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Title: Studies of cationic amphiphilic drug catalysed membrane degradation
Author: Sebai, Sarra C.
ISNI:       0000 0001 3392 1146
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2007
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Although drug molecules are designed to bind specifically to targets such as receptors that are embedded within biological membranes, it is becoming increasingly evident that a large fraction of these compounds interact non-specifically with the membrane and I or other proteins. In particular, the non-specific binding of positron emission tomography (PET) radioligands to tissue, both in-vivo and in-vitro, is poorly understood. This phenomenon is a major confounding factor in the development of new radioligands for receptor imaging in-vivo. To address this issue, studies on the interaction of central nervous system (eNS) drugs, belonging to the cationic amphiphilic drug (CAD) family, with model membrane assemblies were conducted. Experiments were performed using three CADs: Haloperidol (HPD), Spiperone .(SPIP) and WAY, on condensed fluid lamellar phases and membrane vesicles. CADmembranes interactions were studied by small angle X-ray scattering (SAXS), soIidstate nuclear magnetic resonance (SS-NMR), fluorescence assays, and fluorescence microscopy. CADs were found to partition rapidly to the polar I apolar region of the membrane; this was demonstrated by SAXS where CADs affected the bilayer spacing. At physiological pH, the protonated groups on the CAD catalyze the acid-hydrolysis of the ester linkage present in the phospholipid chains, producing a fatty acid and singlechain lipid. 'The single-chain lipids destabilize the membrane, causing membranous . fragments and small vesicles to separate and diffuse away from the host. These membrane fragments carry the drug molecules with them. The entire process, from drug adsorption to drug release within mi~ell~ fragments, occurs on a timescale of seconds I minutes. Given the rate at which this occurs it is probable that this process is a significant mechanism for drug transport. Kinetic studies were conducted to determine the rate of the lipid hydrolysis in the condensed fluid lamellar phase, by varying CAD's counterions, the lipid composition and the stored curvature elastic stress in the bilayer. The lipid hydrolysis kinetics was fitted to a pseudo-first order exponential decay, and hydrolysis rates were determined. Hydrolysis rates are specific to the CAD molecules, with WAY hydrolysing the bilayer as twice as fast as SPIP. In addition, evidence is presented that the stored curvature elastic stress in the membrane modulates the hydrolysis kinetics. Interestingly, the rate of membrane hydrolysis appears to correlate with in-vivo nonspecific binding of the PET radioligands. The measured rate of membrane hydrolysis may provide useful insight into the mechanism of non-specific binding on a molecular level and possibly in the design ofnew radiotracers.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available