Effects of gamma- and hydroxypropyl-gamma-cyclodextrins on the transport of doxorubicin across an in vitro model of blood-brain barrier.
Association between doxorubicin (DOX) and gamma-cyclodextrin (gamma-CD) or hydroxypropyl-gamma-CD (HP-gamma-CD) has been examined to increase the delivery of this antitumoral agent to the brain. The stoichiometry and the stability constant of gamma-CD or HP-gamma-CD and DOX complexes were determined in physiological medium by UV-visible spectroscopy. By using an in vitro model of the blood-brain barrier (BBB), endothelial permeability and toxicity toward the brain capillary endothelial cells of DOX, gamma-CD, and HP-gamma-CD were performed. For each CD, endothelial permeability was relatively low and a disruption of the BBB occurred at 20 microM, 20 mM, and 50 mM DOX, gamma-CD, and HP-gamma-CD, respectively. Increasing amounts of CDs were added to a fixed DOX concentration. Addition of gamma-CD or HP-gamma-CD, up to 15 and 35 mM, respectively, decreased the DOX delivery, probably due to the low complex penetration across the BBB and the decrease in free DOX concentration. Higher CD concentrations increased the DOX delivery to the brain, but this effect is due to a loss of BBB integrity. In contrast to what was observed on Caco-2 cell model with various drugs, CDs are not able to increase the delivery of DOX across our in vitro model of BBB.
Blood-Brain Barrier Laboratory, Université d'Artois-Institut Pasteur de Lille, Lens Cedex, France.
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V
Monnaert
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Betbeder
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Fenart
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Bricout
A M
AM
Lenfant
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Landry
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R
Cecchelli
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Monflier
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Tilloy
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002196:Capillaries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D018920:Coculture Techniques; D004317:Doxorubicin / Q000378:metabolism*; D004553:Electric Conductivity; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D008856:Microscopy, Fluorescence; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D013056:Spectrophotometry, Ultraviolet; D014227:Triazines / Q000494:pharmacology; D047408:gamma-Cyclodextrins / Q000494:pharmacology*
D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D010880:Piperidines; D014227:Triazines; D047408:gamma-Cyclodextrins; C479659:hydroxypropyl-gamma-cyclodextrin; C077022:S 9788; D004317:Doxorubicin