Targeting Tumor-Associated Endothelial Cells: Anti-VEGFR2 Immunoliposomes Mediate Tumor Vessel Disruption and Inhibit Tumor Growth
Targeting Tumor-Associated Endothelial Cells: Anti-VEGFR2 Immunoliposomes Mediate Tumor Vessel Disruption and Inhibit Tumor Growth
复制标题
DOI：
10.1158/1078-0432.ccr-11-1102
复制
发表时间：
2012-01-15
影响因子：
11.5
通讯作者：
Mamot, Christoph
中科院分区：
文献类型：
--
作者：
Wicki, Andreas;Rochlitz, Christoph;Mamot, Christoph
目的：血管生成是肿瘤进展的关键过程。通过结合 VEGF，VEGF 受体 2 (VEGFR2) 是肿瘤相关血管生成中的主要信号传导转导器。因此，设计了针对 VEGF/VEGFR2 信号轴的治疗方法。然而，尚未实现针对肿瘤相关内皮细胞的有效且特异性的化疗靶向。 实验设计：我们采用与聚乙二醇化脂质体阿霉素（PLD）共价连接的抗VEGFR2抗体来特异性消融Rip1Tag2小鼠胰岛素瘤模型、MMTV-PyMT小鼠乳腺癌模型和HT-29人类结肠癌中的肿瘤相关内皮细胞异种移植模型。结果：在每个模型中，负载阿霉素的抗VEGFR2靶向免疫脂质体（ILs）（抗VEGFR2-ILs-dox）的治疗效果优于空脂质体、空抗VEGFR2-ILs、单独抗体和PLD。功效与口服 VEGFR1、-2 和 -3 抑制剂 PTK787 相似。详细的组织病理学和分子分析显示，抗 VEGFR2 ILs-dox 具有很强的抗血管生成作用，并且与血管较少的异种移植模型相比，观察到的抗血管生成治疗在减少血管良好的转基因小鼠模型中的肿瘤负荷方面显着更有效。 结论：抗 VEGFR2 ILs 提供了一种选择性消除表达 VEGFR2 的肿瘤血管系统的高效方法。他们提供了一种新颖且有前途的抗癌策略。临床癌症研究； 18(2)； 454-64。 (C) 2011 年 AACR。
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-VEGFR2ILs-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. Clin Cancer Res; 18(2); 454-64. (C) 2011 AACR.