Delta-like ligand 4-targeted nanomedicine for antiangiogenic cancer therapy
Delta-like ligand 4-targeted nanomedicine for antiangiogenic cancer therapy
复制标题
用于抗血管生成癌症治疗的类 Delta 配体 4 靶向纳米药物
DOI：
10.1016/j.biomaterials.2014.11.039
复制
发表时间：
2015-02-01
期刊：
影响因子：
14
通讯作者：
Fang, Chao
中科院分区：
文献类型：
--
作者：
Liu, Ya-Rong;Guan, Ying-Yun;Fang, Chao
肿瘤血管生成是一个多步骤的过程，涉及肿瘤微环境中的多个分子事件。几种旨在抑制肿瘤血管生成的分子靶向药物已经成功地转化为癌症临床。然而，仍然迫切需要挖掘新的策略来克服一些抗血管生成疗法的不良反应和耐药性。最近发现，肿瘤血管内皮细胞(EC)上存在高表达的Delta样配体4(DLL4)，而DLL4-Notch通路在肿瘤血管生成的发生和维持中起着重要的调节作用。DLL4在肿瘤血管内皮细胞膜上表达上调，提示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的肿瘤治疗。在此，我们制备了一种能特异性靶向血管生成标志物DLL4的纳米DDS，GD16多肽(H_2N-GRCTNFHNFIYICFPD-CONH2，半胱氨酸(3)和半胱氨酸(13)之间的二硫键)负载紫杉醇(GD16-PTX-NP)，用于研究抗血管生成治疗人头颈部癌FaDu(DLL4阴性)裸鼠移植瘤的疗效。结果表明，GD16-PTX-NP具有良好的体内长循环特性，实现了药物的控释。GD16-PTX-NP在抑制人脐静脉内皮细胞(HUVEC)的活力、运动、迁移和管状形成以及Matrigel Plug模型中具有增强的抗血管生成活性，这可归因于GD16与过表达的DLL4相互作用对EC的主动内化作用。GD16-PTX-NP在FaDu肿瘤中显示了准确的体内肿瘤新生血管靶向性，紫杉醇被特异性地输送到肿瘤血管内皮细胞中，导致肿瘤血管内皮细胞显著凋亡和肿瘤组织的坏死。GD16-PDC-NP的抗血管生成活性是其体内抗Fadu肿瘤作用的重要因素，且对小鼠无明显毒性。我们的研究首先介绍了DLL4靶向纳米药物在抗血管生成癌症治疗中的效力和意义。(C)爱思唯尔有限公司出版的2014年。
Tumor angiogenesis is a multistep process involved with multiple molecular events in cancer micro-environment. 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 Cys(3) and Cys(13)) 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-PDC-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. (C) 2014 Published by Elsevier Ltd.