Engineering polysaccharide-based polymeric micelles to enhance permeability of cyclosporin A across Caco-2 cells.
OBJECTIVE
To assess and compare the effectiveness of two types of polysaccharide-based micelles as delivery vehicles for poorly water soluble drugs by monitoring their permeability across Caco-2 cell monolayers.


METHODS
Dextran (DEX) and hydroxypropylcellulose (HPC) were hydrophobically modified (HM) by grafting polyoxyethylene cetyl ether (POE-C16, 15 mol% and 5.4 mol%, respectively). The onset of micellization and mean diameter of polymeric micelles formed by HM-DEX and HM-HPC were determined by fluorescence spectroscopy and dynamic light scattering, respectively. Cyclosporin A (CsA)-loaded polymeric micelles were prepared by a dialysis procedure, and the amount of incorporated CsA was assayed by high performance liquid chromatography (HPLC). The stability of micelles in simulated gastric and intestinal fluids was studied as a function of contact time, and their cytotoxicity toward Caco-2 cells was evaluated using the MTT colorimetric assay. The bidirectional transport across Caco-2 cell monolayers of CsA entrapped in HM-DEX and HM-HPC micelles and of the polymers themselves was evaluated in the presence and absence of P-glycoprotein inhibitor.


RESULTS
The amount of CsA incorporated in HM-HPC and HM-DEX micelles reached 5.5 and 8.5% w/w, respectively (entrapment efficiency of 22% or more). The polymeric micelles exhibited high stability in gastric and intestinal fluids and no significant cytotoxicity toward Caco-2 cells. The apical to basal permeability of CsA across Caco-2 cells increased significantly when loaded in polymeric micelles compared to free CsA.


CONCLUSIONS
Polysaccharide-based polymeric micelles are promising carriers for the oral delivery of poorly water soluble drugs. In vitro tests indicate that, overall, HM-HPC micelles are more effective compared to HM-DEX micelles.
Francis
Mira F
MF
Faculty of Pharmacy, University of Montreal, Montreal, Quebec H3C 3J7, Canada. francoise.winnik@umontreal.ca
Cristea
Mariana
M
Yang
Yali
Y
Winnik
Françoise M
FM
D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D018938:Caco-2 Cells; D002616:Chemical Engineering / Q000379:methods*; D002627:Chemistry, Physical / Q000379:methods; D016572:Cyclosporine / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D008823:Micelles; D010539:Permeability / Q000187:drug effects; D011108:Polymers / Q000737:chemistry / Q000493:pharmacokinetics*; D011134:Polysaccharides / Q000737:chemistry / Q000493:pharmacokinetics*
D008823:Micelles; D011108:Polymers; D011134:Polysaccharides; D016572:Cyclosporine