Tumor priming using metronomic chemotherapy with neovasculature-targeted, nanoparticulate paclitaxel
Tumor priming using metronomic chemotherapy with neovasculature-targeted, nanoparticulate paclitaxel
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使用节律化疗和靶向新血管的纳米颗粒紫杉醇进行肿瘤启动。
DOI：
10.1016/j.biomaterials.2016.04.008
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发表时间：
2016-07-01
期刊：
影响因子：
14
通讯作者：
Chen, Hong-Zhuan
中科院分区：
文献类型：
--
作者：
Luan, Xin;Guan, Ying-Yun;Chen, Hong-Zhuan
肿瘤微环境的正常化是使常规化疗更有效的一种有前途的方法。虽然被动靶向药物纳米载体已经为此目的进行了研究，但主动靶向肿瘤引发仍有待探索。在这项工作中，我们证明了一种有效的肿瘤启动策略，使用积极靶向肿瘤新生血管的纳米粒子的节拍应用。使用水包油乳液方法由PEG化聚丙交酯配制F56肽缀合的紫杉醇负载纳米颗粒（F56-PTX-NP）。Metronomic F56-PTX-NP特异性靶向肿瘤血管内皮细胞（EC），修剪具有强抗血管生成活性的血管，并诱导EC分泌血小板反应蛋白-1（TSP-1）。治疗诱导肿瘤脉管系统正常化，如基底膜和周细胞的覆盖率显著增加所证明的。肿瘤微环境改变，pO（2）升高，间质液压力降低，血管灌注和阿霉素输送增强。诱导了至少9天的“正常化窗口”，这比使用抗血管生成剂的其他方法更长。总之，这些结果表明，有节奏的、主动靶向的纳米药物可以诱导肿瘤血管正常化并调节肿瘤微环境，为有效的联合化疗打开了机会之窗。(C)2016爱思唯尔有限公司版权所有。
Normalization of the tumor microenvironment is a promising approach to render conventional chemotherapy more effective. Although passively targeted drug nanocarriers have been investigated to this end, actively targeted tumor priming remains to be explored. In this work, we demonstrate an effective tumor priming strategy using metronomic application of nanoparticles actively targeted to tumor neovasculature. F56 peptide-conjugated paclitaxel-loaded nanoparticles (F56-PTX-NP) were formulated from PEGylated polylactide using an oil in water emulsion approach. Metronomic F56-PTX-NP specifically targeted tumor vascular endothelial cells (ECs), pruned vessels with strong antiangiogenic activity and induced thrombospondin-1 (TSP-1) secretion from ECs. The treatment induced tumor vasculature normalization as evidenced by significantly increased coverage of basement membrane and pericytes. The tumor microenvironment was altered with enhanced pO(2), lower interstitial fluid pressure, and enhanced vascular perfusion and doxorubicin delivery. A "normalization window" of at least 9 days was induced, which was longer than other approaches using antiangiogenic agents. Together, these results show that metronomic, actively-targeted nanomedicine can induce tumor vascular normalization and modulate the tumor microenvironment, opening a window of opportunity for effective combination chemotherapies. (C) 2016 Elsevier Ltd. All rights reserved.