Primary Supervisor: Professor Matthew I. Gibson, Department of Chemistry

Secondary supervisor: Dr Maria Chiara Arno, University of Birmingham. Addition UoW co-supervisor J. Charmet

PhD project title: Covalent Recruitment of Polymer Therapeutics

University of Registration: University of Warwick

Project outline:

Nanotherapeutics inspired by ‘Ehrlichs Magic Bullet’, aim to target disease (in humans, animals and plants), but still often lack specificity and there remain many questions to solve. We propose that rather than targeting the nanocarrier to the disease, we should modify the diseased tissue such that it ‘grabs’ the nanocarrier. If the modification results in a covalent (irreversible) bond, off-target effects (toxicity) can be removed and low concentrations should be able to achieve large effects.

In this project, we will explore how glycan (sugar) metabolism can be ‘hijacked’ to enable us to engineer the surface of diseased cells specifically. By hijacking how the glycans are processed, we can introduce new functionality onto the cell surface, while achieving selectivity for the diseased tissue. With this knowledge of glycan processing machinery we will target the tissue with therapeutics to give increased efficacy.

This exciting project will combine multidisciplinary aspects from biochemistry to polymer science, with potential for real impact. The GibsonGroup has previously developed nano/polymer systems for advance therapeutics (including antimicrobials) and also shown the proof of principle that we can recruit nanoparticles/polymers to cells.

• Optimization and Stability of Cell–Polymer Hybrids Obtained by “Clicking” Synthetic Polymers to Metabolically Labelled Cell Surface Glycans; Biomacromolecules 2019, 20, 7, 2726-2736
• Engineering Cell Surfaces by Covalent Grafting of Synthetic Polymers to Metabolically-Labelled Glycans, ACS Macro Lett. 2018, 7, 11, 1289-129
• Re-engineering Cellular Interfaces with Synthetic Macromolecules using Metabolic Glycan Labelling, ACS MacroLetters, 2020, 9, 991-1003,

This project will enable a student to be exposed to a unique biomaterials environment and learn/apply multidisciplinary skills in synthetic biomaterials but also cell biology and advanced analytics, using confocal microscopy and flow cytometry. (https://warwick.ac.uk/fac/sci/chemistry/research/gibson/gibsongroup/). It also benefits from collaboration with Dr Arno, an expert in Biomaterials at the University of Birmingham. Her research focusses on the development of functional, biocompatible polymeric materials that can control cell behaviour, including cell proliferation, migration, adhesion, and differentiation.

References:

1. Engineering the Mammalian Cell Surface with Synthetic Polymers: Strategies and Applications, Rapid Commun. 2020, 41, 2000302.
2. Exploiting the role of nanoparticle shape in enhancing hydrogel adhesive and mechanical properties, Nat. Commun. 2020, 11, 1420.

 Key objectives will include:

• Probing glycan uptake and metabolism to hijack the cell surface
• Cell specific targeting by glycans to be monitored by fluorescent probes
• Cell-specific (or selective) chemical labelling using nanoparticles
• Demonstrate function in a 3-D spheroid tumour model

BBSRC Strategic Research Priority: Understanding the Rules of Life: Immunology, Stem Cells & Systems Biology. Integrated Understanding of Health: Ageing, Pharmaceuticals & Regenerative Biology

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Techniques that will be undertaken during the project:

• Carbohydrate Chemistry
• Polymer Chemistry
• 2D and 3D Cell culture
• Confocal microscopy
• Flow Cytometry

Contact: Professor Matt Gibson, University of Warwick