Analytical High-resolution Electron Microscopy Reveals Organ-specific Nanoceria Bioprocessing

Graham, Uschi M.; Yokel, Robert A.; Dozier, Alan; Drummy, Lawrence F.; Mahalingam, Krishnamurthy; Tseng, Michael T.; Birch, Eileen; Fernback, Joseph E.

doi:10.1177/0192623317737254

Cited by 20 publications

(37 citation statements)

References 58 publications

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“…15 One possible explanation might be the dissolution of nanoceria in the liver and subsequent release of cerium ion, resulting in increased cerium in the blood and redistribution to the spleen. 71,84 On the other hand, the observed biokinetic pattern is not consistent with that reported for cerium ion. 14 If this peculiar increase is indeed a true biokinetic phenomenon, better understanding of the underlying physical or physiological mechanisms is needed in order to further develop the PBPK model.…”

Section: Figurecontrasting

confidence: 90%

Physiologically based pharmacokinetic modeling of nanoceria systemic distribution in rats suggests dose- and route-dependent biokinetics

Carlander¹,

Moto²,

Desalegn³

et al. 2018

IJN

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BackgroundCerium dioxide nanoparticles (nanoceria) are increasingly being used in a variety of products as catalysts, coatings, and polishing agents. Furthermore, their antioxidant properties make nanoceria potential candidates for biomedical applications. To predict and avoid toxicity, information about their biokinetics is essential. A useful tool to explore such associations between exposure and internal target dose is physiologically based pharmacokinetic (PBPK) modeling. The aim of this study was to test the appropriateness of our previously published PBPK model developed for intravenous (IV) administration when applied to various sizes of nanoceria and to exposure routes relevant for humans.MethodsExperimental biokinetic data on nanoceria (obtained from various exposure routes, sizes, coatings, doses, and tissues sampled) in rats were collected from the literature and also obtained from the researchers. The PBPK model was first calibrated and validated against IV data for 30 nm citrate coated ceria and then recalibrated for 5 nm ceria. Finally, the model was modified and tested against inhalation, intratracheal (IT) instillation, and oral nanoceria data.ResultsThe PBPK model adequately described nanoceria time courses in various tissues for 5 nm ceria given IV. The time courses of 30 nm ceria were reasonably well predicted for liver and spleen, whereas the biokinetics in other tissues were not well captured. For the inhalation, IT instillation, and oral exposure routes, re-optimization was difficult due to low absorption and, hence, low and variable nanoceria tissue levels. Moreover, the nanoceria properties and exposure conditions varied widely among the inhalation, IT instillation, and oral studies, making it difficult to assess the importance of different factors.ConclusionOverall, our modeling efforts suggest that nanoceria biokinetics depend largely on the exposure route and dose.

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Section: Figurecontrasting

confidence: 90%

Physiologically based pharmacokinetic modeling of nanoceria systemic distribution in rats suggests dose- and route-dependent biokinetics

Carlander¹,

Moto²,

Desalegn³

et al. 2018

IJN

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“…No Ostwald ripening effects were observed in this study where original nanoceria crystals grow due to surface attachment of dissolved ions that come from dissolving nanoceria in the cassette. However, the shedding of ions from nanoceria that are concentrated in macrophages in vivo may provide such supersaturation conditions and this would explain why we observed a dissolution of nanoceria that is accompanied by regrowth of nanoceria or reprecipitation of other cerium phases (cerium phosphate) (Graham et al, 2018).…”

Section: Discussionmentioning

confidence: 92%

“…HRTEM revealed that the type and degree (intensity) of superstructure formation is ligand-dependent. This may be related to the unique agglomerate assemblies of nanoceria discovered previously in different organs after its intravenous administration, such as in the liver vs. the spleen where nanoceria undergoes organ-specific bioprocessing (Graham et al, 2018). Organ-specific bioprocessing and assemblies of nanoceria may depend on available ligand types and concentrations that modify surface functional properties of the nanoceria after uptake, such as particle charge and ability to complex with available organ-specific molecules.…”

Section: Discussionmentioning

confidence: 97%

“…The formation of carboxylic acid-cerium complexes after nanoceria dissolution may enable redistribution of cerium released from nanoceria dissolution within organisms and uptake into plant roots, similar to the role of citrate to release iron from the low-pH environment of endosomes (Arbab et al, 2005). This may explain the organ-specific bioprocessing of ceria (Graham et al, 2018). Ligands that enable nanoceria dissolution in acidic environments may greatly affect nanoceria's fate (dissolution rate and size as well as transport phenomena through ion release).…”

Section: Discussionmentioning

confidence: 99%

“…Nanoceria partially degraded in rat liver and spleen over 90 days after a single intravenous administration of ~ 30 nm ceria, resulting in formation of 1 to 3 nm, crystalline, ceriumcontaining particles that had more reduced (Ce 3+ ) surface cerium. This is thought to have occurred through a dissolution/re-crystallization process (Graham et al, 2014, Graham et al, 2017, Graham et al, 2018.…”

Section: Introductionmentioning

confidence: 99%

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Carboxylic acids accelerate acidic environment-mediated nanoceria dissolution

et al. 2019

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Ligands that accelerate nanoceria dissolution may greatly affect its fate and effects. This project identified carboxylic acids that contribute to nanoceria dissolution in aqueous, acidic environments. Nanoceria has commercial and potential therapeutic applications. It biotransforms in vivo. Citric acid is commonly used to stabilize nanoceria during synthesis and in aqueous dispersions. In this study, citrate-stabilized nanoceria dispersions (~ 4 nm average primary particle size) were placed in dialysis cassettes whose membranes would pass cerium salts but not nanoceria particles. The cassettes were immersed in isoosmotic baths containing carboxylic acids at pH 4.5 at 37 °C, or select agents. Cerium atom material balances were conducted for the cassette and bath by sampling of each chamber and cerium quantitation by inductively coupled plasma mass spectrometry. Samples were also collected for high-resolution transmission electron microscopy observation of nanoceria size (cassette). In carboxylic acid solutions, nanoceria dissolution increased cerium concentration in the bath and decreased the nanoceria primary particle size in the cassette. In solutions of citric, malic, and lactic acid, and in the ammonium ion, ~ 15 nm nanoceria agglomerates persisted. With other carboxylic acids, nanoceria agglomerates grew to ~ 1 micron. Nanoceria particles were stable in solutions containing citrate (pH 7.4), water, or horseradish peroxidase i.e., the dissolution half-lives were very high. Extending these findings to in vivo and environmental systems, one would expect acidic environments containing carboxylic acids to degrade nanoceria by dissolution; two examples would be phagolysosomes and in the plant rhizosphere.

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Cerium Oxide Nanoparticles: Advances in Biodistribution, Toxicity, and Preclinical Exploration

Casals

Zeng

Parra‐Robert

et al. 2020

Small

119

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to contribute to improved treatments by the generation of new diagnostic and therapeutic products. In particular, inorganic nanoparticles (NPs) have emerged as flexible platforms to develop new imaging and therapy agents for detecting and treating diseases at its earliest stages, with benefits superior to any currently used treatments. [1] These materials have been reported as robust drug carriers, versatile scaffolds able to adjust conjugated biomolecules activity, and antennas that can be excited in biologically transparent media. [2] Besides, they can be easily detected and tracked in physiological environments due to their unique physicochemical signatures. [3] Thus, nowadays, with the requirements for more personalized treatments and precision medications, [4] the interest in these materials to develop multimodal/multifunctional nanosized particles that can perform diagnosis [5] and different therapies (such as chemo-, thermo-, radio-, immunotherapies) in a single nanoplatform [6] is continuously growing. [7] Among the broad range of newly proposed nanomaterials, antioxidant NPs add to this list of advantages that they even Antioxidant nanoparticles have recently gained tremendous attention for their enormous potential in biomedicine. However, discrepant reports of either medical benefits or toxicity, and lack of reproducibility of many studies, generate uncertainties delaying their effective implementation. Herein, the case of cerium oxide is considered, a well-known catalyst in the petrochemistry industry and one of the first antioxidant nanoparticles proposed for medicine. Like other nanoparticles, it is now described as a promising therapeutic alternative, now as threatening to health. Sources of these discrepancies and how this analysis helps to overcome contradictions found for other nanoparticles are summarized and discussed. For the context of this analysis, what has been reported in the liver is reviewed, where many diseases are related to oxidative stress. Since well-dispersed nanoparticles passively accumulate in liver, it represents a major testing field for the study of new nanomedicines and their clinical translation. Even more, many contradictory works have reported in liver either cerium-oxide-associated toxicity or protection against oxidative stress and inflammation. Based on this, finally, the intention is to propose solutions to design improved nanoparticles that will work more precisely in medicine and safely in society.

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Analytical High-resolution Electron Microscopy Reveals Organ-specific Nanoceria Bioprocessing

Cited by 20 publications

References 58 publications

Physiologically based pharmacokinetic modeling of nanoceria systemic distribution in rats suggests dose- and route-dependent biokinetics

Physiologically based pharmacokinetic modeling of nanoceria systemic distribution in rats suggests dose- and route-dependent biokinetics

Carboxylic acids accelerate acidic environment-mediated nanoceria dissolution

Cerium Oxide Nanoparticles: Advances in Biodistribution, Toxicity, and Preclinical Exploration

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