Captopril improves tumor nanomedicine delivery by increasing tumor blood perfusion and enlarging endothelial gaps in tumor blood vessels
Captopril improves tumor nanomedicine delivery by increasing tumor blood perfusion and enlarging endothelial gaps in tumor blood vessels
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卡托普利通过增加肿瘤血液灌注和扩大肿瘤血管内皮间隙来改善肿瘤纳米药物的输送。
DOI：
10.1016/j.canlet.2017.09.007
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发表时间：
2017-12-01
期刊：
影响因子：
9.7
通讯作者：
Jiang, Xinguo
中科院分区：
文献类型：
--
作者：
Zhang, Bo;Jiang, Ting;Jiang, Xinguo
肿瘤灌注率低和血管通透性差影响了纳米药物对肿瘤的输送。卡托普利具有扩张血管、临床降压的作用，缓激肽作为卡托普利的下游信号通路部分，具有扩张血管、有效增加血管通透性的作用。这项研究的假设是卡托普利可以扩张肿瘤血管，改善肿瘤血流，同时扩大肿瘤血管内皮细胞间隙，从而增强肿瘤治疗的纳米药物输送。以血管丰富的U87移植瘤为肿瘤模型，采用激光多普勒成像和凝集素标记实验进行肿瘤血流灌注实验。单用100 mg/kg的卡托普利可显著增加肿瘤组织中功能性血管的百分比，改善肿瘤的血液灌注量。肿瘤血管扫描电子显微镜显示，卡托普利治疗后肿瘤血管内皮细胞间隙扩大。肿瘤切片的免疫荧光染色显示，卡托普利显著增加了缓激肽的表达，这可能是肿瘤血流灌注改善和内皮间隙扩大的原因。此外，体内成像、体外成像和肿瘤切片中纳米颗粒的分布表明，与未用卡托普利治疗的对照组相比，单用卡托普利治疗后，115 nm纳米颗粒在肿瘤中的累积增加了2.81倍，分布模式更加均匀。最后，药效学实验证明，卡托普利联合紫杉醇纳米粒在所有治疗组中导致最大的肿瘤缩小和最广泛的肿瘤组织坏死。综上所述，本研究的数据提出了一种新的策略，可以同时改善肿瘤的血流灌注和增加血管的通透性，以改善肿瘤治疗的纳米药物输送。由于卡托普利已经广泛应用于临床，这种策略具有很大的治疗潜力。(C)2017年，由爱思唯尔出版。
Poor tumor perfusion and unfavorable vessel permeability compromise nanomedicine drug delivery to tumors. Captopril dilates blood vessels, reducing blood pressure clinically and bradykinin, as the downstream signaling moiety of captopril, is capable of dilating blood vessels and effectively increasing vessel permeability. The hypothesis behind this study was that captopril can dilate tumor blood vessels, improving tumor perfusion and simultaneously enlarge the endothelial gaps of tumor vessels, therefore enhancing nanomedicine drug delivery for tumor therapy. Using the U87 tumor xenograft with abundant blood vessels as the tumor model, tumor perfusion experiments were carried out using laser Doppler imaging and lectin-labeling experiments. A single treatment of captopril at a dose of 100 mg/kg significantly increased the percentage of functional vessels in tumor tissues and improved tumor blood perfusion. Scanning electron microscopy of tumor vessels also indicated that the endothelial gaps of tumor vessels were enlarged after captopril treatment. Immunofluorescence-staining of tumor slices demonstrated that captopril significantly increased bradykinin expression, possibly explaining tumor perfusion improvements and endothelial gap enlargement. Additionally, imaging in vivo, imaging ex vivo and nanoparticle distribution in tumor slices indicated that after a single treatment with captopril, the accumulation of 115-nm nanoparticles in tumors had increased 2.81-fold with a more homogeneous distribution pattern in comparison to non-captopril treated controls. Finally, pharmacodynamics experiments demonstrated that captopril combined with paclitaxel-loaded nanoparticles resulted in the greatest tumor shrinkage and the most extensive necrosis in tumor tissues among all treatment groups. Taken together, the data from the present study suggest a novel strategy for improving tumor perfusion and enlarging blood vessel permeability simultaneously in order to improve nanomedicine delivery for tumor therapy. As captopril has already been extensively used clinically, such a strategy has great therapeutic potential. (C) 2017 Published by Elsevier B.V.