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Interaction of self-assembling cyclic peptide-polymer nanotubes with biological models
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Ellacott, Sean H. (2020) Interaction of self-assembling cyclic peptide-polymer nanotubes with biological models. PhD thesis, University of Warwick.
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WRAP_Theses_Ellacott_2020.pdf - Submitted Version - Requires a PDF viewer. Download (12Mb) | Preview |
Official URL: http://webcat.warwick.ac.uk/record=b3492921~S15
Abstract
Cyclic peptide-polymer nanotubes (CPNT) are an emerging class of nanomaterials with a strong potential for biological applications. This thesis aims to investigate the interaction of different CPNT systems with different biological models. Firstly, the place of CPNT in the wider family of synthetic nanocylinders is put into perspective, with a focus on existing applications.
Secondly, the behaviour of a library of CPNT with differing polymer composition and proclivity for self-assembly was studied in cellular models (cell lines and tumour spheroids). This study focuses on the relationship between self-assembly and cellular uptake and its findings show that relatively short CPNT (~15 nm) are taken up the most effectively, with specific patterns in intracellular localisation in both type of models.
Thirdly, the cellular uptake and the in vivo properties of stabilised elongated CPNT (>100 nm) are compared to those of short dynamic CPNT (~10 nm), using cell lines and rat models. Despite exhibiting lower levels of cellular uptake than their dynamic counterparts, stabilised CPNT are shown to be promising drug delivery vehicles thanks to their longer circulation in vivo allied to an efficient excretion. In parallel, the addition of integrin-targeting moieties to dynamic CPNT is also looked into. Targeting CPNT promote uptake in cell lines overexpressing αvβ3 integrins. Clear limitations for any use for drug delivery purposes can be highlighted, as their blood clearance is accelerated compared to non-targeting CPNT. This was explained by a higher propensity for recognition by the immune system as demonstrated by the high levels detected in the liver and spleen.
Fourthly, the interaction of a library of charged polymers and CPNT with lipid bilayer models is investigated, using complementary techniques. Charged CPNT show higher levels of interaction than charged polymers and neutral CPNT on the lipid model employed. Further studies employing spectroscopy techniques and neutron reflectivity support a model of interaction for charged CPNT. The interaction is demonstrated to lead to the formation of pores in the bilayer, excluding any embedding of the CP in the hydrophobic tail regions. By anchoring to negatively charged head groups, the CPNT can insert in the bilayer and form a diffuse hydrated layer at the surface of the outer leaflet. Antibacterial activity is also briefly assessed in this work.
Overall, this thesis gathers key insights on the behaviour of various CPNT in lipid bilayer, cellular and animal models.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QD Chemistry T Technology > TA Engineering (General). Civil engineering (General) |
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Library of Congress Subject Headings (LCSH): | Nanotubes, Cyclic peptides, Self-assembly (Chemistry), Biopolymers | ||||
Official Date: | May 2020 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Department of Chemistry | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Perrier, Sébastien | ||||
Format of File: | |||||
Extent: | xxxv, 260 leaves : illustrations (some colour) | ||||
Language: | eng |
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