Photochemical internalization (PCI) is a unique procedure for site-specific delivery of several types of membrane-impermeable molecules to the cytosol of target cells. The technology is based on photochemical-induced release of endocytosed macromolecules from endosomes and lysosomes into the cytosol. The purpose of this study was to evaluate the therapeutic potential of PCI of the type I ribosomal-inactivating
protein gelonin in an animal model. The
photosensitizer aluminum phthalocyanine disulfonate (AlPcS(2a)) was injected intraperitoneally (10 mg/kg) into athymic female BALB/c (nu/nu) nude mice (8-9 mice per group) with subcutaneously growing human
adenocarcinoma (WiDr)
tumors 48 hr before exposure to 135 J/cm(2) of red light focused on the
tumor. Six hours before light exposure a single dose of 50 microg
gelonin was administrated intratumorally.
Tumor growth was measured at least twice a week. After immunomagnetic separation of in vivo growing
tumor cells the subcellular localization of the
photosensitizer was evaluated by fluorescence microscopy. The
photosensitizer localized in endocytic vesicles in in vivo growing WiDr cells. Furthermore, it was found that in vitro
gelonin treatment of WiDr cells isolated from
photosensitizer-treated mice potentiated a light-induced decrease of clonal survival. Complete remission in 6 of 9 (67%) of the treated mice were induced. Our findings indicate that photochemical treatment with the
photosensitizer AlPcS(2a) activates the cytotoxic potential of
gelonin in vivo. These results demonstrate that the synergistic effect of combining photoactivation of
photosensitizer located in endocytic vesicles and
gelonin is indeed a result of PCI of
gelonin.