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Title: A lipidic α-amino acid based adjuvant/carrier system for peptide delivery and enhancing peptide immunogenicity
Author: Flinn, Nicholas Sean
ISNI:       0000 0001 3470 6667
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1996
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Many pharmacologically active drugs are restricted in their use due to their instability in biological environments and poor oral absorption. In particular, with the recent advances in molecular biology, peptide and protein drugs show vast potential yet fail from the point of view of their intact delivery to the required site of action. This dissertation attempts to approach these problems by means of chemical modification of poorly absorbed, unstable peptides. The α-amino acids with long alkyl side chains, the so-called lipidic amino acids and their homo-oligomers, the lipidic peptides, represent a class of compounds which combine structural features of lipids with those of amino acids and peptides. These novel compounds provide an excellent means of amplifying peptide lipophilicity to enhance membrane transport and also increase the biological stability of the peptide by protecting it from enzymatic degradation. This phenomenon has been demonstrated with the poorly absorbed, enzymatically labile peptides thyrotropin releasing hormone (TRH) and luteinizing hormone releasing hormone (LHRH), in Caco-2 cell studies, with both homogenates and intact monolayers. The novel conjugates developed have also been absorbed and detected after oral administration and appear to be stable for a considerable time in vivo. The lipidic amino acids have also been used to help increase the lipophilicity of polylysine which was developed to produce high antibody responses to synthetic peptides. To attain higher antibody responses, the antigen must be anchored to the cell membranes, however the polylysine system is not lipophilic enough to fulfil this requirement. Thus by incorporating lipidic amino acids to the polylysine system, the membrane binding effects and the metabolic stability of this novel Lipid-Core-Peptide (LCP) system is enhanced, allowing the system to anchor down to the cell membrane, and improve the antibody response to the immunogen. Studies with a selection of peptide epitopes from Chlamydia trachomatis, FMDV and β-haemolytic M-protein, attached to the LCP system are presented and show the LCP system to act as a possible peptide vaccine carrier/adjuvant system, which elicits high antibody responses over a long duration without the need for other toxic adjuvant preparations.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Drug delivery; Oral absorption