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Title: Cellular uptake of PMPC-PDPA polymersomes in mammalian cells
Author: Avila Olias, Maria Milagros
ISNI:       0000 0004 5356 6040
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2014
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Polymersomes (synthetic polymeric vesicles), formed by the self-assembly of amphiphilic block copolymers in water attract great attention as drug delivery systems and as diagnostic/imaging tools. Our group has shown that 2-(methacryloyloxy)ethyl phosphorylcholine-block-2-(diisopropylamino)ethyl methacrylate (PMPC-PDPA) polymersomes are of special interest due to their ability to encapsulate a wide range of therapeutic molecules including anticancer compounds, antibiotics, antibodies, and nucleic acids, and their capacity to deliver their cargo intracellularly, both in vitro and in vivo, without promoting cellular toxicity or stress. The favourable uptake kinetics and toxicological profile of PMPC-PDPA polymersomes justify a thorough study on the cellular interactions and mechanisms underlying their uptake, which was the aim of this thesis. Exploring different polymersome production methods we studied the impact that the physical properties of PMPC-PDPA polymersomes (nanoparticle size and shape) have on their cellular uptake. Using flow cytometry and fluorescence microscopy we demonstrated that both spherical and tubular polymersomes could be used as intracellular delivery vectors. In addition, spherical and tubular polymersomes presented different uptake kinetic profiles, opening new avenues to modulate the temporal delivery of a cargo. In a parallel line of work we identified receptor-mediated endocytosis as a common pathway for the internalisation of PMPC-PDPA polymersome in mammalian cells. Studying polymersome uptake in the presence of antagonists and neutralising antibodies, we identified two families of transmembrane proteins mediating PMPCPDPA polymersome endocytosis and the specific receptors facilitating polymersome uptake. In addition, different endocytic pathways and molecules (i.e. dynamin, BAR domain proteins) were investigated in relation with polymersome internalisation by means of chemical inhibitors, dominant negative proteins and siRNA knockdown. Polymersome endocytosis seems to be dominated by a high level of promiscuity and the ability of PMPC-PDPA polymersome to induce their uptake, which could be translated in new therapeutic applications with a great clinical impact.
Supervisor: Battaglia, Giuseppe ; Smythe, Elizabeth Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available