Rowland, Ruth Elizabeth Sarah;
(2005)
The exploitation of internalina fragments in drug delivery systems.
Doctoral thesis (Ph.D.), University College London.
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Abstract
The objective o f the work reported in this thesis was to investigate the potential of the protein intemalin when attached to nanoparticles to secure transport across the gut wall. Intemalin, also called intemalin A or InlA, is a surface protein expressed by the pathogenic bacteria Listeria monocytogenes in response to temperature and other environmental cues that indicate the bacterium is in a suitable host. Intemalin has been shown to interact with E-cadherin, a protein involved in structural maintenance of the epithelial cells lining the gut wall. Cadherins are found throughout the human body and the prefix E or N etc. indicates the location where they are most commonly found, E for epithelial, N for neuronal etc. The interaction between intemalin and E-cadherin causes a rearrangement of the actin cytoskeleton in the cell and this encourages the membrane o f the epithelial cells to engulf the bacteria. The bacteria are then intemalised and have achieved their first step in establishing infection. Once the bacteria are inside the cell they use a panoply of further pathogenic factors to establish and propagate the infection. It is the specific interaction between the intemalin (or a fragment of intemalin) and the E-cadherin that this research addresses as a potential system to deliver dmgs across the gut wall as a method of targeting vectors containing the dmg. Many dmgs are still administered by injection, but non-invasive methods, including oral, pulmonary, buccal, vaginal, rectal and dermal delivery, are preferred. Orally administered dmgs are the most convenient and practical and have the highest patient compliance. The gut wall provides a major barrier to the oral delivery of some, particularly macromolecule pharmaceuticals. It is one o f the major physical barriers that the immune system employs as a first line of defence against infection. There are many tools the immune system employs to protect the GI tract; the presence of normal flora to compete for receptor sites with invaders, mucus that entraps invaders and the propulsion that moves the mucus and thus the microorganisms and entities entrapped within it out o f the body. Also the temperature, pH, digestive enzymes and patrolling immune cells help keep foreign entities out of the body. Pharmaceuticals that are required by the body need to cross this barrier. Orally administered formulations achieve higher patient compliance so this work set out to investigate a method o f employing the bacterial armament to physical carrier systems which have already been exploited experimentally in these laboratories using invasin (Hussain & Florence 1998) and tomato lectin (Hussain et al 1997). 15 The effect of the intemalin protein surface adsorbed onto polystyrene nanoparticles was investigated using the Caco-2 system. The Caco-2 cell system allows for the evaluation of drug delivery systems that will be orally administered in an isolated and realistic, but less complex manner. This is due to their ease of cultivation and that they spontaneously differentiate into enterocyte-like cells, under normal tissue culture conditions these cell mimic the lining of the gastrointestinal tract. The study was also expanded to include the transport and effect of incubation of different partial dendrimers (dendrons) with the Caco-2 system. The research reported in this thesis establishes that the transport of polystyrene nanoparticles through Caco-2 cells is modified by the surface adsorption of a recombinant version of intemalin. Further experiments indicated there was a protein interaction between the E-cadherin and the synthesised protein.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D. |
| Title: | The exploitation of internalina fragments in drug delivery systems. |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis Digitised by Proquest. |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10122302 |
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