Interactions on the nanoscale: what happens when nanomaterials meet complex fluids

Recent advancements in nanotechnology have significantly expanded its potential in pharmaceutical applications, with lipid mesophases (LNPs) emerging as versatile carriers for drug delivery. Despite their promise, the interactions between LNPs and complex physiological fluids remain insufficiently understood. This thesis investigates the physicochemical interactions between LNPs and fluids from the cervicovaginal and colorectal tracts, as well as the eye, aiming to inform the development of more effective drug delivery systems.

Initially, this work reviews an overview of LNP drug delivery systems, highlighting the role of the biomacromolecular corona in influencing lipid self-assembly profiles. It addresses the challenges of bridging the gap between in vitro behaviour and in vivo performance, focusing on optimising drug delivery strategies through an understanding of these fundamental interactions.

Additionally, this work explores the impact of LNP structure and composition on vaginal cells, revealing critical insights into the poorly understood phenomenon of protein corona formation. The study of five distinct LNP formulations interacting with VK2 vaginal epithelial cells clarifies how structural and compositional diversity affects cellular integrity and response to nanoparticle interventions, thereby informing the design of more effective vaginal drug delivery systems.

Furthermore, an analysis of the interaction between simulated colorectal fluids and various LNP formulations demonstrates the influence of fluid composition on LNP size and structure. This research highlights the importance of tailoring LNP characteristics to accommodate site-specific conditions, thereby enhancing the efficacy of colorectal drug delivery systems.

This study also demonstrates the dynamic behaviour of LNPs in simulated vaginal and lacrimal fluids, the study isolates the contributions of pH and protein interactions to LNP structure and size modulation. The comparative analysis of four LNP formulations underscores the critical role of composition in determining phase behaviour, offering valuable insights into the development of advanced drug delivery systems for complex physiological environments.

This comprehensive study employs advanced techniques including small-angle X-ray scattering, cryo-transmission electron microscopy, dynamic light scattering, proteomics, nanoparticle tracking analysis, capillary electrophoresis, flow cytometry, and confocal microscopy. These methodologies provide a robust evaluation of LNP size, structural integrity, and phase behaviour, contributing significantly to the field of nanomedicine and the optimisation of nanoparticle-based drug delivery systems.