S-Nitrosated human serum albumin dimer as novel nano-EPR enhancer applied to macromolecular anti-tumor drugs such as micelles and liposomes
S-Nitrosated human serum albumin dimer as novel nano-EPR enhancer applied to macromolecular anti-tumor drugs such as micelles and liposomes
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DOI：
10.1016/j.jconrel.2015.08.036
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发表时间：
2015-11-10
影响因子：
10.8
通讯作者：
Maruyama, Toru
中科院分区：
文献类型：
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作者：
Kinoshita, Ryo;Ishima, Yu;Maruyama, Toru
增透性和滞留(EPR)效应是实体瘤特有的现象，可作为发展大分子抗癌治疗的基础。我们先前已经发现，重组人血清白蛋白二聚体，特别是其S亚硝化形式(SNO-HSA-二聚体)，是EPR效应的增强剂。在本研究中，我们考察了SNO-HSA-二聚体对两种大分子抗肿瘤药物N-(2-羟丙基)甲基丙烯酰胺聚合物与锌原卟啉偶联形成胶束并用于荧光研究的影响。另一种是聚乙二醇化阿霉素脂质体(Doxil)，这是一种被批准用于医疗用途的隐形脂质体的典型例子。在具有高渗透性血管系统的C26肿瘤小鼠中，SNO-HSA-二聚体使药物的肿瘤积聚增加了3-4倍，从而发挥了抗肿瘤作用。用伊文思蓝进行的实验显示，肿瘤所有部位的EPR效应都有所增加。此外，SNO-HSA-二聚体改善了Doxil的抗转移作用，并减少了其在非肿瘤器官如肝脏和肾脏的少量摄取。在以低通透性血管为特征的B16肿瘤中，在SNO-HSA-二聚体存在下，Doxil的肿瘤积聚增加了更多(6倍)，并且改善了积聚导致肿瘤体积减少和动物生存增加。服用SNO-HSA-二聚体本身是安全的，因为它对血压、心率或几个生化参数没有影响。这些结果表明，SNO-HSA-二聚体有望增强EPR效应，从而增强大分子抗癌药物的特异性治疗效果。(C)2015爱思唯尔B.V.保留所有权利。
The enhanced permeability and retention (EPR) effect is a unique phenomenon of solid tumors, and it can serve as a basis for the development of macromolecular anticancer therapy. We have previously found that recombinant human serum albumin dimer, and especially its S-nitrosated form (SNO-HSA-Dimer), is an enhancer of the EPR effect. In this study, we investigated the influence of SNO-HSA-Dimer on the anti-tumor effect of two types of macromolecular anti-tumor drugs, namely N-(2-hydroxypropyl) methacrylamide polymer conjugated with zinc protoporphyrin, which forms micelles and can be used for fluorescence studies. The other was PEGylated liposomal doxorubicin (Doxil), a typical example of a stealth liposome approved for medical usage. In mice having C26 tumors with highly permeable vasculature, SNO-HSA-Dimer increases tumor accumulation of the drugs by a factor 3-4 and thereby their anti-tumor effects. Experiments with Evans blue revealed increased EPR effect in all parts of the tumor. Furthermore, SNO-HSA-Dimer improves the anti-metastatic effects of Doxil and reduces its minor uptake in non-tumorous organs such as liver and kidney. Tumor accumulation of Doxil in B16 tumors, which are characterized by a low permeable vasculature, increased even more (6-fold) in the presence of SNO-HSA-Dimer, and the improved accumulation lead to decreased tumor volume and increased survival of the animals. The administration of SNO-HSA-Dimer itself is safe, because it has no effect on blood pressure, heart rate or on several biochemical parameters. The present findings indicate that SNO-HSA-Dimer is promising for enhancing the EPR effect and consequently the specific, therapeutic effects of macromolecular anticancer drugs. (c) 2015 Elsevier B.V. All rights reserved.