Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
Biomaterials. 2015 Feb;42:161-71. doi: 10.1016/j.biomaterials.2014.11.039. Epub 2014 Dec 16.
Tumor angiogenesis is a multistep process involved with multiple molecular events in cancer microenvironment. Several molecular-targeted agents aiming to suppress tumor angiogenesis have been successfully translated into cancer clinic. However, new strategies are still urgently desired to be excavated to overcome the poor response and resistance in some antiangiogenic therapies. Recently, Delta-like ligand 4 (Dll4) is identified to be specifically over-expressed on tumor vascular endothelial cells (EC), and the Dll4-Notch pathway serves as a critical regulator in the development and maintenance of tumor angiogenesis. The intensively up-regulated phenotype of Dll4 on the membrane of tumor vascular EC implies that Dll4 may act as a targetable address for drug delivery system (DDS) to achieve targeted antiangiogenic cancer therapy. Here, a nano-DDS, GD16 peptide (H2N-GRCTNFHNFIYICFPD-CONH2, containing a disulfide bond between Cys3 and Cys13) conjugated nanoparticles loading paclitaxel (GD16-PTX-NP), which can specifically target the angiogenic marker Dll4, was fabricated for the investigation of antiangiogenic therapeutic efficacy in human head and neck cancer FaDu (Dll4-negative) xenograft in nude mice. The results demonstrate that GD16-PTX-NP achieved controlled drug release and exhibited favorable in vivo long-circulating feature. GD16-PTX-NP exerted enhanced antiangiogenic activity in the inhibition of human umbilical vein endothelial cell (HUVEC) viability, motility, migration, and tube formation, and in the Matrigel plug model as well, which can be definitely ascribed to the active internalization mediated by the interaction of GD16 and the over-expressed Dll4 on EC. GD16-PTX-NP showed accurate in vivo tumor neovasculature targeting property in FaDu tumor, where the paclitaxel was specifically delivered into the tumor vascular EC, leading to significant apoptosis of tumor vascular EC and necrosis of tumor tissues. The antiangiogenic activity of GD16-PTX-NP significantly contributed to its in vivo anticancer efficacy in Fadu tumor; moreover, no overt toxicity to the mice was observed. Our research firstly presents the potency and significance of a Dll4-targeted nanomedicine in antiangiogenic cancer therapy.
肿瘤血管生成是一个涉及癌症微环境中多个分子事件的多步骤过程。几种旨在抑制肿瘤血管生成的分子靶向药物已成功转化为癌症临床治疗。然而，仍然迫切需要新的策略来挖掘，以克服一些抗血管生成治疗中的反应不佳和耐药性。最近，Delta-like ligand 4 (Dll4) 被鉴定为肿瘤血管内皮细胞 (EC) 上特异性过表达，Dll4-Notch 途径作为肿瘤血管生成发育和维持的关键调节剂。肿瘤血管 EC 膜上 Dll4 高度上调的表型暗示 Dll4 可能作为药物递送系统 (DDS) 的靶向地址，以实现靶向抗血管生成癌症治疗。在这里，构建了一种纳米 DDS，GD16 肽（H2N-GRCTNFHNFIYICFPD-CONH2，Cys3 和 Cys13 之间含有二硫键）连接的载紫杉醇纳米颗粒（GD16-PTX-NP），可特异性靶向血管生成标志物 Dll4，用于研究在裸鼠人头颈癌 FaDu（Dll4-阴性）异种移植中的抗血管生成治疗效果。结果表明，GD16-PTX-NP 实现了药物的控制释放，并表现出良好的体内长循环特性。GD16-PTX-NP 在抑制人脐静脉内皮细胞 (HUVEC) 活力、运动、迁移和管形成方面表现出增强的抗血管生成活性，并且在 Matrigel plugs 模型中也是如此，这可以归因于 GD16 与 EC 上过表达的 Dll4 相互作用介导的主动内化。GD16-PTX-NP 在 FaDu 肿瘤中表现出对肿瘤新生血管的准确体内靶向特性，其中紫杉醇被特异性递送到肿瘤血管 EC 中，导致肿瘤血管 EC 的显著凋亡和肿瘤组织的坏死。GD16-PTX-NP 的抗血管生成活性显著促进了其在 FaDu 肿瘤中的体内抗癌疗效；此外，未观察到对小鼠有明显毒性。我们的研究首次展示了一种针对 Dll4 的纳米药物在抗血管生成癌症治疗中的效力和意义。
