IN-VIVO BIOLOGICAL BEHAVIOR OF A WATER-MISCIBLE FULLERENE - C-14 LABELING, ABSORPTION, DISTRIBUTION, EXCRETION AND ACUTE TOXICITY

Background: Water-soluble fullerenes have recently been shown to exhib it considerable in vitro biological activity including cytotoxicity, s ite-selective DNA cleavage and inhibition of HIV protease. To assess t he potential of these compounds as drugs, studies on the in vivo behav ior of fullerenes are needed. We therefore set out to synthesize a rad iolabeled, water-soluble fullerene, in order to obtain data on the ora l absorption, distribution and excretion of this class of compounds. R esults: We synthesized a C-14-labeled water-soluble [60]fullerene usin g dipolar trimethylenemethane, which undergoes cycloaddition to [60]fu llerene. When administered orally to rats, this compound was not effic iently 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. Th e compound was also able to penetrate the blood-brain barrier. Acute t oxicity of the water-miscible fullerene was found to be quite low. Con clusions: Although the water-soluble fullerenes (and possibly their si mple metabolites) are not acutely toxic, they are retained in the body for long periods, raising concerns about chronic toxic effects. The f act that fullerenes distribute rapidly to many tissues suggests that t hey may eventually be useful to deliver highly polar drugs through mem branes to a target tissue, however, and they may even have application s in the delivery of drugs to the brain. Recent advances in fullerene synthetic chemistry may also make it possible to control fullerene abs orption/excretion profiles in the future.