E. Allemann et al., PHOTODYNAMIC ACTIVITIES AND BIODISTRIBUTION OF FLUORINATED ZINC PHTHALOCYANINE DERIVATIVES IN THE MURINE EMT-6 TUMOR-MODEL, International journal of cancer, 72(2), 1997, pp. 289-294
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.