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1.
Eur J Drug Metab Pharmacokinet ; 43(5): 543-554, 2018 Oct.
Article in English | MEDLINE | ID: mdl-29520718

ABSTRACT

BACKGROUND AND OBJECTIVES: Fullerene-based compounds are a novel class of molecules being developed for a variety of biomedical applications, with nearly 1000 publications in this area in the last 4 years alone. One such compound, the e,e,e-methanofullerene(60)-63-tris malonic acid (designated C3), is a potent catalytic superoxide dismutase mimetic which has shown neuroprotective efficacy in a number of animal models of neurologic disease, including Parkinsonian Macaca fascicularis monkeys. The aim of this study was to characterize its toxicity and pharmacokinetics in mice and monkeys. METHODS: To assess pharmacokinetics in mice, we synthesized and administered 14C-C3 to mice using various routes of delivery, including orally. To assess potential toxicity in primates, serial blood studies and electrocardiograms (ECGs) were obtained from monkeys treated with C3 (3 or 7 mg/kg/day) for 2  months. RESULTS AND CONCLUSIONS: The plasma half-life of C3 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. C3 was quite stable, with minimal metabolism of the compound even after 7 days of treatment. The LD50 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 C3 that have therapeutic efficacy appear to be well tolerated after 2 years (mice) or 2 months (non-human primates) of treatment.


Subject(s)
Fullerenes/pharmacokinetics , Fullerenes/toxicity , Infarction, Middle Cerebral Artery/drug therapy , MPTP Poisoning/drug therapy , Neuroprotective Agents/pharmacokinetics , Neuroprotective Agents/toxicity , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Fullerenes/administration & dosage , Fullerenes/blood , Half-Life , Heart Rate/drug effects , Hepatobiliary Elimination , Infarction, Middle Cerebral Artery/blood , Lethal Dose 50 , MPTP Poisoning/blood , MPTP Poisoning/chemically induced , Macaca fascicularis , Male , Metabolic Clearance Rate , Mice, Inbred C57BL , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/blood , Renal Elimination , Tissue Distribution
2.
Anal Bioanal Chem ; 409(28): 6575-6581, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28939916

ABSTRACT

With their intriguing structures and properties, metallofullerenols have attracted considerable attention in biological and medical applications. Due to the increasing biomedical interest, effective detection methods are important to monitor and control metallofullerenols. However, the detection of metallofullerenols becomes very difficult after polyhydroxylated modification due to the lack of detectable features. Antibody-based immunoassay methods have been important tools for detection and will better meet the needs of analysis of metallofullerenols. Thus, the antigenicity of metallofullerenol has been studied for the first time. In this study, no immune response was detected when metallofullerenol Gd@C82(OH)x was used as immunogen. However, the polyclonal antibody against metallofullerenol was produced using metallofullerenol-KLH (keyhole limpet hemocyanin) as immunogen, indicating that metallofullerenol can act as hapten. The specificity of the obtained antibody was investigated. It has been found that the hydroxyl groups on the surface of the carbon cage, the encapsulated metal, and the size and shape of the carbon cage did not affect the recognition specificity of the antibody. Based on the obtained antibody, an indirect competitive enzyme immunoassay was developed for the determination of metallofullerenol with detection limits of 18 ng/mL in PBS. This enzyme immunoassay method was successfully used to detect metallofullerenol in serum. This work can provide an innovative way to determine metallofullerenols. Graphical abstract The polyclonal antibody against metallofullerenol was produced using metallofullerenol-KLH (keyhole limpet hemocyanin) as immunogen. Based on the obtained antibody, a competitive enzyme immunoassay was developed for the determination of metallofullerenol.


Subject(s)
Antibody Formation , Fullerenes/blood , Fullerenes/immunology , Gadolinium/blood , Gadolinium/immunology , Immunoenzyme Techniques/methods , Animals , Antibodies/immunology , Antibody Specificity , Cattle , Female , Fullerenes/chemistry , Gadolinium/chemistry , Hemocyanins/chemistry , Hemocyanins/immunology , Rabbits
3.
J Appl Toxicol ; 35(12): 1452-64, 2015 Dec.
Article in English | MEDLINE | ID: mdl-25727383

ABSTRACT

A comprehensive distribution study was conducted in female rats and mice exposed to a suspension of uniformly carbon-14-labeled C60 ([(14) C(U)]C60 ). Rodents were administered [(14) C(U)]C60 (~0.9 mg kg(-1) body weight) or 5% polyvinylpyrrolidone-saline vehicle alone via a single tail vein injection. Tissues were collected at 1 h and 1, 7, 14 and 30 days after administration. A separate group of rodents received five daily injections of suspensions of either [(14) C(U)]C60 or vehicle with tissue collection 14 days post exposure. Radioactivity was detected in over 20 tissues at all time points. The highest concentration of radioactivity in rodents at each time point was in liver, lungs and spleen. Elimination of [(14) C(U)]C60 was < 2% in urine and feces at any 24 h time points. [(14) C(U)]C60 and [(14) C(U)]C60 -retinol were detected in liver of rats and together accounted for ~99% and ~56% of the total recovered at 1 and 30 days postexposure, respectively. The blood radioactivity at 1 h after [(14) C(U)]C60 exposure was fourfold higher in rats than in mice; blood radioactivity was still in circulation at 30 days post [(14) C(U)]C60 exposure in both species (<1%). Levels of oxidative stress markers increased by 5 days after exposure and remained elevated, while levels of inflammation markers initially increased and then returned to control values. The level of cardiovascular marker von Willebrand factor, increased in rats, but remained at control levels in mice. This study demonstrates that [(14) C(U)]C60 is retained in female rodents with little elimination by 30 days after i.v. exposure, and leads to systemic oxidative stress.


Subject(s)
Cardiovascular Diseases/chemically induced , Fullerenes/pharmacokinetics , Oxidative Stress/drug effects , Administration, Intravenous , Animals , Biomarkers/analysis , Biotransformation , Carbon Radioisotopes , Cardiovascular Diseases/blood , Cardiovascular Diseases/immunology , Cardiovascular Diseases/urine , Female , Fullerenes/blood , Fullerenes/toxicity , Fullerenes/urine , Liver/drug effects , Liver/metabolism , Lung/drug effects , Lung/metabolism , Metabolic Clearance Rate , Metabolomics , Mice, Inbred C57BL , Organ Specificity , Oxidative Stress/immunology , Rats, Sprague-Dawley , Species Specificity , Spleen/drug effects , Spleen/metabolism , Tissue Distribution
4.
Arch Toxicol ; 86(12): 1809-27, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22562437

ABSTRACT

The fullerene C(60), due to the physicochemical properties of its spherical cage-like molecule build exclusively from carbon atoms, is able to both scavenge and generate reactive oxygen species. While this unique dual property could be exploited in biomedicine, the low water solubility of C(60) hampers the investigation of its behavior in biological systems. The C(60) can be brought into water by solvent extraction, by complexation with surfactants/polymers, or by long-term stirring, yielding pristine (unmodified) fullerene suspensions. On the other hand, a modification of the C(60) core by the attachment of various functional groups results in the formation of water-soluble fullerene derivatives. Assessment of toxicity associated with C(60) preparations is of pivotal importance for their biomedical application as cytoprotective (antioxidant), cytotoxic (anticancer), or drug delivery agents. Moreover, the widespread industrial utilization of fullerenes may also have implications for human health. However, the alterations in physicochemical properties imposed by the utilization of different methods for C(60) solubilization profoundly influence toxicological effects of fullerene preparations, thus making the analysis of their potential therapeutic and environmental toxicity difficult. This review provides a comprehensive evaluation of the in vitro and in vivo toxicity of fullerenes, focusing on the comparison between pristine and derivatized C(60) preparations and the mechanisms of their toxicity to mammalian cells and tissues.


Subject(s)
Cell Survival/drug effects , Fullerenes/toxicity , Mutagens , Oxidative Stress/drug effects , Animals , Cardiovascular Diseases/chemically induced , Cardiovascular Diseases/pathology , Eye Diseases/chemically induced , Eye Diseases/pathology , Fullerenes/blood , Fullerenes/chemistry , Furans/chemistry , Humans , Kidney Diseases/chemically induced , Kidney Diseases/pathology , Nervous System Diseases/chemically induced , Nervous System Diseases/pathology , Reactive Oxygen Species/toxicity , Skin Diseases/chemically induced , Skin Diseases/pathology
5.
Toxicol Lett ; 206(2): 172-7, 2011 Oct 10.
Article in English | MEDLINE | ID: mdl-21787853

ABSTRACT

We examined the biodistribution of C(60) in rats after tail vein administration using LC-MS/MS. C(60) was detected in various tissues, such as brain, kidneys, liver, lungs, and spleen of rats. On the other hand, no C(60) was found in blood. The highest C(60) concentration was observed in the lungs, followed by spleen, liver, kidneys, and brain. These results suggested that C(60) injected in the tail vein could be filtered by lung capillary vessels and accumulate in the lungs prior to being distributed to other tissues. Moreover, C(60) not being detected in the blood indicates that clearance of C(60) from the blood by filtration might effectively occur in the lungs. The time-dependent variation in the biodistribution of C(60) was evaluated. A time-dependent decrease in C(60) concentrations was observed in all tissues, except spleen. Moreover, a decreasing trend of C(60) levels differed among tissues, which could be due to differences in accumulation. These results suggest that unmodified C(60) and/or C(60) metabolites by metabolic enzymes could be excreted into feces and/or urine. In further studies, the metabolic and excretion pathways of C(60) should be evaluated to understand the toxicokinetics of C(60).


Subject(s)
Fullerenes/pharmacokinetics , Animals , Chromatography, High Pressure Liquid , Drug Carriers/administration & dosage , Drug Carriers/analysis , Drug Carriers/pharmacokinetics , Fullerenes/administration & dosage , Fullerenes/analysis , Fullerenes/blood , Injections, Intravenous , Limit of Detection , Liposomes , Lung/chemistry , Lung/metabolism , Male , Materials Testing , Metabolic Clearance Rate , Rats , Rats, Wistar , Spleen/chemistry , Spleen/metabolism , Tandem Mass Spectrometry , Tissue Distribution
6.
Methods Mol Biol ; 697: 145-53, 2011.
Article in English | MEDLINE | ID: mdl-21116963

ABSTRACT

Sensitive and fast analytical techniques are needed to determine the concentration of nanoparticles in biological samples (e.g., blood and tissues) for biodistribution and toxicity studies. This chapter describes a method for the use of capillary zone electrophoresis (CZE) and micellar electrokinetic chromatography (MEKC) for the quantitation of fullerene nanoparticles in human serum matrix. Data on the fullerene-based nanoparticle carboxyfullerene (C3 fullerene) in human serum is presented as an example.


Subject(s)
Chromatography, Micellar Electrokinetic Capillary/methods , Electrophoresis, Capillary/methods , Nanoparticles/analysis , Serum/chemistry , Calibration , Fullerenes/analysis , Fullerenes/blood , Fullerenes/pharmacokinetics , Humans , Reference Standards , Tissue Distribution
7.
Toxicol Pathol ; 37(4): 456-62, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19346503

ABSTRACT

Ultrafine particles are ubiquitous in ambient urban and indoor air from multiple sources and may contribute to adverse respiratory and cardiovascular diseases. Recently, it has been demonstrated that ultrafine particles (UFPs) are translocated from the lung into the systemic circulation. The exact pathway, however, for the translocation in the lung remains unclear. In this study, we examined the translocation pathway of intratracheally instilled C60 fullerene particles from the lung into the blood circulation in the mouse. Using light microscopy, aggregated particles of fullerene were observed in the capillary lumen in the lung and the pulmonary lymph nodes immediately after instillation. Electron microscopic analysis demonstrated an increased number of pinocytotic vesicles (caveolae) of various sizes in the type 1 alveolar epithelial cells (AEC) and endothelial cells; occasional caveolae containing some particulate substances were observed. In addition, particles of various sizes were observed throughout the structure of the air-blood barrier (ABB). These findings suggest that fullerene particles may pass the ABB by both diffusion and caveolae-mediated pinocytosis, resulting in immediate translocation into the systemic circulation.


Subject(s)
Blood-Air Barrier/metabolism , Caveolae/metabolism , Fullerenes/pharmacokinetics , Particulate Matter/pharmacokinetics , Pinocytosis , Trachea/metabolism , Animals , Blood-Air Barrier/ultrastructure , Caveolae/ultrastructure , Diffusion , Female , Fullerenes/administration & dosage , Fullerenes/blood , Histocytochemistry , Mice , Microscopy, Electron, Transmission , Particulate Matter/administration & dosage , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/ultrastructure
8.
Environ Toxicol Chem ; 27(9): 1852-9, 2008 Sep.
Article in English | MEDLINE | ID: mdl-19086313

ABSTRACT

The growing usage of nanomaterials is causing emerging concern regarding their environmental behavior in aquatic environments. A major need is the capability to detect and quantify nanomaterials in complex water matrices. Carbon60 fullerene is of special interest because of the widespread application of nanocarbon technology. The present study focuses on how to separate and concentrate fullerenes from water containing salts and organic matter and then quantify their concentrations using liquid chromatography coupled with mass spectrometry (LC/MS). The stable aqueous C60 aggregates (nC60) prepared in the present study were approximately 60 to 70 nm in diameter and had an ultraviolet (UV) extinction coefficient of 0.0263 L/mg-cm at 347 nm, which equated to a UV detection limit of 0.4 mg/L based upon an absorbance of 0.01 cm(-1). Ultraviolet analysis is not applicable to use in waters containing salts or organics (e.g., tap water) because of their interferences and potential to aggregate nC60. The LS/MS analysis detected C60 as single fullerene rather than aggregates. Three techniques were developed to separate and concentrate nC60 from ultrapure and tap water into toluene to facilitate LC/MS determination: Evaporation of sample to dryness; extraction using 20% NaCl into toluene; and solid-phase extraction. The first two methods had limitations for use in complex water matrices, but aqueous nC60 concentration as low as 300 ng/L in water were quantified using solid-phase extraction (SPE) separation method. This is the first publication on the application of extraction methods for nC60 from ultrapure and tap waters and determination of detection limits by LC/MS.


Subject(s)
Fullerenes/analysis , Water Pollutants, Chemical/analysis , Water/analysis , Animals , Calibration , Chromatography, High Pressure Liquid , Fullerenes/blood , Mass Spectrometry , Rats , Reference Standards , Salts/chemistry , Solid Phase Extraction , Spectrophotometry, Ultraviolet , Water Pollutants, Chemical/blood , Water Supply/analysis
9.
Electrophoresis ; 28(10): 1518-24, 2007 May.
Article in English | MEDLINE | ID: mdl-17447247

ABSTRACT

With the increasing interest in using nanoparticles as vehicles for drug delivery and image contrast agents, there is a need to develop assays for their detection and quantitation in complex matrices to facilitate monitoring their biodistribution. In this study, we developed a CE approach for the analysis of two nanoparticles: carboxyfullerene (C3) and dendrofullerene (DF1) in both standard solutions and a serum matrix. These highly soluble, charged C(60) derivatives were characterized by CZE using either a bare or dynamically coated fused-silica capillaries. The resolution of both nanoparticles was slightly lower with the coated capillary; however, their migration times were faster. While separation of the DF1 nanoparticles using MEKC resulted in a greater number of observable peaks, the peak profile of C3 was basically unchanged regardless of whether SDS micelles were added to the running buffers or not. The MEKC and/or CZE assays were then used to quantitate the C3 and DF1 nanoparticles in spiked human serum samples. The quantitation of the nanoparticles was linear from 0-500 microg/mL with detection limits ranging from 0.5 to 6 microg/mL.


Subject(s)
Chromatography, Micellar Electrokinetic Capillary/methods , Electrophoresis, Capillary/methods , Fullerenes/analysis , Fullerenes/blood , Nanostructures/analysis , Buffers , Calibration/standards , Electrophoresis, Capillary/instrumentation , Humans , Hydrogen-Ion Concentration , Indicators and Reagents , Reproducibility of Results , Sensitivity and Specificity , Serum/chemistry
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