On the Mechanism and Dynamics of Uptake and Permeation of Polyether-Copolyester Dendrimers Across an In Vitro Blood–Brain Barrier Model

• Published in: Journal of pharmaceutical sciences 2009-10, Vol.98 (10), p.3748-3760
• Main Authors: Dhanikula, Renu Singh, Hammady, Taha, Hildgen, Patrice
• Format: Article
• Language: English
• Subjects: Atenolol - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - chemistry; Biological and medical sciences; blood-brain barrier; Blood-Brain Barrier - chemistry; Caveolins - antagonists & inhibitors; Cell Line; Cell Survival; Clathrin - antagonists & inhibitors; dendrimers; Dendrimers - chemistry; Dendrimers - toxicity; Electric Impedance; Endothelial Cells - drug effects; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Fluorescent Dyes; General pharmacology; Half-Life; Humans; in vitro models; Medical sciences; Membranes, Artificial; nanotechnology; Permeability; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polyesters - chemistry; Polyesters - toxicity; Theophylline - metabolism
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1002/jps.21669

Dendrimers have emerged as a promising drug delivery system due to their well defined size, tailorability, and multifunctional nature. However, their application in brain delivery is relatively a new area of research. The present study was aimed at evaluating the uptake and permeation of polyether-copolyester (PEPE) dendrimers across the blood–brain barrier model and exploring the underlying mechanisms. Saturation was observed in the uptake of rhodamine B labeled PEPE dendrimers by brain vascular endothelial (bEnd.3) cells at high concentrations. Clathrin and caveolin inhibitors produced partial inhibition of the dendrimer uptake, signifying contribution of both pathways in the uptake process. PEPE dendrimers were able to cross in vitro BBB model in high amounts with Papp of 19.7±1.9×10−6 cm/s and 38.6±4.1×10−6 cm/s for den-1-(G2)-400 and den-2-(G2)-400, respectively; and only 11–14% reduction in transendothelial electrical resistance during initial 4 h. The results of this study suggest that architecture of dendrimers plays a major role not only in influencing the extent and mechanism of uptake by bEnd.3 cells but also permeation across the BBB model. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3748–3760, 2009