Pharmacokinetics and Toxicology of the Neuroprotective e,e,e-Methanofullerene(60)-63-tris Malonic Acid [C3] in Mice and Primates

Abstract

The plasma half-life of C was 8.2 ± 0.2 h, and there was wide tissue distribution, including uptake into brain. The compound was cleared by both hepatic and renal excretion. C was quite stable, with minimal metabolism of the compound even after 7 days of treatment. The LD in mice was 80 mg/kg for a single intraperitoneal injection, and was > 30 mg/kg/day for sustained administration; therapeutic doses are 1-5 mg/kg/day. For primates, no evidence of renal, hepatic, electrolyte, or hematologic abnormalities were noted, and serial ECGs demonstrated no alteration in cardiac electrical activity. Thus, doses of C that have therapeutic efficacy appear to be well tolerated after 2 years (mice) or 2 months (non-human primates) of treatment.

Evaluation of the Biodistribution of Serinolamide-Derivatized C60 Fullerene

“…For example, there have been many reports of C 60 derivatives with less hydrophilic coverage than that of the present study, such as hydroxylated and carboxylated fullerenes, which showed greater retention in the lungs, muscle, and RES organs, in addition to longer residence times in vivo (~30 h) [26,38,41,[58][59][60][61]. However, leaving some lipophilic character on the C 60 surface can result in the penetration of certain restrictive membranes, such as the blood-brain-barrier, as was recently reported by Dugan and coworkers when administering 14 C-labeled e,e,e-methanofullerene(60)-63-tris malonic acid (C 3 ) [40]. C 3 showed significant liver and kidney uptake at 12 and 24 h p.i., which resulted in fecal excretion as the route of clearance.…”

“…Matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) was performed using an Autoflex MALDI An important aspect of designing drug delivery platforms is the study of the biodistribution and excretion profile of the compound. Thus far, the biodistribution profiles of C 60 reported in the literature, including C 60 -serinol, are discordant [38][39][40][41]. This work aims to reevaluate the in vivo behavior of this nanomaterial non-invasively, using the imaging technique positron emission tomography (PET).…”

Reduction of Leukocyte Microvascular Adherence and Preservation of Blood-Brain Barrier Function by Superoxide-Lowering Therapies in a Piglet Model of Neonatal Asphyxia

“…On the other hand, C 3 has several features which may prove attractive clinically. It acts catalytically (27), and therefore retains activity for as long as it is present, has a plasma half-life of 8 h, and demonstrates significant brain uptake in both rodents and non-human primates (29, 45). C 3 is also highly water soluble and has oral bioavailability (45).…”

“…It acts catalytically (27), and therefore retains activity for as long as it is present, has a plasma half-life of 8 h, and demonstrates significant brain uptake in both rodents and non-human primates (29, 45). C 3 is also highly water soluble and has oral bioavailability (45). While C 3 is roughly 100-fold less active than SOD itself (27), its ability to access mitochondria as well as other intracellular compartments may enhance its overall biological efficacy, especially as it appears to have a good safety profile with long-term (2 years, mice; 2 months, primates) chronic administration (19, 45).…”

“…C 3 is also highly water soluble and has oral bioavailability (45). While C 3 is roughly 100-fold less active than SOD itself (27), its ability to access mitochondria as well as other intracellular compartments may enhance its overall biological efficacy, especially as it appears to have a good safety profile with long-term (2 years, mice; 2 months, primates) chronic administration (19, 45). Newborn infants could theoretically be treated with C 3 via oral fluids such as formula, or intravenously.…”