Quaternary ammonium beta-cyclodextrin nanoparticles for enhancing doxorubicin permeability across the in vitro blood-brain barrier.
This study describes novel quaternary ammonium beta-cyclodextrin (QAbetaCD) nanoparticles as drug delivery carriers for doxorubicin (DOX), a hydrophobic anticancer drug, across the blood-brain barrier (BBB). QAbetaCD nanoparticles show 65-88 nm hydrodynamic radii with controllable cationic properties by adjusting the incorporated amount of quaternary ammonium group in their structure. ATR-FTIR studies confirm the complexation between the QAbetaCD nanoparticles and DOX. QAbetaCD nanoparticles are not toxic to bovine brain microvessel endothelial cells (BBMVECs) at concentrations up to 500 microg x mL(-1). They also do not change the integrity of BBMVEC monolayers, an in vitro BBB model, including transendothelial electrical resistance value, Lucifer yellow permeability, tight junction protein occludin and ZO-1 expression and morphology, cholesterol extraction, and P-glycoprotein (P-gp) expression and efflux activity, at a concentration of 100 microg x mL(-1). Some QAbetaCD nanoparticles not only are twice as permeable as dextran (M(w) = 4000 g x mol(-1)) control, but also enhance DOX permeability across BBMVEC monolayers by 2.2 times. Confocal microscopy and flow cytometry measurements imply that the permeability of QAbetaCD nanoparticles across the in vitro BBB is probably due to endocytosis. DOX/QAbetaCD complexes kill U87 cells as effectively as DOX alone. However, QAbetaCD nanoparticles completely protect BBMVECs from cytotoxicity of DOX at 5 and 10 microM after 4 h incubation. The developed QAbetaCD nanoparticles have great potential in safely and effectively delivering DOX and other therapeutic agents across the BBB.
Gil
Eun Seok
ES
Department of Surgery, Pennsylvania State University, Hershey, Pennsylvania 17033, USA. eun.gil@tufts.edu
Li
Jianshu
J
Xiao
Huining
H
Lowe
Tao Lu
TL
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000098:blood supply / Q000166:cytology / Q000187:drug effects; D002417:Cattle; D002463:Cell Membrane Permeability / Q000187:drug effects; D004317:Doxorubicin / Q000378:metabolism*; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D013499:Surface Properties; D047392:beta-Cyclodextrins / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology
D004337:Drug Carriers; D000644:Quaternary Ammonium Compounds; D047392:beta-Cyclodextrins; D004317:Doxorubicin