The ROS scavenging and renal protective effects of pH-responsive nitroxide radical-containing nanoparticles
The ROS scavenging and renal protective effects of pH-responsive nitroxide radical-containing nanoparticles
复制标题
DOI：
10.1016/j.biomaterials.2011.07.014
复制
发表时间：
2011-11-01
期刊：
影响因子：
14
通讯作者：
Nagasaki, Yukio
中科院分区：
文献类型：
--
作者：
Yoshitomi, Toru;Hirayama, Aki;Nagasaki, Yukio
基于纳米颗粒的治疗的最终目标是在微疾病环境中使纳米药物具有功能性，而不产生任何副作用。在这里，我们揭示了我们的pH响应型含氮氧自由基纳米颗粒(RNP(PH))在肾脏酸性病变中解体，并作为活性氧物种(ROS)的清除剂，导致急性肾损伤(AKI)的缓解。以含2，2，6，6-四甲基哌啶-N-氧基(TEMPO)基团的两亲嵌段共聚物作为疏水链段的侧链，制备了RNP(PH)。自组装的RNP(PH)在pH低于7.0时，由于纳米颗粒疏水核心中氨基的质子化而解体，从而提高了ROS清除活性。采用小鼠肾缺血再灌注AKI模型，观察RNP(PH)对ROS损伤的治疗作用。与无pH触发崩解的RNP(非PH)不同，RNP(PH)具有极高的ROS清除活性和肾脏保护作用。值得注意的是，由于RNP(PH)核心中的氮氧自由基在非靶区的区域化，氮氧自由基的副作用被显着抑制。通过电子自旋共振波谱分析证实了RNP(PH)的形态变化，这些发现为环境敏感的纳米颗粒体内特异性崩解的真正治疗效果提供了证据。(C)2011爱思唯尔有限公司。保留所有权利。
The ultimate objective of nanoparticle-based therapy is to functionalize nanomedicines in a micro-disease environment without any side effects. Here, we reveal that our pH-responsive nitroxide radical-containing nanoparticles (RNP(PH)) disintegrate within the renal acidic lesion and act as scavengers of reactive oxygen species (ROS), leading to a relief of acute kidney injury (AKI). RNP(PH) was prepared using amphiphilic block copolymers possessing 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) moieties via amine linkage as a side chain of the hydrophobic segment. The self-assembled RNP(PH) disintegrated at pH below 7.0 because of a protonation of the amino groups in the hydrophobic core of the nanoparticles, thereby resulting in an improvement in ROS scavenging activity. Using a renal ischemia-reperfusion AKI model in mice, the therapeutic effect of RNP(PH) on ROS damage was evaluated. Unlike the RNP without pH-triggered disintegration (RNP(Non-PH)) the RNP(PH) showed extremely high ROS scavenging activity and renal protective effects. It is interesting to note that the side effect of nitroxide radicals was markedly suppressed due to the compartmentalization of nitroxide radicals in the core of RNP(PH) in untargeted area. The morphology changes in RNP(PH) were confirmed by analyzing electron spin resonance spectra, and these findings provide the evidence of the real therapeutic effect of the environment-sensitive specific disintegration of nanoparticles in vivo. (C) 2011 Elsevier Ltd. All rights reserved.