Magon, MS; (2017) Mechanisms of endocytosis of polymersomes and applications in intracellular delivery. Doctoral thesis , UCL (University College London).

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Abstract

The complexity of cell biology calls for research on the fundamental rules underlying biological mechanisms. Endocytosis is a major cellular regulator of homoeostatic processes that allows for 'ingestion' of materials from the outside to the inside of the cell. It plays a fundamental role in processes such as uptake of nutrients, receptor signalling, cell migration, cell attachment, cell-cell interactions, neurotransmission, cell division or tissue clearance from pathogens and cell debris. Viruses and intracellular bacteria exploit endocytosis to access the protective cell micro-environment to grow and reproduce. While they come in different shapes and sizes, we do not fully understand how these physical properties are related to endocytosis. In this thesis I investigate how shape and size are sensed by cells in the endocytic processes. I used advanced microscopy techniques, nanotechnology, cell biology and quantitative data analysis to uncover the principles of shape- and size- dependent effects on endocytosis kinetics and intracellular trafficking. Using synthetic polymeric nanoparticles of finely controlled properties, we mimicked their nature's counterparts in order to access information about the effect of isolated properties, avoiding the complexity of a biological system. We show that spherical particles have substantially different kinetics and trafficking profiles compared to tubular or high genus particles. The size of the spheres ranging between 20 nm and 100 nm also affected the kinetics of endocytosis. Moreover, the nanoparticle system is applied to bypass natural viruses' endocytic pathway and to employ it for intracellular gene delivery. Artificial polymeric envelopes are constructed for adeno-associated viruses in order to improve gene expression in mammalian cells. With this thesis I aim to demonstrate that physical approaches and the development of novel methodologies allow us to address challenging questions in cell biology that could otherwise remain unanswered.

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