 Key Publications - 2006The synthesis and properties of unsymmetrical 3,7-diaminophenothiazin-5-ium iodide salts: Potential photosensitisers for photodynamic therapy. S.A. Gorman, A. L. Bell, J. Griffiths, D. Roberts, S.B. Brown, Dyes and Pigments (2006), 71(2), 153-160. A series of unsym. 3,7-(N,N-disubstituted-amino)-phenothiazin-5-ium iodides have been prepd. by stepwise reaction of secondary amines with phenothiazin-5-ium tetraiodide hydrate. The singlet oxygen generating efficiencies and polarity characteristics of the dyes are compared with those of Methylene Blue, and the factors influencing the potential value of these compds. as photosensitizers for photodynamic therapy are discussed. Preliminary data for the in vivo anti-tumor efficacy of the compounds suggest that high lipophilicity is an important requirement for high activity. An overview of synthetic approaches to porphyrin, phthalocyanine, and phenothiazine photosensitizers for photodynamic therapy. S.A. Gorman, S.B. Brown, J. Griffiths, Journal of Environmental Pathology, Toxicology and Oncology (2006), 25(1-2), 79-108. The mechanistic basis of photodynamic therapy is reviewed briefly, and the factors that are important in improving photosensitizers are examd. The methods for prepg. the three classes of PDT photosensitizers, namely, porphyrins, phthalocyanines, and phenothiazines, are reviewed. Phthalocyanine-mediated photodynamic therapy induces cell death and a G0/G1 cell cycle arrest in cervical cancer cells. S.L. Haywood-Small, D.I. Vernon, J. Griffiths, J. Schofield, S.B. Brown, Biochemical and Biophysical Research Communications (2006), 339(2), 569-576. We have developed a series of novel photosensitizers which have potential for anticancer photodynamic therapy (PDT). Photosensitizers include zinc phthalocyanine tetra-sulfonic acid and a family of derivs. with amino acid substituents of varying alkyl chain length and degree of branching. Subcellular localization of these photosensitizers at the phototoxic IC50 concn. in human cervical carcinoma cells (SiHa Cells) was similar to that of the lysosomal dye Lucifer Yellow. Subsequent nuclear relocalization was obsd. following irradn. with 665 nm laser light. The PDT response was characterized using the Sulforhodamine B cytotoxicity assay. Flow cytometry was used for both DNA cell cycle and dual Annexin V-FITC/propidium iodide anal. Phototoxicity of the derivs. was of the same order of magnitude as for tetrasulfonated phthalocyanine but with an overall trend of increased phototoxicity with increasing amino acid chain length. Our results demonstrate cell death, inhibition of cell growth, and G0/G1 cell cycle arrest during the phthalocyanine PDT-mediated response. |
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