Grant No. P30 CA23100) and the UCSD Histology and Immunohistochemistry core facility.

    A.C. Kummel and W.C. Trogler have an equity interest in Nanocyte Medical, Inc., a company that may potentially benefit from the research results, and also serve on the company's Scientific Advisory Board. S.L. Blair has a family member with an equity interest in Nanocyte Medical, Inc., a company that may potentially benefit from the research results. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.

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