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Title: Ligand-mediated oral uptake of nanospheres in the rat
Author: Hussain, Nasir
ISNI:       0000 0001 3585 141X
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1996
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The thesis is concerned with the exploitation of the phenomena of intestinal particulate absorption for delivery of biodegradable colloidal carriers incorporating gastrointestinal labile molecules thereby affording protection of the latter against the hostile and degrading milieu of the intestine. Peyer's patches, are the main portals of entry of both living and inert particulate matter mediated by its unique enterocyte, the M-cell, which displays considerable phagocytic activity enabling it to sample luminal contents for xenobiotics to underlying macrophages. Numerous agents have been shown to bind specifically to the M-cell and attempts to target using these ligands have met little success due partly to differential binding specificity of the cell according to the animal model employed. As the M-cell represents less than 1% of the total enterocyte population more success can be achieved if the intestine as a whole is used as the bioadhesive target. Bioadhesion of sub-micron particulates to the intestine significantly enhances their uptake as exemplified by certain invasive enterobacteriaceae. Thus three differing ligands covalently conjugated to 500nm polystyrene nanospheres were employed to enhance particulate intestinal absorption. Tissue extracted polymer was quantified using gel permeation chromatography. The non-toxic Tomato lectin was investigated due to its epithelial bioadhesive properties. Oral administration of tomato lectin conjugated nanospheres for 5 days resulted in 25% systemic absorption compared to <1% absorption of blocked nanospheres with N-acetylchitotetraose. The reticuloendothelial system was unable to sequestrate the nanospheres indicating for the first time that orally absorbed nanospheres coated with glycoproteins behave in a similar manner to intravenously injected particles (eg pegylayted-liposomes) designed to avoid the liver and spleen. The final part of the thesis is concerned with exploiting bacterial mechanisms of epithelial internalization. Invasin is a 986-amino acid outer membrane protein that confers Yersinia to invade non-phagocytic mammalian cells such as enterocytes. The carboxyl-terminal 192 amino acids which is sufficient to promote bacterial uptake was isolated as maltose binding fusion protein (MBP) from genetically engineered E. coli and coupled to nanospheres. After a single dose approximately 13% was found in the systemic circulation compared to two controls, MBP-coupled nanospheres and invasin-coupled nanospheres blocked with mucin which both exhibited < 2% in the blood. All nanospheres avoided the reticuloendothelial system.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Drug delivery; Biodegradable colloidal carriers