PHOTODYNAMIC ACTIVITIES AND BIODISTRIBUTION OF FLUORINATED ZINC PHTHALOCYANINE DERIVATIVES IN THE MURINE EMT-6 TUMOR-MODEL

The photodynamic properties and biodistribution pattern of zinc dodeca fluoro-4-sulphophthalocyanine (ZnPcF12S1), zinc hexadecafluorophthaloc yanine (ZnPcF16) and zinc phthalocyanine (ZnPc) were evaluated in the murine EMT 6 tumour model. All 3 dyes were formulated as a Cremophor o il-water emulsion after initial solubilization in methanol, acetone an d pyridine, respectively. Comparison of their phototoxicity after in v itro incubation with EMT-6 cells and exposure to various fluences of r ed light showed that ZnPcF12S1 is about 50 times move active than ZnPc F16, reflecting better cell-penetrating properties. Solubilisation of ZnPc in 1-methyl-2-pyrrolidinone prior to formulation resulted in loss of photoactivity upon dilution in serum due to precipitation of the d ye 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 monosul phonated ZnPcF12S1 with perfluorinated ZnPcF16 showed improved pharmac okinetics in mice, including lower liver and spleen retentions and hig her tumor-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 po st-injection of 1 mu mol.kg(-1) of ZnPcF12S1 induced mortality. Loweri ng the drug and/or light dose or extending the time interval between d rug administration and irradiation to 72 hr avoided adverse effects bu t also resulted in poor tumour response. The best tumour control (25% of animals) was obtained at 0.1 mu mol.kg(-1) and a fluence of 400 J.c m(-2) at 24 hr post-injection. In contrast, ZnPcF16 required a 20-fold higher drug dose to induce a similar tumour response. The systemic sh ock following PDT with the amphiphilic ZnPcF12S1 likely results from e xtensive cellular effects. (C) 1997 Wiley-Liss, Inc.