Targeting tumor-associated endothelial cells: anti-VEGFR2 immunoliposomes mediate tumor vessel disruption and inhibit tumor growth.

نویسندگان

  • Andreas Wicki
  • Christoph Rochlitz
  • Annette Orleth
  • Reto Ritschard
  • Imke Albrecht
  • Richard Herrmann
  • Gerhard Christofori
  • Christoph Mamot
چکیده

PURPOSE 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. EXPERIMENTAL DESIGN 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.

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عنوان ژورنال:
  • Clinical cancer research : an official journal of the American Association for Cancer Research

دوره 18 2  شماره 

صفحات  -

تاریخ انتشار 2012