Long-term bioavailability of redox nanoparticles effectively reduces organ dysfunctions and death in whole-body irradiated mice
Long-term bioavailability of redox nanoparticles effectively reduces organ dysfunctions and death in whole-body irradiated mice
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DOI：
10.1016/j.biomaterials.2017.03.011
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发表时间：
2017-06-01
期刊：
影响因子：
14
通讯作者：
Nagasaki, Yukio
中科院分区：
文献类型：
--
作者：
Feliciano, Chitho P.;Tsuboi, Koji;Nagasaki, Yukio
放射防护剂已被开发用于保护患者免受电离辐射的损伤和致命影响。然而，除了靶向活性氧（ROS）的固有能力之外，在辐射防护剂中保持显著水平的生物利用度的能力是期望的，因为这将增加和延长它们的辐射防护功效并改善其安全性。在这里，我们报告了一种新的基于纳米颗粒的放射防护剂的开发，其具有改善的生物利用度，抑制了通常与低分子量（LMW）抗氧化剂相关的不良反应。我们开发了生物相容性和胶体稳定的纳米颗粒，其中氮氧自由基共价结合（氧化还原纳米颗粒，RNPN）有效地清除辐射诱导的ROS，与传统的低分子量抗氧化剂相比，其生物利用度和组织停留时间延长。氮氧自由基在RNPN核心的限制阻止其快速代谢和排泄出体外。纳米尺寸的制剂防止RNPN在健康细胞中的内化，从而保持细胞中氧化还原反应的正常功能。当在全身照射前3 - 24小时给予纳米颗粒时，这种改善的药理学性能显著降低了辐射诱导的器官功能障碍，并增加了致死照射小鼠的存活时间。(C)2017爱思唯尔有限公司版权所有
Radioprotective agents have been developed to protect patients against the damaging and lethal effects of ionizing radiation. However, in addition to the intrinsic ability to target reactive oxygen species (ROS), the ability to retain a significant level of bioavailability is desirable in radioprotective agents because that would increase and prolong their radioprotective efficacy and improve its safety. Here, we report the development of a novel nanoparticle-based radioprotective agent with improved bioavailability, which suppressed the adverse effects typically associated with low-molecular-weight (LMW) antioxidants. We developed biocompatible and colloidally stable nanoparticles in which nitroxide radicals that were covalently conjugated (redox nanoparticles, RNPN) effectively scavenged radiation-induced ROS with a characteristically prolonged bioavailability and tissue-residence time compared with that of conventional LMW antioxidants. The confinement of the nitroxide radicals in the RNPN core prevented its rapid metabolism and excretion out of the body. The nano-sized formulation prevented internalization of RNPN in healthy cells, thereby preserving the normal function of the redox reactions in the cell. This improved pharmacological performance dramatically reduced the radiation-induced organ dysfunctions and increased the survival time of the lethally irradiated mice when the nanoparticles were administered 3 -24 h before whole-body irradiation. (C) 2017 Elsevier Ltd. All rights reserved.