Department of Materials Science, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8573, Japan; Radiation Biology Research Group, Biomedical Research Section, Atomic Research Division, Philippine Nuclear Research Institute, Department of Science and Technology (PNRI-DOST), Commonwealth Avenue, Diliman, Quezon City, Philippines.
Proton Medical Research Center, University of Tsukuba, Japan.
Biomaterials. 2017 Jun;129:68-82. doi: 10.1016/j.biomaterials.2017.03.011. Epub 2017 Mar 14.
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, RNP) 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 RNP core prevented its rapid metabolism and excretion out of the body. The nano-sized formulation prevented internalization of RNP 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.
放射防护剂已被开发出来，以保护患者免受电离辐射的破坏性和致死性影响。然而，除了固有靶向活性氧（ROS）的能力外，放射防护剂还需要保持较高的生物利用度，因为这可以提高和延长其放射防护效果，并提高其安全性。在这里，我们报告了一种新型基于纳米颗粒的放射防护剂的开发，该放射防护剂具有提高的生物利用度，可抑制与低分子量（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，其中通过共价键连接的氮氧自由基（氧化还原纳米颗粒，RNP）有效地清除了辐射诱导的 ROS，与传统的 LMW 抗氧化剂相比，其生物利用度和组织驻留时间明显延长。氮氧自由基在 RNP 核内的限制防止了其快速代谢和从体内排出。纳米尺寸的制剂阻止了 RNP 在健康细胞中的内化，从而保持了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引起的器官功能障碍，并增加了致死性照射的小鼠的存活时间。
