Hexadecafluorinated zinc phthalocyanine: Photodynamic properties against the EMT-6 tumour in mice and pharmacokinetics using Zn-65 as a radiotracer

Hexadecafluorinated zinc phthalocyanine (ZnPcF(16)), an analogue of zinc phthalocyanine (ZnPc) in which all hydrogen atoms have been substituted by fluorine, was prepared as a single isomeric product via the condensation of tetrafluorophthalonitrile with zinc acetate. Fluorination renders the ZnPc soluble in most common solvents. The photodynamic properties and pharmacokinetics of the ZnPcF(16) were evaluated in EMT-6 tumour-bearing Balb/c mice using Zn-65-radiolabelled analogues. Both dyes, administered i.v. at 1 mu mol kg(-1) as Cremophor emulsions, revealed good tumour uptake [approximately 8-9 per cent of the injected dose per g tissue (%ID g(-1))] at 24 h post injection (p.i.), with the fluorinated dye reaching higher concentrations (approximately 11% ID g(-1)) at 48 h p.i. and subsequently higher tumour-blood ratios due to rapid blood clearance. ZnPcF(16) at a dose of 5 mu mol kg(-1) (4.3 mg kg(-1)) induced complete tumour regression after phototherapy (24 h p.i., 650-700 nm band, 360 J cm(-2), 200 mW cm(-1)). At a dose of 2 mu mol kg(-1) and phototherapy at 24 h p.i., the tumour volume doubling time increased to 11 days vs 6 days for the control tumours. A similar tumour growth delay was observed when phototherapy was conducted at 48 h or 72 h after dye injection implying that tumour response correlates with tumour dye concentrations rather than serum concentrations. As a result of its low solubility, the administered dose of ZnPc was limited to 1 mu mol kg(-1) and al this drug level significant tumour response was only observed when the dye was solubilised a's the pyridinium salt. Isolation of the neoplastic cells after in vivo dye administration and in vitro exposure to red light followed by a colony formation assay showed that the ZnPcF(16) exhibited a 1-2 order of magnitude higher potential for direct cell killing as compared with Photofrin and about a five times lower efficiency than ZnPc. However, all three photosensitisers induced complete occlusion of tumour vasculature immediately after PDT, suggesting that tumour regression mainly resulted from vascular stasis. The ZnPcF(16) offers several advantages over ZnPc for clinical applications, including improved solubility in most solvents, resulting in facilitated drug formation, favourable pharmacokinetics as well as the potential use in fluorine magnetic resonance (F-MR) imaging.