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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 27, 2004; DOI: 10.1124/jpet.104.071845

0022-3565/04/3113-1115-1120$20.00
JPET 311:1115-1120, 2004
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NEUROPHARMACOLOGY

Effects of {gamma}- and Hydroxypropyl-{gamma}-cyclodextrins on the Transport of Doxorubicin across an in Vitro Model of Blood-Brain Barrier

V. Monnaert, D. Betbeder, L. Fenart, H. Bricout, A. M. Lenfant, C. Landry, R. Cecchelli, E. Monflier, and S. Tilloy

Blood-Brain Barrier Laboratory, Université d'Artois-Institut Pasteur de Lille (V.M., D.B., H.B., A.M.L., C.L., R.C., E.M., S.T.) and Cellial Technologies (L.F.), Faculté des Sciences Jean Perrin, Lens Cedex, France

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 µM, 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.

Received for publication May 26, 2004
Accepted July 27, 2004.

Address correspondence to: Dr. Sébastien Tilloy, Université d'Artois, Faculté des Sciences Jean Perrin, rue Jean Souvraz, SP 18, 62307 Lens Cedex, France. E-mail: sebastien.tilloy{at}univ-artois.fr






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