Validation of the Transferrin Receptor for Drug Targeting to Brain Capillary Endothelial Cells<i>In Vitro</i>

Visser, Corine C.; Stevanović, Sanja; Voorwinden, L. Heleen; Gaillard, Pieter J.; Crommelin, Daan J.A.; Danhof, Meindert; Boer, Albertus G. de

doi:10.1080/10611860410001701706

Cited by 90 publications

(44 citation statements)

References 13 publications

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“…In this study, we employed nystatin, indomethacin, and methyl-␤-cyclodextrin as inhibitors of caveolae-mediated endocytosis. Nystatin and methyl-␤-cyclodextrin inhibit caveolae-mediated endocytosis by interacting with cholesterol in the plasma membrane (1,36), and indomethacin inhibits the process by inhibiting the internalization of caveolae and the return of plasmalemmal vesicles to the cell surface (37,41). However, albumin uptake by RLE-6TN cells was not inhibited by these inhibitors (Fig.…”

Section: Discussionmentioning

confidence: 84%

Clathrin-mediated endocytosis of FITC-albumin in alveolar type II epithelial cell line RLE-6TN

Yumoto¹,

Nishikawa²,

Okamoto³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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-We examined mechanisms of FITC-albumin uptake by alveolar type II epithelial cells using cultured RLE-6TN cells. Alkaline phosphatase activity and the expression of cytokeratin 19 mRNA, which are characteristic features of alveolar type II epithelial cells, were detected in RLE-6TN cells. The uptake of FITCalbumin by the cells was time and temperature dependent and showed the saturation kinetics of high-and low-affinity transport systems. FITC-albumin uptake was inhibited by native albumin, by chemically modified albumin, and by metabolic inhibitors and bafilomycin A 1, an inhibitor of vacuolar H ϩ -ATPase. Confocal laser scanning microscopic analysis after FITCalbumin uptake showed punctate localization of fluorescence in the cells, which was partly localized in lysosomes. FITC-albumin taken up by the cells gradually degraded over time, as shown by fluoroimage analyzer after SDS-PAGE. The uptake of FITC-albumin by RLE-6TN cells was not inhibited by nystatin, indomethacin, or methyl-␤-cyclodextrin (inhibitors of caveolae-mediated endocytosis) but was inhibited by phenylarsine oxide and chlorpromazine (inhibitors of clathrin-mediated endocytosis) in a concentration-dependent manner. Uptake was also inhibited by potassium depletion and hypertonicity, conditions known to inhibit clathrin-mediated endocytosis. These results indicate that the uptake of FITC-albumin in cultured alveolar type II epithelial cells, RLE-6TN, is mediated by clathrin-mediated but not by caveolae-mediated endocytosis, and intracellular FITC-albumin is gradually degraded in lysosomes. Possible receptors involved in this endocytic system are discussed. albumin clearance; caveolae-mediated endocytosis; endocytic receptor; modified albumin; protein transport THE DISTAL AIR SPACES OF THE lung (alveolar region) are lined with a continuous epithelium comprising two major types of epithelial cells, type I and type II. Type I epithelial cells have a squamous morphology and cover ϳ90 -95% of the alveolar surface area. Type II cells are cuboidal epithelial cells and cover ϳ5-10% of the surface area, although the number of type II cells in alveolar epithelia is similar to or more than that of type I cells. Type II cells also serve as progenitors of type I cells (13,40). Alveolar lining fluid contains various physiologically important proteins such as albumin, immunoglobulin G, and transferrin. The concentration of albumin in alveolar fluid is usually much lower than that in the blood, whereas the concentration would increase to 40 -65% of plasma level in hydrostatic pulmonary edema and to 75-95% in lung injury pulmonary edema. The clearance of serum proteins from the alveolar space is a critical process in recovery from pulmonary edema and in maintaining the normal alveolar milieu (17,22). Therefore, understanding the mechanisms of protein transport in alveolar epithelial cells is important for the development of better therapeutic approaches. In addition, such information could provide new insights into improved strategies for pulmonary delivery of ex...

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Section: Discussionmentioning

confidence: 84%

Clathrin-mediated endocytosis of FITC-albumin in alveolar type II epithelial cell line RLE-6TN

Yumoto¹,

Nishikawa²,

Okamoto³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Each of these inhibitors acts on a different endocytic mechanism on the BBB. Phenylarsine oxide has been reported to be an inhibitor of clathrin-mediated endocytosis [23]. Filipin blocks the caveolae-mediated process in non-specific adsorptive endocytosis [24].…”

Section: Mechanisms Of Cellular Uptake Of Dna Complexed To Dab-lf Denmentioning

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 can be used for the delivery of anticancer drugs to the brain due to the overexpression of this receptor on the surface of the endothelial cells of the blood-brain barrier (BBB) [508]. Gan and Feng [509] [49,512,513].…”

Section: Transferrin-based Targetingmentioning

confidence: 99%

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

Pérez-Herrero

Fernández‐Medarde

2015

European Journal of Pharmaceutics and Biopharmaceutics

1,383

754

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Cancer is the second worldwide cause of death, exceeded only by cardiovascular diseases. It is characterized by uncontrolled cell proliferation and an absence of cell death that, except for hematological cancers, generates an abnormal cell mass or tumor. This primary tumor grows thanks to new vasculatization and, in time, adquires metastatic potential and spreads to other body sites, which causes metastasis and finally death. Cancer is caused by damage or mutations in the genetic material of the cells due to environmental or inherited factors. While surgery and radiotherapy are the primary treatment used for local and non-metastatic cancers, anti-cancer drugs (chemotherapy, hormone and biological therapies) are the choice currently used in metastasic cancers. Chemotherapy is based on the inhibition of the division of rapidly growing cells, which is a characteristic of the cancerous cells, but unfortunately, it also affects normal cells with fast proliferation rates, like the hair follicles, bone marrow and gastrointestinal tract cells, generating the characteristic side effects of chemotherapy. The indiscriminate destruction of normal cells, the toxicity of conventional chemotherapeutic Código de campo cambiado

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Validation of the Transferrin Receptor for Drug Targeting to Brain Capillary Endothelial CellsIn Vitro

Cited by 90 publications

References 13 publications

Clathrin-mediated endocytosis of FITC-albumin in alveolar type II epithelial cell line RLE-6TN

Clathrin-mediated endocytosis of FITC-albumin in alveolar type II epithelial cell line RLE-6TN

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

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

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