Transferrin receptor on endothelium of brain capillaries

Jefferies, Wilfred A.; Brandon, Malcolm R.; Hunt, S. V.; Williams, Alan F.; Gatter, Kevin C.; Mason, David Y.

doi:10.1038/312162a0

Cited by 966 publications

(523 citation statements)

References 6 publications

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“…The cell viability was tested with a live−dead viability assay. Our study revealed no signs of lost viability of the BCECs after they had been incubated for 24 h with various concentrations of SPIONs (35,70, and 140 μg/ mL) ( Figure 2). A Trypan Blue stain experiment conducted to count the amount of dead cells in wells incubated for 24 h with or without 140 μg/insert and exposed to a magnetic force for 5 h revealed no statistical difference between cell viability under the two conditions (p < 0.05).…”

Section: ■ Results and Discussionmentioning

confidence: 71%

Uptake and Transport of Superparamagnetic Iron Oxide Nanoparticles through Human Brain Capillary Endothelial Cells

Thomsen

Linemann

Pondman

et al. 2013

ACS Chem. Neurosci.

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ABSTRACT:The blood−brain barrier (BBB) formed by brain capillary endothelial cells (BCECs) constitutes a firm physical, chemical, and immunological barrier, making the brain accessible to only a few percent of potential drugs intended for treatment inside the central nervous system. With the purpose of overcoming the restraints of the BBB by allowing the transport of drugs, siRNA, or DNA into the brain, a novel approach is to use superparamagnetic iron oxide nanoparticles (SPIONs) as drug carriers. The aim of this study was to investigate the ability of fluorescent SPIONs to pass through human brain microvascular endothelial cells facilitated by an external magnet. The ability of SPIONs to penetrate the barrier was shown to be significantly stronger in the presence of an external magnetic force in an in vitro BBB model. Hence, particles added to the luminal side of the in vitro BBB model were found in astrocytes cocultured at a remote distance on the abluminal side, indicating that particles were transported through the barrier and taken up by astrocytes. Addition of the SPIONs to the culture medium did not negatively affect the viability of the endothelial cells. The magnetic force-mediated dragging of SPIONs through BCECs may denote a novel mechanism for the delivery of drugs to the brain.

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Section: ■ Results and Discussionmentioning

confidence: 71%

Uptake and Transport of Superparamagnetic Iron Oxide Nanoparticles through Human Brain Capillary Endothelial Cells

Thomsen

Linemann

Pondman

et al. 2013

ACS Chem. Neurosci.

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“…Since Tf receptors are present on the surface of the cerebral capillaries (Fishman et al, 1985;Jeffries et al, 1984;Partridge et al, 1987) and endocytosis of Tf is known to occur in these capillaries (Partridge et al, 1987), it has been suggested that Mn (in the trivalent oxidation state) enters the endothelial cells complexed with Tf. Mn is then released from the complex in the endothelial cell interior by endosomal acidification and the apo-Tf Tf complex is returned to the luminal surface (Morris et al, 1992a;Morris et al, 1992b) without the assistance of DMT1 (Divalent Metal Transporter-1) (Moos et al, 2006).…”

Section: Manganese Transport Into Brain Transferrin/transferrin Recepmentioning

confidence: 99%

Manganese neurotoxicity: A focus on the neonate

Erikson

Thompson

Aschner

et al. 2007

Pharmacology & Therapeutics

219

141

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Manganese (Mn) is an essential trace metal found in all tissues, and it is required for normal amino acid, lipid, protein, and carbohydrate metabolism. While Mn deficiency is extremely rare in humans, toxicity due to overexposure of Mn is more prevalent. The brain appears to be especially vulnerable. Mn neurotoxicity is most commonly associated with occupational exposure to aerosols or dusts that contain extremely high levels (> 1-5 mg Mn/m 3 ) of Mn, consumption of contaminated well water, or parenteral nutrition therapy in patients with liver disease or immature hepatic functioning such as the neonate. This review will focus primarily on the neurotoxicity of Mn in the neonate. We will discuss putative transporters of the metal in the neonatal brain and then focus on the implications of high Mn exposure to the neonate focusing on typical exposure modes (e.g., dietary and parenteral). Although Mn exposure via parenteral nutrition is uncommon in adults, in premature infants, it is more prevalent, so this mode of exposure becomes salient in this population. We will briefly review some of the mechanisms of Mn neurotoxicity and conclude with a discussion of ripe areas for research in this underreported area of neurotoxicity.

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“…Despite acting as an entrance gateway to the brain, the BBB does possess specific receptor-mediated transport mechanisms that can potentially be exploited as a means to target drugs and genes to the brain. As iron can reach the brain by using transferrin (Tf) receptors overexpressed on the blood-brain barrier [6], targeting the transferrin receptor (TfR) strategy has been widely investigated for the delivery of drugs and genes to the brain [7][8]. Among the non-viral gene delivery systems currently under development, generation 3 diaminobutyric polypropylenimine dendrimer (DAB) appears to be particularly promising.…”

mentioning

confidence: 99%

Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex

Somani

Robb

Pickard

et al. 2015

Journal of Controlled Release

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The possibility of using gene therapy for the treatment of brain diseases such as brain cancer, Alzheimer's and Parkinson's diseases, is currently hampered by the lack of gene delivery systems able to cross the blood-brain barrier and deliver DNA to the brain following intravenous administration. On the basis that lactoferrin can effectively reach the brain by using specific receptors for crossing the blood-brain barrier, we propose to investigate if a lactoferrin-bearing generation 3-diaminobutyric polypropylenimine (DAB) dendrimer would allow the transport of plasmid DNA to the brain after intravenous administration.In this work, we demonstrated that the conjugation of lactoferrin to the dendrimer led to an enhanced DNA uptake by 2.1-fold in bEnd.3 murine brain capillary endothelial cells compared to the unmodified dendriplex in vitro. In vivo, the intravenous administration of lactoferrin-bearing DAB dendriplex resulted in a significantly increased gene expression in the brain, by more than 6.4-fold compared to that of DAB dendriplex, while decreasing gene expression in the lung and the kidneys. Gene expression in the brain was significantly higher than in any other major organs of the body. Lactoferrin-bearing generation 3 polypropylenimine dendrimer is therefore a highly promising delivery system for systemic gene delivery to the brain. KEYWORDSBrain delivery; blood-brain barrier; gene expression; dendrimer; lactoferrin 2 1. Introduction Brain diseases, including glioma, Alzheimer's and Parkinson's diseases, currently represent one of the largest and fastest growing area of unmet clinical need. Brain cancer is the leading cause of cancer death in young people and accounts for more than one third of cancer deaths in children aged under 10. Alzheimer's disease is the most common type of dementia, affecting almost 500 000 people in the UK. The symptoms of this disease develop gradually and become more severe over the course of several years. In addition, there is currently no cure for Parkinson's disease, which affects 127 000 people in the UK [1][2][3][4]. Gene therapy has emerged as a promising therapeutic strategy, as the genetic basis for many of these diseases is known. However, the possibility of using genes as medicines to treat brain pathologies is limited by the lack of safe and efficacious delivery systems able to cross the blood-brain barrier (BBB) and to deliver DNA to the brain after intravenous administration, without secondary effects to healthy tissues. In addition, locally administered treatments fail to achieve a widespread gene expression in the target cells throughout the entire brain, which is necessary for a successful treatment of most brain pathologies [2-3, 5]. There is therefore an urgent need to develop safe and efficacious non-viral gene-based nanomedicines able to cross the BBB after intravenous administration, in order to ultimately provide better treatment options for brain diseases than currently available. Despite acting as an entrance gateway to the brain, the BBB does...

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Transferrin receptor on endothelium of brain capillaries

Cited by 966 publications

References 6 publications

Uptake and Transport of Superparamagnetic Iron Oxide Nanoparticles through Human Brain Capillary Endothelial Cells

Uptake and Transport of Superparamagnetic Iron Oxide Nanoparticles through Human Brain Capillary Endothelial Cells

Manganese neurotoxicity: A focus on the neonate

Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex

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