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Title: Polymer-drug conjugates based on hyaluronic acid for the treatment of rheumatoid arthritis
Author: Singh, Jennifer.
Awarding Body: University of Paisley
Current Institution: University of the West of Scotland
Date of Award: 2004
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The work represents an initial appraisal ofhow polymer-drug conjugates based upon hyaluronic acid (HA) may behave at sites of inflammation relative to unmodified HA. Three polymer drug conjugates were synthesized in which a model drug, p-nitroaniline (pNA) has been joined to HA via a peptide spacer group containing alanine (ala) and valine (val). The conjugates are: HA-ala-pNA, HA-val-ala-pNA, and HA-ala-ala-ala-pNA. Each of the conjugates was subjected to the degradative effects of both hyaluronidase and hydroxyl radicals by the Fenton reaction (generated by Fe2 + ions and H202) . Hyaluronidase digestion was followed both by measurement of reducing hexosamine end-groups and rheologically. The degradative effects of hydroxyl radicals were followed by rheology alone. On incubation with hyaluronidase, end-group analysis showed that the rate of degradation of HA-ala-ala-ala-pNA preparation did not appear to differ significantly from that of unmodified HA. The hyaluronic acid-val-ala-pNA sample appeared to show a higher degradation rate than HA itself initially, after which it slowed relative to HA itself. With HA-ala-pNA the rate of hydrolysis of the HA backbone was found to be considerably lower that that observed for the other materials. Viscometric studies on the effects of hydroxyl radicals showed that, as expected, the rate of decrease in viscosity of the unmodified HA increased with increasing [Fe2J and that H202 alone showed a depolymerising effect on the HA in a concentration-dependent manner. The initial viscosity of the HA-ala-pNA and HA-ala-ala-ala-pNA was considerably lower than that of the unmodified H.-and hence any degradation was difficult to follow although some effects could Q\? observed with the higher concentrations of Fe::+. The HA-\al-ala-pNA conjugate showed a higher initial viscosity than native HA. The reason for this is not clear and would require more experimentation. Like the unmodified hyaluronic acid, on exposure to hydroxyl radicals, a rapid initial depolymerization of the conjugates was observed the rate of which increased with increasing concentration of Fe:!+.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: null Rheumatoid arthritis Chemotherapy Polymeric drugs Drug delivery systems Hyaluronic acid