Pegylation of a chlorin(e6) polymer conjugate increases tumor targeting ofphotosensitizer

Photodynamic therapy is emerging as a viable modality for the treatment of many cancers. A limiting factor in its use against intracavity tumors such as disseminated ovarian cancer is insufficient selectivity of the photosens itizer for tumor compared with normal tissue. We report on an approach to i mprove tumor targeting by exploiting differences between cell types and by chemical modification of a photosensitizer conjugate. Attachment of polyeth ylene glycol (pegylation) to a polyacetylated conjugate between poly-l-lysi ne and chlorin(c6) increased the relative phototoxicity in vitro toward an ovarian cancer cell line (OVCAR-5) while reducing it toward a macrophage ce ll line (J774), compared with the nonpegylated conjugate. Surprisingly, the increased phototoxicity of the pegylated conjugate correlated with reduced oxygen consumption. Pegylation also reduced the tendency of the conjugate to aggregate and reduced the consumption of oxygen when the conjugates were illuminated in solution in serum containing medium, suggesting a switch in photochemical mechanism from type II (singlet oxygen) to type I (radicals or electron transfer). Pegylation led to more mitochondrial localization as shown by confocal fluorescence microscopy in OVCAR-5 cells, and, on illumi nation, produced a switch in cell death mechanism toward apoptosis not seen with J774 cells. Conjugates were injected i.p. into nude mice bearing i.p. OVCAR-5 tumors, and the pegylated conjugate gave higher amounts of photose nsitizer in tumor and higher tumor:normal tissue ratios and increased the d epth to which the chlorin(c6) penetrated into the peritoneal wall. Taken to gether, these results suggest that pegylation of a polymer-photosensitizer conjugate improves tumor-targeting and may increase the efficacy of photody namic therapy for ovarian cancer.