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Title: Molecularly Imprinted Polymers as an alternative to biological receptors in toxicology
Author: Settipani, Julie
ISNI:       0000 0004 8498 3947
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2019
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Consumer and environmental safety decisions are based on exposure and hazard data interpreted using risk assessment approaches. The adverse outcome pathway (AOP) conceptual framework has been presented as a logical sequence of events occurring across multiple levels of biological organisation. This aims to increase the mechanistic understanding of the key events occurring following exposure from a chemical to develop the scientific rationale underpinning a risk assessment. The AOP approach brings many challenges including the identification of Molecular Initiating Events (MIEs), the initial interactions between a molecule and a biomolecule or biosystem that can be causally linked to an adverse outcome. One of the major types of MIEs is receptor ligand interaction. Although studying these interactions has been possible for years, the in vitro assays currently available are expensive and time-consuming, mainly because they rely on the natural receptor for recognition. Natural receptors are expensive, molecularly unstable, and difficult to produce and store. Therefore the need for the development of more suitable binding assays is important. Among the existing alternatives to using a natural receptor as a recognition material Molecularly Imprinted Polymers (MIPs) offers promising technology. However, designing MIPs which closely represent a natural receptor is a significant challenge. Natural receptors bind to a variety of molecules with differing affinities, leading to a range of responses which are dependant upon the molecular interactions and 3D properties involved. Reproducing this level of complexity with single MIPs, which are inherently highly specific, represents a real challenge. For this purpose the choice of natural receptor to focus on, template to use for imprinting, validation dataset of ligand to compare the selectivity of MIPs and natural receptor and monomer to use in MIPs synthesis was crucial. Therefore, computational tools and molecular modelling were used initially to make the most sensible choice possible. Several MIPs were produced using solid-phase synthesis and tested using surface plasmon resonance and fluorescence polarisation. However, as these techniques did not enable suitable analyses of the MIPs, a novel assay based on fluorescent MIPs and magnetic template was designed. This assay demonstrated promising results and the performance of the fluorescent MIPs were studied and compared to those of the natural receptor. The MIPs binding pattern proved to be too different from the natural receptor to be used as an analogue. However, the results obtained and the successful design of this assay paved the way toward the design of more suitable analogues based on molecular imprinting.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Thesis