 Key Publications - 2004Photosensitized inactivation of microorganisms. G. Jori, S.B. Brown, Photochemical & Photobiological Sciences (2004), 3(5), 403-405. Despite major advances in medicine in the last 100 yr, microbiol.-based diseases continue to present enormous global health problems. New approaches that are effective, affordable and widely applicable and that are not susceptible to resistance are urgently needed. The photodynamic approach is known to meet at least some of these criteria and, with the creation and testing of new photosensitizers, may develop to meet all of them. The approach, involving the combination of light and a photosensitizing drug, is currently being applied to the treatment of diseases caused by bacteria, yeasts, viruses and parasites, as well as to sterilisation of blood and other products. A comparative analysis of phenothiazinium salts for the photosensitisation of murine fibrosarcoma (RIF-1) cells in vitro, I. Walker, S.A. Gorman, R.D. Cox, D.I. Vernon, J. Griffiths, S.B. Brown, Photochemical & Photobiological Sciences (2004), 3, 653-659. Photodynamic therapy (PDT) is a treatment combining a photosensitizer, mol. oxygen and visible light of characteristic wavelength to produce cytotoxic reactive oxygen species (ROS). Within our center, a series of phenothiazinium salts were synthesized and initial characterization studies performed to det. any potential use for PDT. All photosensitizers within the series were shown to have useful spectral properties for PDT, with absorbance λmax above 667 nm. The Log P values of the compds. were shown to range from -0.9 to > +2.0. Furthermore, Log P values were shown to be important in detg. the site of subcellular localization and as such the site of photooxidative damage. Derivs. with a Log P value of greater than +1.0 were shown to initially localize to the lysosomes then relocalize throughout the cytoplasm following illumination, whereas compds. with intermediate Log P values (-0.7 to +1.0) all remained lysosomal. Only methylene blue (Log P -0.9) was shown to redistribute to the nucleus upon illumination. Following treatment of RIF-1 cells with each phenothiazinium salt for 1 h and subsequent exposure to 665 nm laser light at a fluence rate of 10 mW cm-2 (18 J cm-2), it was detd. that the most potent photosensitizer was 260-fold more potent than methylene blue. Furthermore, the PDT efficacy of the photosensitizers was shown to be related to the level of mitochondrial damage induced directly following illumination. The present and future role of photodynamic therapy in cancer treatment. S.B. Brown, E.A. Brown, I. Walker, Lancet Oncology (2004), 5(8), 497-508. It is more than 25 yr since photodynamic therapy (PDT) was proposed as a useful tool in oncol, but the approach is only now being used more widely in the clinic. The understanding of the biol. of PDT has advanced, and efficient, convenient, and inexpensive systems of light delivery are now available. Results from well-controlled, randomized phase III trials are also becoming available, esp. for treatment of non-melanoma skin cancer and Barrett's esophagus, and improved photosensitizing drugs are in development. PDT has several potential advantages over surgery and radiotherapy; i.e., it is comparatively non-invasive, it can be targeted accurately, repeated doses can be given without the total-dose limitations assocd. with radiotherapy, and the healing process results in little or no scarring. PDT can usually be done in an outpatient or day-case setting, is convenient for the patient, and has no side-effects. Two photosensitizing drugs, porfirmer sodium and temoporfin, have now been approved for systemic administration, and aminolevulinic acid and Me aminolevulinate have been approved for topical use. Here, we review current use of PDT in oncol. and look at its future potential as more selective photosensitizing drugs become available. The solid-phase conjugation of purpurin-18 with a synthetic targeting peptide. Walker, Ian; Vernon, David I.; Brown, Stanley B Bioorganic & Medicinal Chemistry Letters (2004), 14(2), 441-443. Effect of elevating the skin temperature during topical ALA application on in vitro ALA penetration through mouse skin and in vivo PpIX production in human skin. van den Akker, Johanna T. H. M.; Boot, Kristian; Vernon, David I.; Brown, Stanley B.; Groenendijk, Laurens; van Rhoon, Gerard C.; Sterenborg, Henricus J. C. M. Photochemical & Photobiological Sciences (2004), 3(3), 263-267. |
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