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

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Abstract

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.

Original languageEnglish
Pages (from-to)3684-3697
Number of pages14
JournalMolecular Pharmaceutics
Volume14
Issue number11
DOIs
Publication statusPublished - 6 Nov 2017

Keywords

  • bile
  • bile salts
  • cholesterol
  • colloids
  • digested phospholipid
  • dynamic light scattering
  • gastrointestinal
  • mixed micelle
  • molecular dynamics
  • nephelometry
  • oleic acid
  • pH
  • phase behavior
  • ternary phase diagram

Cite this

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title = "Computational Models of the Intestinal Environment. 3. The Impact of Cholesterol Content and pH on Mixed Micelle Colloids",
abstract = "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.",
keywords = "bile, bile salts, cholesterol, colloids, digested phospholipid, dynamic light scattering, gastrointestinal, mixed micelle, molecular dynamics, nephelometry, oleic acid, pH, phase behavior, ternary phase diagram",
author = "Suys, {Estelle J A} and Warren, {Dallas B} and Porter, {Christopher J H} and Hassan Benameur and Pouton, {Colin W} and Chalmers, {David K}",
year = "2017",
month = "11",
day = "6",
doi = "10.1021/acs.molpharmaceut.7b00446",
language = "English",
volume = "14",
pages = "3684--3697",
journal = "Molecular Pharmaceutics",
issn = "1543-8384",
publisher = "American Chemical Society",
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AU - Suys, Estelle J A

AU - Warren, Dallas B

AU - Porter, Christopher J H

AU - Benameur, Hassan

AU - Pouton, Colin W

AU - Chalmers, David K

PY - 2017/11/6

Y1 - 2017/11/6

N2 - 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.

AB - 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.

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KW - cholesterol

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KW - digested phospholipid

KW - dynamic light scattering

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KW - molecular dynamics

KW - nephelometry

KW - oleic acid

KW - pH

KW - phase behavior

KW - ternary phase diagram

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