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Y.D. Ron, D. Weinberger, M. Blank, M. Mandel, T. Livnat, M. Lusky, T. Barliya, A. Orenstein, D. Meruelo, G. Lavie; "Competitive Quenching" between Photosensitizers. A Novel Concept in Protecting Cells from Verteporfin-induced Phototoxicity using Hypericin . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1646.
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Purpose: Photodynamic therapy (PDT) with verteporfin is the accepted treatment for subfoveal choroidal neovascularization in AMD. Time interval of fifteen minutes between I.V administration and the activation by laser irradiation relies on the pharmacokinetics of verteporfin. It is impossible to avoid some degree of spillover of the photosensitizer to adjacent retinal pigment epithelium (RPE) which can lead to extensive injury to this tissue. A novel concept termed "competitive quenching" employing a secondary photosensitizer to quench the photosensitizing activity of a primary sensitizer has been developed. We show that competitive quenching can be achieved by using the perihydroxylated dianthraquinone- hypericin, to protect RPE cells from the photodynamic effect. Methods: RPE cell cultures and endothelial cell cultures were used. Hypericin was added to the cultures. verteporfin was added at different time intervals after the hypericin. The cultures were irradiated using red light (wavelength of 690nm) to selectively excite verteporfin. Cell viability analyses were done. In order to determine the distribution of hypericin among the different layers of the retina and choroid, and its pharmacokinetic properties, animal model was used. Results: Accumulation of hypericin in the RPE cell cultures and endothelial cell cultures protected the cells against the photodynamic effect of verteporfin and increased their survival substantially. The animal model showed that hypericin is bioavailable to the retina and choroid. We show that differnet concentration of hypericin can be found in the retina, RPE and choroid 15 minutes, 2,4,6,8 hours following I.V administration. Conclusions: We show here, in vitro, that high degree of protection from the phototoxicity of verteporfin and light can be generated in RPE or other epithelial cells loaded with hypericin. We demonstrate in rats that conditions can be achieved in which hypericin disperses in the retina and choroid, while verteporfin is confined to the intravascular compartment. By that, using the pharmacokinetic properties of hypericin to achieve maximum protection of the adjacent RPE cells without interfering in the photodynamic process. "Competitive quenching" with hypericin may potentially be developed to protect retinal tissues from verteporfin-mediated phototoxicity during photodynamic therapy.
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