Quasielastic Light Scattering and Cholesterol Thermodynamic Activity Studies of the Micelle-to-Vesicle Transition in Conjugated Ursodeoxycholate-Lecithin-Cholesterol Solutions

Abstract

We have conducted a detailed quasielastic light scattering (QELS) study of aqueous solutions containing conjugated ursodeoxycholate (UDC), lecithin (L), and cholesterol (Ch), and have correlated the QELS results with measurements of the Ch thermodynamic activity ( A τ) previously reported by our laboratory (Jain et al., Pharm Res. 9, 792 (1992)). Parallel studies of pure taurochenodeoxycholate (TCDC)-L-Ch solutions and mixed tauroursodeoxycholate (TUDC) and TCDC solutions were also conducted. In the conjugated UDC-L and TUDC/TCDC (1:1)-L cases, micelles (mean hydrodynamic radius, R̄ H: 20-25 Å) dominated the scattering at low Ch concentrations, vesicles ( R̄ H H: 300-400 Å) dominated at high Ch concentrations, and at intermediate Ch concentrations vesicles and micelles were both detectable. Based on measurements of the total scattered light intensity, the vesicles represented only a small fraction of the total lipid concentration (<3%) even at the highest Ch concentrations studied. In all cases, vesicle formation occurred at A τ values less than one (i.e., less than the activity of Ch monohydrate). In contrast, the TCDC-L-Ch system demonstrated only micelles up to unit A τ. Using information on the nature of the micellar species present in these systems, we developed a novel quantitative model of the Ch activity data which indicates that UDC-L mixed micelles bind Ch in a highly cooperative multisite process, whereas TCDC-L mixed micelles exhibit much less cooperativity. A thermodynamic model of vesicle formation, which accounts for the differences between the TUDCL-Ch and TCDC-L-Ch systems in terms of the activities of L and Ch corresponding to each system, is also presented.