Antiangiogenic photodynamic therapy (PDT) using Visudyne causes effective suppression of tumor growth

Abstract

We previously observed that antiangiogenic photodynamic therapy (PDT), namely, laser irradiation at 15 min after administration of photosensitizer, by using stable liposomal benzoporphyrin derivative monoacid ring A (BPD-MA), in which the liposomes were composed of dipalmitoylphosphatidylcholine, palmitoyloleoylphosphatidylcholine, cholesterol, and dipalmitoylphosphatidylglycerol (10:10:10:2.5 as a molar ratio), was quite effective for cancer treatment. On the other hand, Visudyne, a commercialized liposomal formulation of BPD-MA, is based on more fluid lipids, namely, dimyristoylphosphatidylcholine and egg yolk phosphatidylglycerol, and is thought to be less stable in the presence of serum. The data of spin column chromatography indicated a little faster transfer of BPD-MA from Visudyne to lipoprotein fraction when Visudyne was incubated with serum than when the stable liposomal BPD-MA was used. The phototoxicity of Visudyne against a human endothelial cell line, ECV304, was almost the same as that of stable liposomal BPD-MA after PDT treatment. Therefore, we examined the antiangiogenic scheduling of PDT with Visudyne. Tumor growth of Meth-A sarcoma-bearing mice was strongly suppressed when the antiangiogenic scheduling was performed with Visudyne, namely, irradiation at 15 min after injection of the drug, in comparison with the conventional scheduling in which laser irradiation is done at 3 h post-injection. This greater effectiveness of PDT at 15 min was suggested to be caused by hemostasis, based on observations made in a dorsal air sac angiogenesis model. Visudyne-mediated antiangiogenic PDT cured 40 or 60% of Meth-A-bearing mice completely when 0.25 or 0.5 mg/kg BPD-MA, respectively, was used. These data suggest that the antiangiogenic scheduling is effective in Visudyne-mediated cancer PDT despite the transferring of BPD-MA from the liposomal fraction to lipoproteins in the bloodstream.