HEC-cysteamine conjugates: Influence of degree of thiolation on efflux pump inhibitory and permeation enhancing properties

Within the present study hydroxyethyl cellulose-cysteamine conjugates are investigated regarding bio-compatibility, in situ gelling, permeation enhancing and efflux pump inhibitory properties. For this purpose, a series of concentrations of sodium periodate was prepared to oxidize HEC leading to ring opening of glucose subunits. The resulting polymers showing varying degrees of oxidation (DO) were then conjugated with cysteamine stabilized via reductive amination. Consequently, HEC-cysteamine conjugates with increasing degree in thiolation were obtained. Since the conjugates are positively charged, potency of cytotoxicity was tested by resazurin assay. In situ gelling properties of the conjugates were studied to investigate change of their viscosity due to inter- and/or intramolecular crosslinking via disulfide bonds. The influence of the presence of the conjugates on transport of rhodamine 123 and fluoresceinisothiocyanate-dextran 4 (FD4) representing model compounds for P-glycoprotein (P-gp) inhibition and permeation enhancing studies, respectively, across Caco-2 cell monolayers was determined. The conjugates showed a degree of thiolation in the range of 316-2158 mu mol/g. Within 30 min, dynamic viscosity of the conjugate with the lowest degree of thiolation 0.5% (m/v) increased up to 300-fold. The conjugates showed a degree of thiolation-dependent increase in cytotoxicity but they all were found comparatively low cytotoxic. The addition of the conjugate with thiol group content of 1670 mu mol/g resulted in the highest improvement in the transport of both rhodamine 123 and FD4 as compared to buffer control. Accordingly, the degree of thiolation strongly influences the properties of the conjugates and the modulation of the degree of thiolation could be exploited for development of various drug delivery systems. (C) 2011 Elsevier B.V. All rights reserved.