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Inhibition of Tumor Growth by Endohedral Metallofullerenol Nanoparticles Optimized as Reactive Oxygen Species Scavenger

Division of Nanomedicine and Nanobiology, National Center for Nanosciences and Technology of China, Beijing, China (F.L., J.M., Y.Z., C.C., X.-J.L.); Center for Food Safety and Applied Nutrition, Food and Drug Administration, College Park, Maryland (J.-J.Y.); Laboratory for Bio-Environmental Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, China (J.M., Y.Z., G.X., X.G., B.S., C.C.); Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas (P.P.F.); and Laboratory of Molecular Imaging, Department of Radiology, Howard University, Washington, DC (P.C.W.)

Intraperitoneal injection of [Gd@C₈₂(OH)₂₂]_n nanoparticles decreased activities of enzymes associated with the metabolism of reactive oxygen species (ROS) in the tumor-bearing mice. Several physiologically relevant ROS were directly scavenged by nanoparticles, and lipid peroxidation was inhibited in this study. [Gd@C₈₂(OH)₂₂]_n nanoparticles significantly reduced the electron spin resonance (ESR) signal of the stable 2,2-diphenyl-1-picryhydrazyl radical measured by ESR spectroscopy. Like-wise, studies using ESR with spin-trapping demonstrated efficient scavenging of superoxide radical anion, hydroxyl radical, and singlet oxygen (¹O₂) by [Gd@C₈₂(OH)₂₂]_n nanoparticles. In vitro studies using liposomes prepared from bovine liver phosphatidylcholine revealed that nanoparticles also had a strong inhibitory effect on lipid peroxidation. Consistent with their ability to scavenge ROS and inhibit lipid peroxidation, we determined that [Gd@C₈₂(OH)₂₂]_n nanoparticles also protected cells subjected in vitro to oxidative stress. Studies using human lung adenocarcinoma cells or rat brain capillary endothelial cells demonstrated that [Gd@C₈₂(OH)₂₂]_n nanoparticles reduced H₂O₂-induced ROS formation and mitochondrial damage. [Gd@C₈₂(OH)₂₂]_n nanoparticles efficiently inhibited the growth of malignant tumors in vivo. In summary, the results obtained in this study reveal antitumor activities of [Gd@C₈₂(OH)₂₂]_n nanoparticles in vitro and in vivo. Because ROS are known to be implicated in the etiology of a wide range of human diseases, including cancer, the present findings demonstrate that the potent inhibition of [Gd@C₈₂(OH)₂₂]_n nanoparticles on tumor growth likely relates with typical capacity of scavenging reactive oxygen species.

Received for publication April 28, 2008.

Accepted for publication July 15, 2008.

Address correspondence to: Dr. Xing-Jie Liang, Laboratory of Nanobiomedicine and Nanosafety, Division of Nanomedicine and Nanobiology, National Center for Nanoscience and Technology of China, 11, First North Rd., Zhongguancun, Beijing, People's Republic of China, 100190. E-mail: liangxj{at}nanoctr.cn