Shahina Akter: Self-assembly of sodium caprate: colloidal architectures for oral peptide delivery

Abstract

The oral delivery of peptide therapeutics is still a major challenge due to the poor intestinal permeability and low bioavailability. Sodium caprate (C10), a widely used intestinal permeation enhancer, has demonstrated great potential in enhancing oral peptide absorption. However, the self-assembly behavior of C10 under physiologically relevant intestinal conditions is not well understood, which hampers the rational design of C10-based formulations. The main objective of this thesis was to develop a combined approach of coarse-grained molecular dynamics (CG-MD) simulations and small-angle scattering techniques to describe the self-assembly behavior of C10 on different length scales and under biorelevant conditions.

To this end, CG-MD simulations were systematically compared with small angle X-ray scattering (SAXS) and dynamic light scattering (DLS) measurements to define a computational model that can accurately describe the pH- and concentration-dependent self-assembly of C10. The established methodology was then applied to increasingly more complex systems with contrast variation, small-angle neutron scattering (SANS), cryogenic transmission electron microscopy (cryo-TEM), and CG-MD simulations. This integrated experimental-computational approach enabled us to characterize C10 self-assembly in simulated intestinal fluids, in the presence of a model peptide therapeutic and in combination with the oppositely charged polymer poly-L-lysine (PLL), thus revealing how biorelevant components and intermolecular interactions influence aggregate morphology and internal organization.

In summary, the present thesis lays the foundation for a complementary framework of CG-MD and small-angle scattering to study the self-assembly of amphiphiles in complex biological settings. The work combines molecular simulations and experimental structural characterization to provide a general platform for understanding and predicting the colloidal behavior of sodium caprate and related fatty acid systems. The method described here provides a foundation for rational design and optimization of permeation enhancers and colloidal formulations for improving oral peptide delivery.