Hardmeier Samame, Mark Stephan Edward; (2024) Development of a modular nanostructure: Saccharide modified nanomaterials for applications in adenocarcinoma detection via mucoadhesion. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Colon cancer, particularly mucinous colorectal adenocarcinoma (MCA), represents a significant challenge in oncology due to its low survival rates and resistance to traditional chemotherapeutic approaches. Early detection is paramount for improving patient outcomes, yet current diagnostic methods, such as standard colonoscopy, often rely on subjective assessments and may miss subtle lesions. In this context, we propose the development of a novel nanoparticle-based fluorescent agent tailored for the early detection of MCA. Our study focuses on exploiting the unique glycoprotein surface of MCA, particularly the overexpressed mucin-2 (MUC2), as a target for nanoparticle binding. To achieve this, we synthesised fluorescent poly(lactic-co-glycolic acid) (PLGA) as well as silica nanoparticles and modified their surfaces to facilitate interactions with MUC2. We endeavoured to create dendritic scaffolds on nanoparticle surfaces. Then, we attempted to functionalise the particles with glucose and galactose molecules to enhance binding affinity through sugar-sugar interactions. We monitored the synthesis of saccharide monolayer particles and saccharide functionalised dendritic particles, applying a range of analytical techniques to assess the functionalisation's efficacy. Key methods used include thermogravimetric analysis, transmission electron microscopy, fluorescence spectroscopy, mass spectrometry, and colourimetric assays. Through comprehensive biological evaluations, including assessments of cytotoxicity and targeting properties, we investigated the interaction of glucose- and galactose-functionalised nanoparticles with MUC2 and glycan-expressing colon cancer cells (CaCo-2). While verifying functionalised dendritic particles was inconclusive, our findings are at least consistent with successful functionalisation. In conclusion, our study underscores the potential of saccharide-functionalised fluorescent nanoparticles as targeted agents for mucinous tissues, offering a promising foundation for further research to enhance early detection and treatment strategies for MCA.

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