In vivo documentation of photochemical internalization, a novel approach to site specific cancer therapy.
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.
Selbo
P K
PK
Department of Biophysics, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway. p.k.selbo@labmed.uio.no
Sivam
G
G
Fodstad
O
O
Sandvig
K
K
Berg
K
K
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D004705:Endocytosis; D005260:Female; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D009942:Organometallic Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000627:therapeutic use*; D010940:Plant Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D054789:Ribosome Inactivating Proteins, Type 1; D012270:Ribosomes / Q000187:drug effects*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D007211:Indoles; D009942:Organometallic Compounds; D017319:Photosensitizing Agents; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C064331:aluminum phthalocyanine disulfonate; C025674:GEL protein, Gelonium multiflorum