title: Photochemical internalization augments tumor vascular cytotoxicity and specificity of VEGF(121)/rGel fusion toxin.
abstract: Vascular targeting for cancer is increasingly recognized as a therapeutic strategy although the lack of objective responses and the development of resistance are major limitations for clinically-available drugs. Endothelial targeted toxins exert increased toxicity compared to antiangiogenic drugs and may therefore overcome these limitations. The specificity and toxicity of targeted toxins may be increased by utilization of a drug delivery system which provides selective release of the targeted toxins in the target cells. Photochemical internalization (PCI) is a non-invasive modality which causes translocation into the cytosol of agents that are trapped in endosomes. This study describes the first use of PCI in combination with a recombinant fusion toxin targeting tumor vasculature. Endothelial cells bearing VEGFR2 treated with VEGF121/rGel showed dramatic enhancement of toxicity after PCI utilizing the photosensitizer TPCS2a (Amphinex®). We compared the PCI of VEGF121/rGel to that of bleomycin which is currently under clinical evaluation. The VEGFR2 specificity of VEGF121/rGel was shown to be preserved by the PCI treatment. PCI of VEGF121/rGel was further shown to induce vascular collapse and edema in the invasive areas of CT26.CL25 colon carcinoma tumors as shown by CD31 IHC. Antitumor effects, as assessed by tumor growth delay were found for PCI of VEGF121/rGel and PCI of bleomycin with cure rates of 40% and 33% respectively. PCI of VEGF121/rGel was, however, better tolerated compared to PCI of bleomycin. Thus, PCI of vascular targeted toxins provides higher specificity and increased tolerability compared to PCI of bleomycin and may represent an interesting clinical future for the PCI technology.
authors: Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway. Electronic address: anette.weyergang@rr-research.no.
authors: Anette
authors: A
authors: Weyergang
authors: Department of Experimental Therapeutics, Immunopharmacology and Targeted Therapy Laboratory, M.D. Anderson Cancer Center, Houston, USA.
authors: Lawrence H
authors: LH
authors: Cheung
authors: Department of Experimental Therapeutics, Immunopharmacology and Targeted Therapy Laboratory, M.D. Anderson Cancer Center, Houston, USA.
authors: Michael G
authors: MG
authors: Rosenblum
authors: Department of Experimental Therapeutics, Immunopharmacology and Targeted Therapy Laboratory, M.D. Anderson Cancer Center, Houston, USA.
authors: Khalid A
authors: KA
authors: Mohamedali
authors: Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors: Qian
authors: Q
authors: Peng
authors: Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors: Johannes
authors: J
authors: Waltenberger
authors: Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors: Kristian
authors: K
authors: Berg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002460:Cell Line; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000627:therapeutic use; D011166:Porphyrins / Q000008:administration & dosage / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D017319:Photosensitizing Agents; D011166:Porphyrins; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C559366:meso-tetraphenyl chlorin disulphonate; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Cytosolic delivery; Fusion toxins; Photochemical internalization; Photodynamic; VEGFR; Vascular targeting