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Engineering Polysaccharide-Based Polymeric Micelles to Enhance Permeability of Cyclosporin A Across Caco-2 Cells

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Purpose.

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.

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Abbreviations

AP:

apical side

BL:

basolateral side

CsA:

cyclosporin A

DEX:

dextran T10

HPC:

hydroxypropylcellulose

P85:

Pluronic P85

PGI:

P-glycoprotein inhibitor

P-gp:

P-glycoprotein

POE-C16:

polyoxyethylene (10) cetyl ether

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Authors and Affiliations

  1. Faculty of Pharmacy, University of Montreal, Montreal, Quebec, H3C 3J7, Canada

    Mira F. Francis & Francçoise M. Winnik

  2. “Petru Poni”, Institute of Macromolecular Chemistry, Iasi, 700487, Romania

    Mariana Cristea

  3. Department of Chemistry, University of Montreal, Montreal, Quebec, H3C 3J7, Canada

    Yali Yang & Francçoise M. Winnik

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  1. Mira F. Francis
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Francis, M., Cristea, M., Yang, Y. et al. Engineering Polysaccharide-Based Polymeric Micelles to Enhance Permeability of Cyclosporin A Across Caco-2 Cells. Pharm Res 22, 209–219 (2005). https://doi.org/10.1007/s11095-004-1188-0

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