Determining the Pharmacokinetics and Long-Term Biodistribution of SiO<sub>2</sub> Nanoparticles In Vivo Using Accelerator Mass Spectrometry

Malfatti, Michael; Palko, Heather A.; Kuhn, Edward A.; Turteltaub, Kenneth W.

doi:10.1021/nl302412f

Cited by 45 publications

(43 citation statements)

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“…24 On the other hand, Malfatti et al investigated the long-term biodistribution of carbon-14-labeled silica nanoparticles of 33 nm in mice, and demonstrated their persistence in the RES of liver, spleen, and lungs over 56 days following injection. 25 Taking our result and those of others into account, it appears that the liver, spleen, lungs, and kidneys are targeted by silica nanoparticles regardless of animal, silica type, or exposure routes.…”

supporting

confidence: 63%

“…Some researchers have recently described the biodistribution and excretion kinetics of silica nanoparticles. [20][21][22][23][24][25] However, most of this information was obtained after intravenous injection, which introduces nanoparticles directly into the circulatory system. In practice, oral administration is important, for example, in food or water, and results in kinetic behaviors unlike those associated after intravenous injection because nanoparticles must encounter stomach acid and cross the epithelium of the gastrointestinal (GI) tract in order to reach the blood circulation.…”

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confidence: 99%

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Tissue distribution and excretion kinetics of orally administered silica nanoparticles in rats

An¹,

Lee²,

Kim³

et al. 2014

IJN

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Purpose The effects of particle size on the tissue distribution and excretion kinetics of silica nanoparticles and their biological fates were investigated following a single oral administration to male and female rats. Methods Silica nanoparticles of two different sizes (20 nm and 100 nm) were orally administered to male and female rats, respectively. Tissue distribution kinetics, excretion profiles, and fates in tissues were analyzed using elemental analysis and transmission electron microscopy. Results The differently sized silica nanoparticles mainly distributed to kidneys and liver for 3 days post-administration and, to some extent, to lungs and spleen for 2 days post-administration, regardless of particle size or sex. Transmission electron microscopy and energy dispersive spectroscopy studies in tissues demonstrated almost intact particles in liver, but partially decomposed particles with an irregular morphology were found in kidneys, especially in rats that had been administered 20 nm nanoparticles. Size-dependent excretion kinetics were apparent and the smaller 20 nm particles were found to be more rapidly eliminated than the larger 100 nm particles. Elimination profiles showed 7%–8% of silica nanoparticles were excreted via urine, but most nanoparticles were excreted via feces, regardless of particle size or sex. Conclusion The kidneys, liver, lungs, and spleen were found to be the target organs of orally-administered silica nanoparticles in rats, and this organ distribution was not affected by particle size or animal sex. In vivo, silica nanoparticles were found to retain their particulate form, although more decomposition was observed in kidneys, especially for 20 nm particles. Urinary and fecal excretion pathways were determined to play roles in the elimination of silica nanoparticles, but 20 nm particles were secreted more rapidly, presumably because they are more easily decomposed. These findings will be of interest to those seeking to predict potential toxicological effects of silica nanoparticles on target organs.

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confidence: 63%

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confidence: 99%

Tissue distribution and excretion kinetics of orally administered silica nanoparticles in rats

An¹,

Lee²,

Kim³

et al. 2014

IJN

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“…Furthermore, the inherent high sensitivity of the technique allows for studies where high specific activities of radiolabeled compounds are not possible. AMS has been utilized for both rodent and human studies including: nanoparticle dosimetry (Malfatti et al, 2012) and pharmacokinetic and metabolic evaluation of therapeutics and environmental contaminants (Henderson and Pan 2010; Wagner et al, 2011; Malfatti et al, 2014; Madeen et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

Malfatti

Enright

et al. 2017

Chemico-Biological Interactions

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Organophosphorus-based (OP) nerve agents represent some of the most toxic substances known to mankind. The current standard of care for exposure has changed very little in the past decades, and relies on a combination of atropine to block receptor activity and oxime-type acetylcholinesterase (AChE) reactivators to reverse the OP binding to AChE. Although these oximes can block the effects of nerve agents, their overall efficacy is reduced by their limited capacity to cross the blood-brain barrier (BBB). RS194B, a new oxime developed by Radic et al. (J. Biol. Chem., 2012) has shown promise for enhanced ability to cross the BBB. To fully assess the potential of this compound as an effective treatment for nerve agent poisoning, a comprehensive evaluation of its pharmacokinetic (PK) and biodistribution profiles was performed using both intravenous and intramuscular exposure routes. The ultra-sensitive technique of accelerator mass spectrometry was used to quantify the compound's PK profile, tissue distribution, and brain/plasma ratio at four dose concentrations in guinea pigs. PK analysis revealed a rapid distribution of the oxime with a plasma t1/2 of ∼1 hr. Kidney and liver had the highest concentrations per gram of tissue followed by lung, spleen, heart and brain for all dose concentrations tested. The Cmax in the brain ranged between 0.03-0.18% of the administered dose, and the brain-to-plasma ratio ranged from 0.04 at the 10 mg/kg dose to 0.18 at the 200 mg/kg dose demonstrating dose dependent differences in brain and plasma concentrations. In vitro studies show that both passive diffusion and active transport contribute little to RS194B traversal of the BBB. These results indicate that biodistribution is widespread, but very low quantities accumulate in the guinea pig brain, indicating this compound may not be suitable as a centrally active reactivator.

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“…We must first notice that most NP concentrations we used here are realistic, as bioaccumulation studies have demonstrated concentrations in NPs as high as 100 μg mL −1 were achieved for many days in rat liver. 29 We choose a conservative value of 10 μg mL −1 in this discussion.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Interferences of Silica Nanoparticles in Green Fluorescent Protein Folding Processes

et al. 2015

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We investigated the relationship between unfolded proteins, silica nanoparticles and chaperonin to determine whether unfolded proteins could stick to silica surfaces and how this process could impair heat shock protein activity. The HSP60 catalyzed green fluorescent protein (GFP) folding was used as a model system. The adsorption isotherms and adsorption kinetics of denatured GFP were measured, showing that denaturation increases GFP affinity for silica surfaces. This affinity is maintained even if the surfaces are covered by a protein corona and allows silica NPs to interfere directly with GFP folding by trapping it in its unstructured state. We determined also the adsorption isotherms of HSP60 and its chaperonin activity once adsorbed, showing that SiO2 NP can interfere also indirectly with protein folding through chaperonin trapping and inhibition. This inhibition is specifically efficient when NPs are covered first with a layer of unfolded proteins. These results highlight for the first time the antichaperonin activity of silica NPs and ask new questions about the toxicity of such misfolded proteins/nanoparticles assembly toward cells.

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Determining the Pharmacokinetics and Long-Term Biodistribution of SiO₂ Nanoparticles In Vivo Using Accelerator Mass Spectrometry

Cited by 45 publications

References 45 publications

Tissue distribution and excretion kinetics of orally administered silica nanoparticles in rats

Tissue distribution and excretion kinetics of orally administered silica nanoparticles in rats

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

Interferences of Silica Nanoparticles in Green Fluorescent Protein Folding Processes

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Determining the Pharmacokinetics and Long-Term Biodistribution of SiO2 Nanoparticles In Vivo Using Accelerator Mass Spectrometry

Cited by 45 publications

References 45 publications

Tissue distribution and excretion kinetics of orally administered silica nanoparticles in rats

Tissue distribution and excretion kinetics of orally administered silica nanoparticles in rats

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

Interferences of Silica Nanoparticles in Green Fluorescent Protein Folding Processes

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Determining the Pharmacokinetics and Long-Term Biodistribution of SiO₂ Nanoparticles In Vivo Using Accelerator Mass Spectrometry