Structure‐Photodynamic Activity Relationships of a Series of 4‐Substituted Zinc Phthalocyanines

Abstract— Radioiodinated zinc phthalocyanine including [125I]ZnPcI4 and differently sulfonated [65Zn]ZnPcS (ZnPcS4, ZnPcS3, ZnPcS2 and ZnPcS1.75, a mixture of adjacent di and 25% mono) were prepared in order to study cell uptake and release kinetics in EMT‐6 cells. The same compounds were evaluated for their in vitro phototoxicity and the biological parameters were compared to partition coefficients to arrive at quantitative structure‐activity relationships (QSAR). At 1 μM in 1% serum, at 37°C, all dyes showed rapid cell uptake during the first hour followed by a slow accumulation phase. After 24 h, the highest cellular concentration was observed with the lipophilic ZnPcI4, followed by the amphiphilic ZnPcS2 and ZnPcS1.75. The hydrophilic ZnPcS4 and ZnPcS3 showed lower uptake. Dye release from dyeloaded cells during incubation in dye‐free medium could reach up to 60% and was shown to depend mainly on the amount of drug incorporated rather than the type of compound. These results suggest that care should be taken in interpreting dye toxicity data, which involve in vitro cell manipulations in dye‐free medium, particularly during in vitro/in vivo protocols. The EMT‐6 cell survival after 1 h or 24 h incubation with 1 μM dye in 1% serum followed by exposure to red light was assessed by means of the colorimetric 3‐(4,5‐dimethylthiazol‐2‐yl)‐diphenyl‐tetrazolium bromide (MTT) assay. Photocytotoxicities correlated inversely with the tendencies of the dyes to aggregate. Increased dye uptake by the cells also correlated with their activities, except for the lipophilic ZnPcI4, which showed the highest cell uptake but little phototoxicity. The QSAR between phototoxicity and the log of the partition coefficients (phosphate‐buffered saline and n‐octanol) gave a parabola with optimal partition values corresponding to the adjacent sulfonated ZnPcS2.

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