Polymer-drug conjugates based on hyaluronic acid for the treatment of rheumatoid arthritis

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...

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Main Author: Singh, Jennifer
Published: University of the West of Scotland 2004
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Online Access:http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415937
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spelling ndltd-bl.uk-oai-ethos.bl.uk-4159372015-07-02T03:27:50ZPolymer-drug conjugates based on hyaluronic acid for the treatment of rheumatoid arthritisSingh, Jennifer2004The 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:!+.616.7227061University of the West of Scotlandhttp://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415937Electronic Thesis or Dissertation
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sources NDLTD
topic 616.7227061
spellingShingle 616.7227061
Singh, Jennifer
Polymer-drug conjugates based on hyaluronic acid for the treatment of rheumatoid arthritis
description 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:!+.
author Singh, Jennifer
author_facet Singh, Jennifer
author_sort Singh, Jennifer
title Polymer-drug conjugates based on hyaluronic acid for the treatment of rheumatoid arthritis
title_short Polymer-drug conjugates based on hyaluronic acid for the treatment of rheumatoid arthritis
title_full Polymer-drug conjugates based on hyaluronic acid for the treatment of rheumatoid arthritis
title_fullStr Polymer-drug conjugates based on hyaluronic acid for the treatment of rheumatoid arthritis
title_full_unstemmed Polymer-drug conjugates based on hyaluronic acid for the treatment of rheumatoid arthritis
title_sort polymer-drug conjugates based on hyaluronic acid for the treatment of rheumatoid arthritis
publisher University of the West of Scotland
publishDate 2004
url http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.415937
work_keys_str_mv AT singhjennifer polymerdrugconjugatesbasedonhyaluronicacidforthetreatmentofrheumatoidarthritis
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