Long-term bioavailability of redox nanoparticles effectively reduces organ dysfunctions and death in whole-body irradiated mice.
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 RNPNcore prevented its rapid metabolism and excretion out of the body. The nano-sized formulation prevented internalization of RNPNin 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.
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.
Chitho P
CP
Feliciano
Proton Medical Research Center, University of Tsukuba, Japan.
Koji
K
Tsuboi
Proton Medical Research Center, University of Tsukuba, Japan.
Kenshi
K
Suzuki
Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, Misasagi-Nakauchicho 5, Yamashinaku, Kyoto, Kyoto 607-8414, Japan.
Hiroyuki
H
Kimura
Department of Materials Science, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8573, Japan; Master's School of Medical Sciences, Graduate School of Comprehensive Human Sciences, Tennoudai 1-1-1, Tsukuba, Ibaraki, 305-8573, Japan; Satellite Laboratory, International Center of Materials Nanoarchitectonics (WPI-MANA), National Institute for Materials Science (NIMS), University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki, 305-8573, Japan. Electronic address: happyhusband@nagalabo.jp.
Yukio
Y
Nagasaki
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001682:Biological Availability; D001775:Blood Circulation / Q000187:drug effects; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D006470:Hemorrhage / Q000150:complications / Q000473:pathology / Q000517:prevention & control; D007279:Injections, Subcutaneous; D008221:Lymphoid Tissue / Q000187:drug effects / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000627:therapeutic use* / Q000633:toxicity; D009589:Nitrogen Oxides / Q000737:chemistry; D009928:Organ Specificity; D010084:Oxidation-Reduction; D011837:Radiation-Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000150:complications / Q000473:pathology / Q000517:prevention & control; D016019:Survival Analysis; D013997:Time Factors; D015431:Weight Loss / Q000187:drug effects; D014916:Whole-Body Irradiation; D014965:X-Rays
D016166:Free Radical Scavengers; D009589:Nitrogen Oxides; D011837:Radiation-Protective Agents; D017382:Reactive Oxygen Species; C039900:nitroxyl
Drug bioavailability; Ionizing radiation; Nitroxide radicals; Radiation protection; Radioprotector; Reactive oxygen species; Redox nanoparticles; Whole-body irradiation