Seegobin, Nidhi; (2025) Nano-carriers for Local Targeting in Inflammatory Bowel Disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The treatment of Inflammatory Bowel Disease (IBD) is limited by severe side effects from non-specific systemic therapies. This thesis explores the potential of natural and synthetic nanotechnology-based drug delivery systems to target colonic inflammation more effectively, minimising adverse effects while improving therapeutic outcomes. The first part of this work assessed the suitability of milk-derived extracellular vesicles (EVs) for colonic drug delivery and their therapeutic effects when administered via oral or rectal routes in a colitis mouse model. Through physiologically relevant gastro-intestinal in vitro stability testing, it was found that EVs remained stable only in the colonic environment and showed potential for delivering hydrophilic drugs. However, no therapeutic effect was seen in vivo following either oral or rectal administration. Their use in IBD was limited by the extracellular mechanism of action of most marketed biologics, suggesting that currently EVs may be more suitable for other therapeutic applications. Given these limitations, the second part of the thesis focused on fabricating synthetic low molecular weight PLGA nanoparticles (NPs) loaded with the lipophilic drug tofacitinib. In colitis mouse models, these PLGA NPs significantly prevented weight loss compared to PLGA or the drug alone, demonstrating their potential to reduce systemic side effects while improving therapeutic efficacy. Lastly, computational methods, including Design of Experiments (DoE) and Machine Learning (ML), were employed to optimise the production of PLGA NPs. These techniques suggest that fitting ML models to DoE-designed factorial datasets provides deeper insights into data relationships compared to DoE alone, highlighting ML's potential in experimental design and optimisation, particularly in resource-constrained settings. Ultimately, this thesis aims to develop natural and synthetic inflammation- targeted nanocarriers, offering a promising alternative to current IBD therapies and improving patient outcomes through enhanced efficacy and reduced side effects.

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