Nanoparticle accumulation and transcytosis in brain endothelial cell layers

Ye, Dong; Raghnaill, Michelle Nic; Bramini, Mattia; Mahon, Eugene; Åberg, Christoffer; Salvati, Anna; Dawson, Kenneth A.

doi:10.1039/c3nr02905k

Cited by 109 publications

(113 citation statements)

References 70 publications

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“…This is consistent with many other nanomaterials taken up by other cell types, whose final intracelluar destination is often the lysosomes. 37,38 endocytosis mechanism studies…”

Section: Intracellular Trafficking Analysismentioning

confidence: 99%

The interactions of single-wall carbon nanohorns with polar epithelium

Shi¹,

Shi

Li³

et al. 2017

IJN

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Single-wall carbon nanohorns (SWCNHs), which have multitudes of horn interstices, an extensive surface area, and a spherical aggregate structure, offer many advantages over other carbon nanomaterials being used as a drug nanovector. The previous studies on the interaction between SWCNHs and cells have mostly emphasized on cellular uptake and intracellular trafficking, but seldom on epithelial cells. Polar epithelium as a typical biological barrier constitutes the prime obstacle for the transport of therapeutic agents to target site. This work tried to explore the permeability of SWCNHs through polar epithelium and their abilities to modulate transcellular transport, and evaluate the potential of SWCNHs in drug delivery. Madin-Darby canine kidney (MDCK) cell monolayer was used as a polar epithelial cell model, and as-grown SWCNHs, together with oxidized and fluorescein isothiocyanate-conjugated bovine serum albumin-labeled forms, were constructed and comprehensively investigated in vitro and in vivo. Various methods such as transmission electron microscopy and confocal imaging were used to visualize their intracellular uptake and localization, as well as to investigate the potential transcytotic process. The related mechanism was explored by specific inhibitors. Additionally, fast multispectral optoacoustic tomography imaging was used for monitoring the distribution and transport process of SWCNHs in vivo after oral administration in nude mice, as an evidence for their interaction with the intestinal epithelium. The results showed that SWCNHs had a strong bioadhesion property, and parts of them could be uptaken and transcytosed across the MDCK monolayer. Multiple mechanisms were involved in the uptake and transcytosis of SWCNHs with varying degrees. After oral administration, oxidized SWCNHs were distributed in the gastrointestinal tract and retained in the intestine for up to 36 h probably due to their surface adhesion and endocytosis into the intestinal epithelium. Overall, this comprehensive investigation demonstrated that SWCNHs can serve as a promising nanovector that can cross the barrier of polar epithelial cells and deliver drugs effectively.

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“…This is consistent with many other nanomaterials taken up by other cell types, whose final intracelluar destination is often the lysosomes. 37,38 endocytosis mechanism studies…”

Section: Intracellular Trafficking Analysismentioning

confidence: 99%

The interactions of single-wall carbon nanohorns with polar epithelium

Shi¹,

Shi

Li³

et al. 2017

IJN

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“…Utilization of TEM gives better insights into the localization and trafficking routes of nanoparticles (18,46), however, due to the nature of these techniques (imaging fixed samples), it does not yield a dynamic picture. Immunohistochemistry in conjunction with confocal fluorescent microscopy has yielded further insights into these dynamics (16,42,47,48).…”

Section: Investigation Of Transcytosis and Other Mechanisms Through Tmentioning

confidence: 99%

“…The combination of transmission electron microscopy (TEM) with traditional Transwell ™ systems has revealed some crucial limitations of these models (18,44,45), which bring into question the reliability and reproducibility of these systems. These limitations include barrier imperfections, such as formation of multiple layers of endothelial cells on the filter and holes (see Figure 3); nanoparticle adhesion to the microporous filter pore; nanoparticle agglomeration in the culture medium and inside the cell; and leakage of the fluorescent dye.…”

Section: Investigation Of Transcytosis and Other Mechanisms Through Tmentioning

confidence: 99%

“…This targeting strategy is based on the coupling or grafting of receptor substrates that are known to cross the BBB via transcytosis, such as transferrin (11), insulin (12,13), or apolipoprotein E (ApoE) (14), to the surface of the nanomaterial which trigger receptor-mediated transcytosis and thereby enable them to cross the BBB (6, 7). The success of such modifications using ApoE has been reported (15)(16)(17), but in many cases the nanoparticles follow and subsequently accumulate along the endo-lysosomal pathway (18), as is commonly observed with uptake of nanoparticles in other in vitro models (19)(20)(21)(22), and never reach the brain. Hence, there is a need for a more specific nanoparticle targeting approach which requires the understanding of the fundamentals behind the transcytosis pathway.…”

Section: Introductionmentioning

confidence: 99%

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Reproducibility in biological models of the blood-brain barrier

Hudecz

Rocks

Fitzpatrick

et al. 2014

European Journal of Nanomedicine

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Abstract:In the past decade, the importance of quality and reproducibility within research has been re-emphasized, consequently becoming a crucial part of scientific experiments. Their implementation into in vitro and in vivo biological experiments is challenging due to various parameters that can influence the final scientific outcome. In parallel to these activities, there is a huge scientific effort to improve today's medicines to make them safer and more efficient, and to cure untreatable diseases, such as many neurodegenerative diseases. Nanosized materials have been recognized as potential drug delivery systems in this arena due to their small size and surface properties, which enable the design and synthesis of safe and efficient delivery vehicles that might be able to cross the bloodbrain barrier. However, the fundamental understanding behind their uptake mechanism and intracellular trafficking remains unknown. Simple and cost-effective in vitro blood-brain barrier models are widely used to address these questions. This paper aims to critically evaluate the current in vitro models using Transwell ™ systems and to discuss alternative approaches towards more reproducible in vivo features.

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“…92,93 In many situations, the microvascular endothelial cells of the human brain are used as an in vitro BBB model, such as hCMEC/D3 cells, 94 human brain microvascular endothelial cells, 95 and human cerebral endothelial cells. 96 Rat is another common experimental animal due to its availability …”

Section: Neurotoxicity On the In Vitro Bbb Modelmentioning

confidence: 99%

Application of dental nanomaterials: potential toxicity to the central nervous system

Feng¹,

Chen²,

Wang³

et al. 2015

IJN

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Nanomaterials are defined as materials with one or more external dimensions with a size of 1–100 nm. Such materials possess typical nanostructure-dependent properties (eg, chemical, biological, optical, mechanical, and magnetic), which may differ greatly from the properties of their bulk counterparts. In recent years, nanomaterials have been widely used in the production of dental materials, particularly in light polymerization composite resins and bonding systems, coating materials for dental implants, bioceramics, endodontic sealers, and mouthwashes. However, the dental applications of nanomaterials yield not only a significant improvement in clinical treatments but also growing concerns regarding their biosecurity. The brain is well protected by the blood–brain barrier (BBB), which separates the blood from the cerebral parenchyma. However, in recent years, many studies have found that nanoparticles (NPs), including nanocarriers, can transport through the BBB and locate in the central nervous system (CNS). Because the CNS may be a potential target organ of the nanomaterials, it is essential to determine the neurotoxic effects of NPs. In this review, possible dental nanomaterials and their pathways into the CNS are discussed, as well as related neurotoxicity effects underlying the in vitro and in vivo studies. Finally, we analyze the limitations of the current testing methods on the toxicological effects of nanomaterials. This review contributes to a better understanding of the nano-related risks to the CNS as well as the further development of safety assessment systems.

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Nanoparticle accumulation and transcytosis in brain endothelial cell layers

Cited by 109 publications

References 70 publications

The interactions of single-wall carbon nanohorns with polar epithelium

The interactions of single-wall carbon nanohorns with polar epithelium

Reproducibility in biological models of the blood-brain barrier

Application of dental nanomaterials: potential toxicity to the central nervous system

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