Abstract
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.
Footnotes
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This study was supported by the Chinese Academy of Sciences (CAS) “Hundred Talents Program” grant 07165111ZX, 973 Programs grant 2006CB705600, Natural Science Foundation of China grants 10525524 and 20751001, and the CAS Knowledge Innovation Program. This work was also supported in part by National Institutes of Health/National Center for Research Resources/Research Centers in Minority Institutions Grant 2G12RR003048, National Institutes of Health grant 5U 54CA091431, and U.S. Army Medical Research and Materiel Command grant W81XWH-05-1-0291.
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ABBREVIATIONS: ROS, reactive oxygen species; ESR, electron spin resonance; [Gd@C82(OH)22]n nanoparticles, gadolinium endohedral metallofullerenol; HO., hydroxyl radical;
, superoxide radical anion; 1O2, singlet oxygen; DPPH, 2,2-diphenyl-1-picrylhydrazyl; rBCEC, rat brain capillary endothelial cell; DMPO, 5,5-dimethyl-1-pyrroline N-oxide; AAPH, 2,2′-Azobis(2-amidinopropane) dihydrochloride; PBS, phosphate-buffered saline; JC-1, 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimida-zolylcarbocyanine iodide; ΔΨm, mitochondrial membrane potential; CM-H2DCFDA, 5-(and 6-)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate, acetyl ester. -
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material. - Received April 28, 2008.
- Accepted July 15, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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