Photopharmica discovering and developing photosensitisers and light sources for medical use.

Key Publications

Photodynamic therapy for cutaneous leishmaniasis: the effectiveness of topical phenothiaziniums in parasite eradication and Th1 immune response stimulation. OE Akilov, S Kosaka, K O'Riordan, T Hasan, Photochemical & Photobiological Sciences (2007), 6(10), 1067-75.

Photodynamic therapy (PDT) is emerging as a therapeutic modality in the clinical management of cutaneous leishmaniasis (CL). The efficacy of PDT against CL has been demonstrated previously with aminolevulinic acid, although the prolonged terms of therapy were less than ideal, and the search for new photosensitizers (PS) is ongoing. However, phenothiaziniums have demonstrated high parasiticidal effects in vitro. The subject of our investigation is the in vivo activity of two PS, 5-ethylamino-9-diethylaminobenzo[a]phenoselenazinium chloride (EtNBSe) and (3,7-Bis(N,N-dibutylamino) phenothiazinium bromide (PPA904). The results of our comparative analysis of the efficacy of these two phenothiazinium analogues demonstrated a high antiparasitic activity of EtNBSe in vitro, and the higher efficacy of PPA904 in a mouse model of CL. The kinetics of photodestruction are different in parasite and mammalian cells, and with both dyes, the macrophages are more susceptible to photodynamic effects than L. major parasites. As the number of parasites in the lesions undergoes a biphasic change, temporarily increasing on days 2-4 and decreasing on days 5-7, more than one treatment is required within an interval of 5 to 7 days. We have also shown that PPA904-PDT can provide an immunomodulating, dose-dependent efflux on IL-12p70 production. This mechanism could be responsible for promoting a more rapid healing in PPA904-PDT treated mice. Our initial data indicate that phenothiaziniums exhibit a high parasiticidal effect in vivo against CL; this finding may be of use in establishing curative PDT regimens for future clinical trials.

The 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.

Photosensitized 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.

The role of light in the treatment of non-melanoma skin cancer using methyl aminolevulinate. Brown, S. B Journal of Dermatological Treatment (2003), 14(Suppl. 3), 11-14

Fluorescence dynamics of ALA-induced PpIX in normal and malignant skin cells. Sudworth, Caroline D; Stringer, Mark R; Cruse-Sawyer, Janet E; Brown, Stanley B. Proceedings of SPIE-The International Society for Optical Engineering (2003), 5142(Therapeutic Laser Applications and Laser-Tissue Interactions), 18-29.

Photodynamic therapy effect of m-THPC (Foscan) in vivo: correlation with pharmacokinetics. Jones, H. J.; Vernon, D. I.; Brown, S. B. British Journal of Cancer (2003), 89(2), 398-404.

A randomized, double-blind, placebo-controlled trial of photodynamic therapy using 5-aminolaevulinic acid for the treatment of cervical intraepithelial neoplasia. Barnett, Adrian A; Haller, J. Christoph; Cairnduff, Fiona; Lane, Geoffrey; Brown, Stanley B.; Roberts, David J. H. International Journal of Cancer (2003), 103(6), 829-832.

The advantages of aminolevulinic acid photodynamic therapy in dermatology. Taylor, E. L.; Brown, S. B. Journal of Dermatological Treatment (2002), 13(Suppl. 1), S3-S11.

Porphyrin accumulation induced by 5-aminolaevulinic acid esters in tumour cells growing in vitro and in vivo. Tunstall, R. G.; Barnett, A. A.; Schofield, J.; Griffiths, J.; Vernon, D. I.; Brown, S. B.; Roberts, D. J. H. British Journal of Cancer (2002), 87(2), 246-250.

Guidelines for topical photodynamic therapy: Report of a workshop of the british photodermatology group. Morton, C. A.; Brown, S. B.; Collins, S.; Ibbotson, S.; Jenkinson, H.; Kurwa, H.; Langmack, K.; McKenna, K.; Moseley, H.; Pearse, A. D.; Stringer, M.; Taylor, D. K.; Wong, G.; Rhodes, L. E. British Journal of Dermatology (2002), 146(4), 552-567.

In vitro photodynamic activity of a series of methylene blue analogues. Mellish, Kirste J.; Cox, Russell D.; Vernon, David I.; Griffiths, John; Brown, Stanley B. Photochemistry and Photobiology (2002), 75(4), 392-397.

Cancer treatment and photodynamic therapy: Opportunities and limitations. Brown, J. E; Brown, S. B.; Vernon, D. I. Advances in Colour Science and Technology (2001), 4(4), 108-116.

5-Aminolaevulinic acid methyl ester transport on amino acid carriers in a human colon adenocarcinoma cell line. Gederaas, Odrun A.; Holroyd, Andrew; Brown, Stanley B.; Vernon, David; Moan, Johan; Berg, Kristian. Photochemistry and Photobiology (2001), 73(2), 164-169

Decreased efficiency of trypsinization of cells following photodynamic therapy: evaluation of a role for tissue transglutaminase. Ball, Denise J.; Mayhew, Stephen; Vernon, David I.; Griffin, Martin; Brown, Stanley B.Photochemistry and Photobiology (2001), 73(1), 47-53.

Investigation of cross-resistance to a range of photosensitizers, hyperthermia and UV light in two radiation-induced fibrosarcoma cell strains resistant to photodynamic therapy in vitro. Mayhew, Stephen; Vernon, David I.; Schofield, Jack; Griffiths, John; Brown, Stanley B. Photochemistry and Photobiology (2001), 73(1), 39-46.

Routine double treatments of superficial basal cell carcinomas using aminolaevulinic acid-based photodynamic therapy. Haller, J. C; Cairnduff, F; Slack, G.; Schofield, J; Whitehurst, C; Tunstall, R.; Brown, S. B.; Roberts, D. J. H. British Journal of Dermatology (2000), 143(6), 1270-1274.

Use of ALA-PDT for endometrial ablation in the treatment of menorrhagia; first clinical trials. Brown, Stanley B; Gannon, Michael J; Holroyd, J. Andrew; Johnson, Nick; Stringer, Mark; Vernon, David I. Photomedicine in Gynecology and Reproduction (2000), 219-226.

Comparison of the pharmacokinetics and phototoxicity of protoporphyrin IX metabolized from 5-aminolevulinic acid and two derivatives in human skin in vivo. Gerscher, Sandra; Connelly, James P; Griffiths, John; Brown, Stanley B.; MacRobert, Alexander J.; Wong, Gavin; Rhodes, Lesley E Photochemistry and Photobiology (2000), 72(4), 569-574.

Mechanism of uptake of a cationic water-soluble pyridinium zinc phthalocyanine across the outer membrane of Escherichia coli. Minnock, Andrew; Vernon, David I.; Schofield, Jack; Griffiths, John; Parish, J. Howard; Brown, Stanley., Antimicrobial Agents and Chemotherapy (2000), 44(3), 522-527.

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