A novel nitric oxide-based anticancer therapeutics by macrophage-targeted poly(L-arginine)-based nanoparticles
A novel nitric oxide-based anticancer therapeutics by macrophage-targeted poly(L-arginine)-based nanoparticles
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DOI：
10.1016/j.jconrel.2015.09.019
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发表时间：
2015-11-10
影响因子：
10.8
通讯作者：
Nagasaki, Yukio
中科院分区：
文献类型：
--
作者：
Kudo, Shinpei;Nagasaki, Yukio
在免疫系统中，肿瘤组织中的巨噬细胞产生一氧化氮（NO），产生包括肿瘤细胞凋亡在内的多种效应，因为巨噬细胞细胞质中的诱导型NO合酶（iNOS）使用L-精氨酸作为底物产生NO。在这里，我们提出了新的NO触发的免疫疗法的基础上，我们新设计的纳米颗粒系统。我们设计了聚（乙二醇）-嵌段-聚（L-精氨酸）（即，聚乙二醇-b-P（L-Arg））嵌段共聚物，并制备了由聚乙二醇-b-P（L-Arg）和硫酸软骨素组成的聚离子复合物胶束（PEG-b-P（L-Arg）/m），用于全身抗癌免疫治疗。iNOS处理PEG-b-P（L-Arg）不产生NO，但在胰蛋白酶预处理后检测到NO分子，表明P（L-Arg）在体外发生水解为单体精氨酸。与对照胶束相比，RAW 264.7巨噬细胞从PEG-b-P（L-Arg）/min大量产生NO;这一发现表明所提出的方法的稳健性。值得注意的是，全身给予PEG-b-P（L-Arg）/m没有明显的副作用，并且以剂量依赖性方式抑制了C26荷瘤小鼠的肿瘤生长速率。我们新设计的纳米颗粒辅助精氨酸递送系统似乎有望成为NO介导的抗癌免疫疗法。(c)2015 Elsevier B. V.版权所有。
In the immune system, macrophages in tumor tissue generate nitric oxide (NO), producing versatile effects including apoptosis of tumor cells, because inducible NO synthase (iNOS) in the cytoplasm of a macrophage produces NO using L-arginine as a substrate. Here, we propose novel NO-triggered immune therapeutics based on our newly designed nanoparticle system. We designed a poly(ethylene glycol)-block-poly(L-arginine) (i.e., PEG-b-P(L-Arg)) block copolymer and prepared polyion complex micelles (PEG-b-P(L-Arg)/m) composed of PEG-b-P(L-Arg) and chondroitin sulfate for systemic anticancer immunotherapy. iNOS treatment of PEG-b-P(L-Arg) did not generate NO, but NO molecules were detected after trypsin pretreatment, indicating that hydrolysis of P(L-Arg) to monomeric arginine was taking place in vitro. RAW264.7 macrophages abundantly generated NO from the PEG-b-P(L-Arg)/min comparison with control micelles; this finding is indicative of robustness of the proposed method. It is interesting to note that systemic administration of PEG-b-P(L-Arg)/m had no noticeable adverse effects and suppressed the tumor growth rate in C26 tumor-bearing mice in a dose-dependent manner. Our newly designed nanoparticle-assisted arginine delivery system seems to hold promise as an NO-mediated anticancer immunotherapy. (c) 2015 Elsevier B.V. All rights reserved.