Subchronic toxicity of silica nanoparticles as a function of size and porosity

Abstract

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

Targeting of Hepatic Macrophages by Therapeutic Nanoparticles

“…Tunable properties of NPs, such as shape, surface charge, and size, may affect their toxicity (135,136). For instance, cerium oxide (CeO 2 ) NPs with rod-like shape showed higher and dosedependently enhanced macrophage cytotoxicity responses with respect to cubic/octahedral NPs (137).…”

Subchronic and chronic toxicity evaluation of inorganic nanoparticles for delivery applications

“…The Liver is the main organ for spherical Stöber and mesoporous silica nanoparticles accumulation 10 days and 60 days following single dose intravenous administration at MTD which can be cleared at the 180 th day. [165] Our results show that at 180 days post single dose intravenous administration of the nanoparticles, subchronic tissue toxicity of SNPs is influenced by the size of the particles. Liver and spleen recovery in mice following administration of the larger Stöber SNPs (432 ± 18.7 nm in diameter with −53.1 ± 1.5 mV zeta potential) took a longer period (180 days) compared to administration of the smaller Stöber SNPs (46 ± 4.9 nm; −40.3 ± 1.9 mV).…”

“…[146] The size of Stöber silica nanoparticles influences the recovery time needed for Balb/c mice from blood and tissue toxicity and inflammation induced symptoms by 50 and 500nm SNPs at MTD dose. [165] Therefore, it seems that long-term toxicity of inorganic nanoparticles, as well as their acute toxicity, are significantly affected by their size. Since the source of nanoparticles and the animal strain as well as experimental conditions are different in these studies, it cannot be concluded if there is a linear correlation or any specific size range that shows higher or lower toxicity.…”

“…Subchronic safety evaluations of inorganic nanoparticles have been done on both sexes (see Table 2). Among these, a few inorganic nanoparticles including iron, [160] silver, [175] and silica nanoparticles [165] have shown sex-related subchronic toxicity. For example, a sex-related difference in the accumulation of silver nanoparticles was noted in the kidneys after subchronic exposure.…”

“…The accumulation of SNPs in these organs correlated with the histology lesions that were mostly small foci of lobular inflammation and ceroid laden macrophages in the liver. [165] Liver and spleen have been reported as the major organs for the toxicity of SNPs (70 nm) at 4 weeks in male BALB/c mice when administered intravenously. [218] Yu and coworkers have also seen liver, lung, and spleen toxicity in female and male ICR mice 14 days after single intravenous injection of lethal doses of amorphous SNPs.…”