Computational Models of the Intestinal Environment. 3. The Impact of Cholesterol Content and pH on Mixed Micelle Colloids

In
this study, we use molecular dynamics (MD) and experimental
techniques (nephelometry and dynamic light scattering) to investigate
the influence of cholesterol content and pH on the colloidal structures
that form in the gastrointestinal (GI) tract upon lipid digestion.
We demonstrate that the ionization state of the molecular species
is a primary driver for the self-assembly of aggregates formed by
model bile and therefore should be considered when performing in silico modeling of colloidal drug delivery systems. Additionally,
the incorporation of physiological concentrations of cholesterol within
the model systems does not affect size, number, shape, or dynamics
of the aggregates to a significant degree. The MD data shows a reduction
in aggregate size with increasing pH, a preference for glycodeoxycholate
(GDX) to occupy the aggregate surface, and that the mixed micellar
aggregates are oblate spheroids (disc-like). The results obtained
assist in understanding the process by which pH and cholesterol influence
self-assembly of mixed micelles within the GI tract. The MD approach
provides a platform for investigation of interactions of drugs and
formulation excipients with the endogenous contents of the GI tract.