In vivo biological behavior of a water-miscible fullerene: 14C labeling, absorption, distribution, excretion and acute toxicity. Chem Biol 2: 385-389

Department of Chemistry, Tokyo Institute of Technology, Japan.
Chemistry & Biology (Impact Factor: 6.65). 07/1995; 2(6):385-9. DOI: 10.1016/1074-5521(95)90219-8
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Water-soluble fullerenes have recently been shown to exhibit considerable in vitro biological activity including cytotoxicity, site-selective DNA cleavage and inhibition of HIV protease. To assess the potential of these compounds as drugs, studies on the in vivo behavior of fullerenes are needed. We therefore set out to synthesize a radiolabeled, water-soluble fullerene, in order to obtain data on the oral absorption, distribution and excretion of this class of compounds.
We synthesized a 14C-labeled water-soluble [60]fullerene using dipolar trimethylenemethane, which undergoes cycloaddition to [60]fullerene. When administered orally to rats, this compound was not efficiently absorbed and was excreted primarily in the feces. When injected intravenously, however, it was distributed rapidly to various tissues, and most of the material was retained in the body after one week. The compound was also able to penetrate the blood-brain barrier. Acute toxicity of the water-miscible fullerene was found to be quite low.
Although the water-soluble fullerenes (and possibly their simple metabolites) are not acutely toxic, they are retained in the body for long periods, raising concerns about chronic toxic effects. The fact that fullerenes distribute rapidly to many tissues suggests that they may eventually be useful to deliver highly polar drugs through membranes to a target tissue, however, and they may even have applications in the delivery of drugs to the brain. Recent advances in fullerene synthetic chemistry may also make it possible to control fullerene absorption/excretion profiles in the future.

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Available from: Shigeru Yamago, Sep 16, 2014
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    • "C 60 fullerenes, comprised of 60 carbon atoms configured as a hollow sphere, are candidate therapeutic agents because they exert multiple effects on the ischemic cascade (Chiang et al., 1995; Jin et al., 2000) and therefore, fullerene-derivatives might influence cerebral ischemia (Lin et al., 2002). When appropriately modified, fullerenes can pass the blood–brain barrier (Yamago et al., 1995). Fullerenols are hydroxylated fullerenes that are neuroprotective because they scavenge free radicals (Fig. S1 in the online-only data supplement) (Chiang et al., 1995). "
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    ABSTRACT: Cerebral inflammation plays a crucial role in the pathophysiology of ischemic stroke and is involved in all stages of the ischemic cascade. Fullerene derivatives, such as fullerenol (OH-F) are radical scavengers acting as neuroprotective agents while glucosamine (GlcN) attenuates cerebral inflammation after stroke. We created novel glucosamine–fullerene conjugates (GlcN-F) to combine their protective effects and compared them to OH-F regarding stroke-induced cerebral inflammation and cellular damage. Fullerene derivatives or vehicle was administered intravenously in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) immediately after transient middle cerebral artery occlusion (tMCAO). Infarct size was determined at day 5 and neurological outcome at days 1 and 5 after tMCAO. CD68- and NeuN-staining were performed to determine immunoreactivity and neuronal survival respectively. Cytokine and toll like receptor 4 (TLR-4) expression was assessed using quantitative real-time PCR. Magnetic resonance imaging revealed a significant reduction of infarct volume in both, WKY and SHR that were treated with fullerene derivatives. Treated rats showed an amelioration of neurological symptoms as both OH-F and GlcN-F prevented neuronal loss in the perilesional area. Cerebral immunoreactivity was reduced in treated WKY and SHR. Expression of IL-1β and TLR-4 was attenuated in OH-F-treated WKY rats. In conclusion, OH-F and GlcN-F lead to a reduction of cellular damage and inflammation after stroke, rendering these compounds attractive therapeutics for stroke.
    Experimental Neurology 01/2015; accepted. DOI:10.1016/j.expneurol.2015.01.005 · 4.70 Impact Factor
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    • "The released siRNA then bound to the RNA-induced silencing complex and cleaved the target mRNA, and the remaining TPFE was cleared from the lung cells and tissues. Although the eventual fate of the TPFE is unclear at this time, according to the pharmacokinetic studies of water-soluble fullerenes2627, majority must have been excreted into the urine and feces. "
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    Scientific Reports 05/2014; 4:4916. DOI:10.1038/srep04916 · 5.58 Impact Factor
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    • "The workers involved in the synthesis of SWCNTs may be exposed by unintentional hand to mouth transfer of nanomaterials. Yamago et al. (1995) reported that the major percentage of radiolabelled functionalized fullerenes were detected in the liver after administrated intravenously to rats. Their potential toxicological impacts are still a matter of investigation, and our actual knowledge on the effects of engineered nanosized contaminants on biological systems remains incomplete (Singh et al. 2009; Skocaj et al. "
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