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Title: Characterisation and Efficacy of a Protoporphyrin IX cyclic arg-gly-asp-phe-Iys Peptide Conjugate for Targeted Photodynamic Therapy
Author: Conway, Clare Louise
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2008
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Abstract:
the combination of a photosensitiser, light and molecular oxygen results in the local formation of reactive oxygen species and a· phototoxic effect. This regime is known as photodynamic therapy (PDT) and is used clinically against a variety of diseases, including cancers. PDT has an inherent specificity due to the absolute requirement for light of a specific wavelength, which can be applied locally. However, photosensitisers generally have little intrinsic selectivity for tumours and much current research is devoted to the development of methods by which the specificity of PDT could be improved. Increasing the selectivity of PDT .by increasing tumour specific photosensitiser accumulation may improve treatment efficacy and reduce any risk of side effects caused by photosensitiser accumulation in non-target tissue. To target photosensitisers to tumours, a cyclic peptide, cRGDfK (L-arginine;L-glycine;L-aspartic acid;D-phenylalanine;L-lysine). was conjugated to the porphyrin photosensitiser, protoporphyrin IX was used. The arginine-glycine-aspartic acid (RGD) motif of the cyclic RGDfK peptide has been shown to specifically bind o.vP3 integrins, heterodimeric glycoproteins significantly upregulated on the surface of proliferating endothelial cells in tumour neovasculature. This study describes in vitro and in vivo characterisation of the novel conjugate and compares its properties to the free photosensitiser. The individual components in the system, protoporphyrin IX and cRGDfK, were shown to retain their respective photodynamic and integrin binding activity following the coupling step and produced a' conjugate of high purity. The PpIX:cRGDfK conjugate was shown to be a good photosensitiser in vitro, causing significant phototoxicity and the induction of apoptosis in several cell lines. The subcellular localisation of photosensitiser seems to be more important for treatment efficacy than the absolute amount of cell-associated photosensitiser as it has the potential to control the mechanism and speed of cell death. Pharmacokinetic analysis of PpIX:cRGDfK treated mice showed significant retention and accumulation of photosensitiser in tumour tissue with higher tumour:normal tissue ratios than the free photosensitiser. However, although the conjugate showed this higher accumulation and improved tumour:non-target tissue ratios, the overall in vivo PDT effect, between dose to light intervals of 0 and 6 hours, was . . not significantly better than for free protoporphyrin IX. These data agreed with the in vitro studies, where increased PpIX:cRGDfK uptake into cells expressing high levels of integrin C1vP3 did not give rise to an increased PDT response. Although PpIX:cRGDfK has been shown to be an effective in vivo and in vitro photosensitiser and to significantly accumulate in tumour cells, there are clearly other factors that determine the overall PDT outcome. Further analysis of treatment conditions, the spatial distribution of photosensitiser within tissue, compound metabolism and the effect of repeat treatments would be reqUired for the exploitation of this technology to its full potential. Supplied by The British Library - 'The world's knowledge'
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.490574  DOI: Not available
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