BQ123 selectively improved tumor perfusion and enhanced nanomedicine delivery for glioblastomas treatment
BQ123 selectively improved tumor perfusion and enhanced nanomedicine delivery for glioblastomas treatment
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BQ123 选择性改善肿瘤灌注并增强纳米药物递送用于胶质母细胞瘤治疗
DOI：
10.1016/j.phrs.2017.12.017
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发表时间：
2018
影响因子：
9.3
通讯作者：
Zhiqing Pang
中科院分区：
文献类型：
--
作者：
Bo Zhang;Honglan Wang;Kai Jin;Ting Jiang;Shun Shen;Zimiao Luo;Yanyan Tuo;Xinguo Jiang;Xianping Liu;Yu Hu;Zhiqing Pang
与周围正常组织相比，肿瘤组织中的血液灌注总是较低，这导致纳米药物向肿瘤的递送不足。受肿瘤组织中内皮素-1（ET 1）及其ETA受体的上调以及ET 1-ETA受体信号传导对维持肿瘤血管的肌源性张力的关键贡献的启发，我们假设ET 1-ETA受体信号传导的抑制可能选择性地改善肿瘤灌注并帮助向肿瘤递送纳米药物。以血管丰富的人U87 MG胶质母细胞瘤为肿瘤模型，免疫荧光染色显示，与正常脑组织相比，胶质母细胞瘤组织中ETA受体过表达。单次给予ETA受体拮抗剂BQ 123（0.5mg/kg）可有效改善肿瘤血流灌注，体内光声成像证实了这一点。此外，通过体内成像、离体成像以及体内分布实验，BQ 123的单次处理可以显著改善肿瘤中115 nm左右的纳米颗粒（NPs）的积累，具有更均匀的分布模式。此外，BQ 123成功地增加了紫杉醇负载的NP的治疗益处，并显著延长了具有正交各向异性胶质母细胞瘤的动物模型的存活时间。总之，本研究提供了一种新的策略，以选择性地改善肿瘤灌注，从而有利于肿瘤治疗的纳米药物递送。由于ET 1-ETA受体信号在多种肿瘤中上调，该策略可能为肿瘤治疗开辟新途径。
Blood perfusion was always lower in tumor tissues as compared with that in surrounding normal tissues which lead to inadequate nanomedicine delivery to tumors. Inspired by the upregulation of both endothelin-1 (ET1) and its ETA receptor in tumor tissues and the crucial contribution of ET1-ETA receptor signaling to maintain myogenic tone of tumor vessels, we supposed that inhibition of ET1-ETA receptor signaling might selectively improve tumor perfusion and help deliver nanomedicine to tumors. Using human U87 MG glioblastomas with abundant vessels as the tumor model, immunofluorescence staining demonstrated that ETA receptor was overexpressed by in glioblastomas tissues compared with normal brain tissues. A single administration of ETA receptor antagonist BQ123 at the dose of 0.5 mg/kg could effectively improve tumor perfusion which was evidenced byin vivophotoacoustic imaging. Additionally, a single treatment of BQ123 could significantly improve the accumulation of nanoparticles (NPs) around 115 nm in tumors with a more homogeneous distribution pattern byin vivoimaging, ex vivo imaging as well asin vivodistribution experiments. Furthermore, BQ123 successfully increased the therapeutic benefits of paclitaxel-loaded NPs and significantly elongated the survival time of orthotropic glioblastomas-bearing animal models. In summary, the present study provided a new strategy to selectively improve tumor perfusion and therefore benefit nanomedicine delivery for tumor therapy. As ET1-ETA receptor signaling was upregulated in a variety of tumors, this strategy might open a new avenue for tumor treatment.