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Title: Interactions between low-density lipoproteins and self-assembled monolayers
Author: Gerrard, A. R.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2006
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The oxidation of low-density lipoprotein (LDL) may be of critical importance in the pathogenesis of atherosclerosis. Oxidation affects the surface structure of the particles, causing a change in receptor affinity that triggers disease progression. The LDL surface presents a complex mixture of both phospholipids and protein and is known to bind to self-assembled monolayers (SAMs). This thesis investigates those interactions. Peptide-modified SAMs that demonstrated selectivity between native and oxidised LDL have been prepared, but the binding mechanism remained elusive. This study investigated the binding of LDL to these SAMs using SPR. Under continuous flow conditions, simple and peptide-modified SAMs were found to bind LDL. Elution strategies employed highlighted differences in the interactions formed with the surfaces following LDL oxidation. The presentation of low ligand concentrations on hexa(ethylene glycol) SAM surfaces also demonstrated LDL binding and one was able to distinguish LDL from oxidised LDL binding. LDL bind pharmaceutical drugs in plasma, affecting the pharmacokinetics of their action. A dimethoxybenzyl epitope from a drug know to bind lipoproteins and albumins bound BSA, liposomes and LDL as model analytes for the study of drug epitope interactions. The wide range of SAMs the LDLD bound to illustrate the complex nature of the LDL surface. The difficulty of trying to separate large complex biological molecules with simple 2-dimensional surface ligands was highlighted, suggesting that true specificity between LDL and oxLDL requires a multifunctional ligand with a better defined 3-D scaffold. The utility of SAMs and real-time SPR in drug development and the prediction of potential plasma interactions in vivo were however demonstrated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available