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A Photobiological and Photophysical-based Study of Phototoxicity of Two Chlorins¹

Wellman Laboratories of Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School, Boston, Massachusetts 02114 [B. W. P., B. O., N. C., R. W. R., T. H.]; and Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire 03755 [B. W. P.]

To understand the fundamental determinants of phototoxic efficacy and absorbed photodynamic dose, the triplet state and photobleaching quantum yields in living cells, cellular uptake, intracellular localization, and correlation with cell viability were studied for the two purpurins tin ethyl etiopurpurin I (SnET₂) and tin octaethylbenzochlorin (SnOEBC) in ovarian cancer cells (OVCAR5). Although the triplet yields of these two photosensitizers were not significantly affected by cellular incorporation, the photobleaching yields were shown to be 3 orders of magnitude higher for cellular-bound sensitizer than for free or albumin-bound photosensitizer and higher for SnET₂ than for SnOEBC for all of the cases. The intracellular concentration of SnOEBC was half that of SnET₂ after 3 h- and 24 h-incubation times for both 0.1 µM and 1.0 µM incubation concentrations. Despite the lower concentrations of SnOEBC, the phototoxicity of the two photosensitizers was comparable at 1-µM incubation concentration and was up to 10-fold higher for SnOEBC at the lower concentration. The subcellular localization established using confocal microscopy and molecular probes showed that both photosensitizers were primarily lysosomally localized. SnOEBC, however, had an extra-lysosomal, mitochondrial localization component. The photophysical measurements allowed calculation of the intracellular singlet oxygen production, which indicated that the photosensitizer-light dose reciprocity was limited by photobleaching for SnET₂ but only minimally for SnOEBC, and this was confirmed through cell-survival studies. Taken together, these data indicate that the critical determinant of differences in phototoxicity between the two molecules was their relative rates of photobleaching and their subcellular localization. The study points to the importance of combining photosensitizer uptake and localization with photophysical measurements in the relevant biological milieu to reasonably interpret and/or predict photosensitization efficacies.

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