Yamago S, Tokuyama H, Nakamura E, Kikuchi K, Kananishi S, Sueki K, Nakahara H, Enomoto S, Ambe F
Department of Chemistry, Tokyo Institute of Technology, Japan.
Chem Biol. 1995 Jun;2(6):385-9. doi: 10.1016/1074-5521(95)90219-8.
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.
最近研究表明，水溶性富勒烯具有显著的体外生物活性，包括细胞毒性、位点选择性DNA切割以及对HIV蛋白酶的抑制作用。为了评估这些化合物作为药物的潜力，需要对富勒烯的体内行为进行研究。因此，我们着手合成一种放射性标记的水溶性富勒烯，以便获取这类化合物口服吸收、分布和排泄的数据。
我们使用偶极三亚甲基甲烷合成了一种14C标记的水溶性[60]富勒烯，该物质可与[60]富勒烯发生环加成反应。给大鼠口服这种化合物后，其吸收效率不高，主要通过粪便排出。然而，静脉注射时，它能迅速分布到各个组织，一周后大部分物质仍保留在体内。该化合物还能够穿透血脑屏障。发现这种可与水混溶的富勒烯急性毒性相当低。
尽管水溶性富勒烯（及其简单代谢物）没有急性毒性，但它们会在体内长期留存，这引发了对其慢性毒性影响的担忧。富勒烯能迅速分布到许多组织这一事实表明，它们最终可能有助于将高极性药物通过细胞膜输送到靶组织，甚至可能在向脑部输送药物方面有应用价值。富勒烯合成化学领域的最新进展也可能使未来控制富勒烯的吸收/排泄情况成为可能。
