Aim of the PhD Project:
- To design and synthesise novel upconversion nanoparticles, that are stable, can be solubilised and feature functional capping ligands.
- To design and synthesise new families of nanogels that can facilitate the incorporation of unconversion nanoparticles and are biocompatible.
- To carry out in-depth material, toxicity and in-vitro evaluation of the novel nanomaterials.
- To apply and target the nanomaterials to the GLP-1/glucagon receptor and to assess β-cell functionality.
Global rates of diabetes mellitus are increasing, and treatment of the disease consumes a growing proportion of healthcare spending across the world. Pancreatic β-cells, responsible for insulin production, decline in mass in type 1 and, to a more limited degree, in type 2 diabetes. However, the extent and rate of loss in both diseases differs between patients resulting in the need for the development of novel diagnostic tools, which could quantitatively assess changes in mass of β-cells over time and potentially lead to earlier diagnosis and improved treatments. Due to small concentrations of b-cells, sensitive imaging modalities are favoured, hence optical imaging has crucial importance for this application. Within this project, for the first time, upconversion nanoparticles will be used to monitor beta-cell fate in diabetes and will aid our understanding of diabetes pathogenesis.
Upconversion nanoparticles (UCNPs) are lanthanide-doped inorganic nanomaterials, which absorb near-infrared radiation and emit visible light. Their unique optical properties make them suitable for fluorescence microscopy, imaging deep tissue, nanomedicine and optogenetics. UCNPs exhibit resistance to photobleaching and have long luminescence lifetimes. Since the early 2000s, the field of UCNPs has rapidly expanded, with particular interest in using UCNPs for bioimaging due to a number of interesting properties:
- Excitation in NIR: This is particularly advantageous over organic fluorophores whichare typically excited by short wavelength light (UV or blue/green visible). This shortwavelength excitation of organic fluorophores has a number of disadvantages. The tissue penetration of this wavelength light is poor, only to a depth of 0.5–2 mm and with 15–40 % of the incident radiation reflected. This means that it is impossible to excite fluorophore deep within the body from an external light source. There is therefore, a significant advantage to excitation in the NIR region, especially in the tissue optical windows at 650-1100 nm, where light has its maximum penetration in tissue.
- Narrow emission bands: Lanthanide ions have characteristic sharp emission bandsdue to the shielding of core-like 4f electrons by outer 5s and 5p electrons, resulting inweak electron-phonon coupling. The 4f-4f transitions are therefore barely affected by the surrounding environment, leading to the sharp emission bands observed. This is particularly useful in UCNP nanosystems in sensing applications as donors/acceptors can be chosen which selectively overlap with one particular UCNP emission band.
- Low photobleaching: Photobleaching is a phenomenon which describes the irreversibleloss of optical properties from fluorophores due to exposure to repeat cycles of excitationand emission. Organic fluorophores exhibit much lower photostability than inorganic materials and typically exhibit photobleaching due to photon induced covalent modification, trapping the fluorophore in a dark (non-emissive) state.
However, one limitation that can often hamper the use of UCNPs is their lack of solubility in aqueous media and the need for surface modification and ligand capping. To this end we aim to develop UCNPs with a nanogel coating (UCNGs) that will be rendered more hydrophilic and biocompatible with a cross-linked polyethylene-glycol based surface shell layer. Nanogels have the ability to retain high volumes of water or biological fluids, and hence maintain their structure. Nanogels have superior properties as they offer: 1) encapsulation stability for sensitive payloads, 2) they have low immunogenicity and toxicity, and can be designed to be fully biodegradable, 3) multiple biological or imaging payloads can be delivered in a single nanogel, facilitating the combination of therapies with imaging, 4) and their synthesis can be water-based and easily scaled.
Students with a background in chemistry with an interest in nanomaterials, spectroscopic characterisation, and in vitro evaluation of UCNGs would be ideal for this project.