Photodynamic activities and biodistribution of fluorinated zinc phthalocyanine derivatives in the murine EMT-6 tumour model

The photodynamic properties and biodistribution pattern of zinc dodecafluoro-4-sulphophthalocyanine (ZnPcF₁₂S₁), zinc hexadecafluorophthalocyanine (ZnPcF₁₆) and zinc phthalocyanine (ZnPc) were evaluated in the murine EMT-6 tumour model. All 3 dyes were formulated as a Cremophor oil–water emulsion after initial solubilization in methanol, acetone and pyridine, respectively. Comparison of their phototoxicity after in vitro incubation with EMT-6 cells and exposure to various fluences of red light showed that ZnPcF₁₂S₁ is about 50 times more active than ZnPcF₁₆, reflecting better cell-penetrating properties. Solubilisation of ZnPc in 1-methyl-2-pyrrolidinone prior to formulation resulted in loss of photo-activity upon dilution in serum due to precipitation of the dye in the aqueous environment. In contrast, initial solubilisation in pyridine likely forms a ZnPc-pyridinium salt, and this preparation was 6 times more phototoxic than ZnPcF₁₂S₁. In vivo comparison of monosulphonated ZnPcF₁₂S₁ with perfluorinated ZnPcF₁₆ showed improved pharmacokinetics in mice, including lower liver and spleen retentions and higher tumour-to-non-target tissue ratios. However, photodynamic therapy (PDT) of the EMT-6 tumour in BALB/c mice with red light, 24 or 48 hr post-injection of 1 μmol · kg⁻¹ of ZnPcF₁₂S₁ induced mortality. Lowering the drug and/or light dose or extending the time interval between drug administration and irradiation to 72 hr avoided adverse effects but also resulted in poor tumour response. The best tumour control (25% of animals) was obtained at 0.1 μmol · kg⁻¹ and a fluence of 400 J · cm⁻² at 24 hr post-injection. In contrast, ZnPcF₁₆ required a 20-fold higher drug dose to induce a similar tumour response. The systemic shock following PDT with the amphiphilic ZnPcF₁₂S₁ likely results from extensive cellular effects. Int. J. Cancer 72:289–294, 1997. © 1997 Wiley-Liss, Inc.