title: Targeting tumor-associated endothelial cells: anti-VEGFR2 immunoliposomes mediate tumor vessel disruption and inhibit tumor growth.
abstract: OBJECTIVE
  Angiogenesis is a key process in tumor progression. By binding VEGF, VEGF receptor-2 (VEGFR2) is a main signaling transducer in tumor-associated angiogenesis. Accordingly, therapeutic approaches against the VEGF/VEGFR2 signaling axis have been designed. However, an efficient and specific chemotherapeutic targeting of tumor-associated endothelial cells has not yet been achieved.
  
  
  METHODS
  We have employed anti-VEGFR2 antibodies covalently linked to pegylated liposomal doxorubicin (PLD) to specifically ablate tumor-associated endothelial cells in the Rip1Tag2 mouse model of insulinoma, in the MMTV-PyMT mouse model of breast cancer, and in the HT-29 human colon cancer xenograft transplantation model.
  
  
  RESULTS
  In each model, anti-VEGFR2-targeted immunoliposomes (ILs) loaded with doxorubicin (anti-VEGFR2-ILs-dox) were superior in therapeutic efficacy to empty liposomes, empty anti-VEGFR2-ILs, antibodies alone, and PLD. Efficacy was similar to that of the oral VEGFR1, -2, and -3 inhibitor PTK787. Detailed histopathologic and molecular analysis revealed a strong antiangiogenic effect of anti-VEGFR2-ILs-dox, and the observed antiangiogenic therapy was significantly more efficient in reducing tumor burden in well-vascularized transgenic mouse models as compared with the less-vascularized xenograft model.
  
  
  CONCLUSIONS
  Anti-VEGFR2 ILs provide a highly efficient approach to selectively deplete VEGFR2-expressing tumor vasculature. They offer a novel and promising anticancer strategy.
authors: Division of Oncology, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland.
authors: Andreas
authors: A
authors: Wicki
authors: Christoph
authors: C
authors: Rochlitz
authors: Annette
authors: A
authors: Orleth
authors: Reto
authors: R
authors: Ritschard
authors: Imke
authors: I
authors: Albrecht
authors: Richard
authors: R
authors: Herrmann
authors: Gerhard
authors: G
authors: Christofori
authors: Christoph
authors: C
authors: Mamot
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis; D001808:Blood Vessels / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology* / Q000627:therapeutic use; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology* / Q000627:therapeutic use; D007340:Insulinoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D047368:Tumor Burden / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000276:immunology* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000922:Immunotoxins; D004317:Doxorubicin; D040301:Vascular Endothelial Growth Factor Receptor-2