Biomedical potential of the reactive oxygen species generation and quenching by fullerenes (C 60 (original) (raw)
Related papers
Biomaterials, 2009
We demonstrated that three different types of water-soluble fullerenes materials can intercept all of the major physiologically relevant ROS. C 60 (C(COOH) 2 ) 2 , C 60 (OH) 22 , and Gd@C 82 (OH) 22 can protect cells against H 2 O 2 -induced oxidative damage, stabilize the mitochondrial membrane potential and reduce intracellular ROS production with the following relative potencies: Gd@C 82 (OH) 22 ! C 60 (OH) 22 > C 60 (C(COOH) 2 ) 2 . Consistent with their cytoprotective abilities, these derivatives can scavenge the stable 2,2-diphenyl-1-picryhydrazyl radical (DPPH), and the reactive oxygen species (ROS) superoxide radical anion (O 2 À ), singlet oxygen, and hydroxyl radical (HO ), and can also efficiently inhibit lipid peroxidation in vitro. The observed differences in free radical-scavenging capabilities support the hypothesis that both chemical properties, such as surface chemistry induced differences in electron affinity, and physical properties, such as degree of aggregation, influence the biological and biomedical activities of functionalized fullerenes. This represents the first report that different types of fullerene derivatives can scavenge all physiologically relevant ROS. The role of oxidative stress and damage in the etiology and progression of many diseases suggests that these fullerene derivatives may be valuable in vivo cytoprotective and therapeutic agents.
The mechanism of cell-damaging reactive oxygen generation by colloidal fullerenes
Biomaterials, 2007
Because of the ability to induce cell death in certain conditions, the fullerenes (C 60 ) are potential anticancer and toxic agents. The colloidal suspension of crystalline C 60 (nano-C 60 , nC 60 ) is extremely toxic, but the mechanisms of its cytotoxicity are not completely understood. By combining experimental analysis and mathematical modelling, we investigate the requirements for the reactive oxygen species (ROS)-mediated cytotoxicity of different nC 60 suspensions, prepared by solvent exchange method in tetrahydrofuran (THF/nC 60 ) and ethanol (EtOH/nC 60 ), or by extended mixing in water (aqu/nC 60 ). With regard to their capacity to generate ROS and cause mitochondrial depolarization followed by necrotic cell death, the nC 60 suspensions are ranked in the following order: THF/nC 60 4EtOH/ nC 60 4aqu/nC 60 . Mathematical modelling of singlet oxygen ( 1 O 2 ) generation indicates that the 1 O 2 -quenching power (THF/ nC 60 oEtOH/nC 60 oaqu/nC 60 ) of the solvent intercalated in the fullerene crystals determines their ability to produce ROS and cause cell damage. These data could have important implications for toxicology and biomedical application of colloidal fullerenes. r
Archives of Toxicology, 2012
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.
Distinct Cytotoxic Mechanisms of Pristine versus Hydroxylated Fullerene
Toxicological Sciences, 2006
The mechanisms underlying the cytotoxic action of pure fullerene suspension (nano-C 60 ) and water-soluble polyhydroxylated fullerene [C 60 (OH) n ] were investigated. Crystal violet assay for cell viability demonstrated that nano-C 60 was at least three orders of magnitude more toxic than C 60 (OH) n to mouse L929 fibrosarcoma, rat C6 glioma, and U251 human glioma cell lines. Flow cytometry analysis of cells stained with propidium iodide (PI), PI/annexin V-fluorescein isothiocyanate, or the redox-sensitive dye dihydrorhodamine revealed that nano-C 60 caused rapid (observable after few hours), reactive oxygen species (ROS)-associated necrosis characterized by cell membrane damage without DNA fragmentation. In contrast, C 60 (OH) n caused delayed, ROSindependent cell death with characteristics of apoptosis, including DNA fragmentation and loss of cell membrane asymmetry in the absence of increased permeability. Accordingly, the antioxidant N-acetylcysteine protected the cell lines from nano-C 60 toxicity, but not C 60 (OH) n toxicity, while the pan-caspase inhibitor z-VAD-fmk blocked C 60 (OH) n -induced apoptosis, but not nano-C 60 -mediated necrosis. Finally, C 60 (OH) n antagonized, while nano-C 60 synergized with, the cytotoxic action of oxidative stress-inducing agents hydrogen peroxide and peroxynitrite donor 3-morpholinosydnonimine. Therefore, unlike polyhydroxylated C 60 that exerts mainly antioxidant/cytoprotective and only mild ROS-independent pro-apoptotic activity, pure crystalline C 60 seems to be endowed with strong pro-oxidant capacity responsible for the rapid necrotic cell death.
A biologically effective fullerene (C60) derivative with superoxide dismutase mimetic properties
Free Radical Biology and Medicine, 2004
Superoxide, a potentially toxic by-product of cellular metabolism, may contribute to tissue injury in many types of human disease. Here we show that a tris-malonic acid derivative of the fullerene C 60 molecule (C 3 ) is capable of removing the biologically important superoxide radical with a rate constant (k C3 ) of 2 Â 10 6 mol À1 s À1 , approximately 100fold slower than the superoxide dismutases (SOD), a family of enzymes responsible for endogenous dismutation of superoxide. This rate constant is within the range of values reported for several manganese-containing SOD mimetic compounds. The reaction between C 3 and superoxide was not via stoichiometric bscavenging,Q as expected, but through catalytic dismutation of superoxide, indicated by lack of structural modifications to C 3 , regeneration of oxygen, production of hydrogen peroxide, and absence of EPR-active (paramagnetic) products, all consistent with a catalytic mechanism. A model is proposed in which electron-deficient regions on the C 60 sphere work in concert with malonyl groups attached to C 3 to electrostatically guide and stabilize superoxide, promoting dismutation. We also found that C 3 treatment of Sod2 À/À mice, which lack expression of mitochondrial manganese superoxide dismutase (MnSOD), increased their life span by 300%. These data, coupled with evidence that C 3 localizes to mitochondria, suggest that C 3 functionally replaces MnSOD, acting as a biologically effective SOD mimetic. D
Possible mechanisms of fullerene C 60 antioxidant action
Novel mechanism of antioxidant activity of buckminsterfullerene C 60 based on protons absorbing and mild uncoupling of mitochondrial respiration and phosphorylation was postulated. In the present study we confirm this hypothesis using computer modeling based on Density Functional Theory. Fullerene's geroprotective activity is sufficiently higher than those of the most powerful reactive oxygen species scavengers. We propose here that C 60 has an ability to acquire positive charge by absorbing inside several protons and this complex could penetrate into mitochondria. Such a process allows for mild uncoupling of respiration and phosphorylation. This, in turn, leads to the decrease in ROS production.
Journal of B.U.ON. : official journal of the Balkan Union of Oncology
Studies on the biological properties of fullerene C(60) and its derivatives started a decade ago as curiosity-driven studies and are now flourishing as an area of transdisciplinary research. This paper summarizes the results of studies on the biological activity and applications of selected functionalized fullerenes that were published in the last few years. Apart from literature data, we present most of our results of in vitro and in vivo studies with fullerenol C(60)(OH)(24) anti-oxidative and free radical scavenger activities in chemical and biological systems; cytotoxicity against human tumor cell lines; protective effects against various cytotoxic drugs and irradiation; effects on cell cycle and apoptosis, and in vivo radioprotective and cardioprotective effects. The fullerene family of carbon molecules has been a central focus in the emerging fields of nanotechnology and nanomedicine. Fullerenes take an important place in the development of nanobiotechnology and nanomedicine-r...
Toxicology, 2000
Fullerenes have attracted considerable attention in recent years due to their unique chemical structure and potential applications. Hence it is of interest to study their biological effects. Using rat liver microsomes as model systems we have examined the ability of the most commonly used fullerene, C60 and its water-soluble derivative, C60(OH)18 to induce membrane damage on photosensitization. For photoexcitation, UV or tungsten lamps were used. Damage was assessed as lipid peroxidation products like conjugated dienes, lipid hydroperoxides and thiobarbituric acid reactive substances (TBARS), protein oxidation in the form of protein carbonyls, besides loss of membrane bound enzymes. Both fullerene derivatives induced significant oxidative damage. The alterations induced were both time- and concentration-dependent. Role of different reactive oxygen species (ROS) in the damage induced was examined by various scavengers of ROS and by deuteration of the buffer. The changes induced by C60 were predominantly due to 1O2 while that by C60(OH)18 was mainly due to radical species. Biological antioxidants such as glutathione, ascorbic acid and α-tocopherol were capable of inhibiting membrane damage induced by both the fullerenes. However, the damage induced by C60(OH)18 was more for both lipids and proteins than that showed by C60. C60 also showed enhancement in the formation of lipid peroxidation in sarcoma 180 ascites microsomes. In conclusion, our studies indicate that fullerene/its derivative can generate ROS on photoexcitation and can induce significant lipid peroxidation/protein oxidation in membranes and these phenomena can be prevented by endogenous/natural antioxidants.
Aqueous C60 Fullerene Solution Effects on Cell Viability
Proceedings of the Latvian Academy of Sciences. Section B. Natural, Exact, and Applied Sciences., 2021
Fullerenes are carbon nanoparticles with the ability to quench reactive oxygen species. The biomedical potential of fullerenes is diminished by their low solubility in water, but many approaches have been developed to bypass this problem, like chemical modification of the carbon cage and the use of the solvent exchange method to transfer fullerenes from one solvent to the other. These two approaches were used in this study. Carboxylated fullerene aqueous solution was acquired using solvent exchange method transferring fullerene nanoparticles (C60) from toluene to water. Effects of varying concentration (0.5, 1, 1.5, 2, 2.5, 3, 5, 10 µM) of aqueous fullerene solution on cell viability and their antioxidative capabilities were evaluated on PC-3 and on monocytes isolated from a blood donor using Resazurin Cell Viability Assay. PC-3 cell viability was drastically affected by the 10 µM fullerene solution but remained relatively stable when treated with other concentrations even after lon...
Free Radical Biology and Medicine, 2007
Photodynamic therapy (PDT) employs the combination of non-toxic photosensitizers (PS) and harmless visible light to generate reactive oxygen species (ROS) and kill cells. Most clinically studied PS are based on the tetrapyrrole structure of porphyrins, chlorins and related molecules, but new nontetrapyrrole PS are being sought. Fullerenes are soccer-ball shaped molecules composed of sixty or seventy carbon atoms and have attracted interest in connection with the search for biomedical applications of nanotechnology. Fullerenes are biologically inert unless derivatized with functional groups, whereupon they become soluble and can act as PS. We have compared the photodynamic activity of six functionalized fullerenes with 1, 2, or 3 hydrophilic or 1, 2, or 3 cationic groups. The octanol-water partition coefficients were determined and the relative contributions of Type I photochemistry (photogeneration of superoxide in the presence of NADH) and Type II photochemistry (photogeneration of singlet oxygen) were studied by measurement of oxygen consumption, 1270-nm luminescence and EPR spin-trapping of the superoxide product. We studied three mouse cancer cell lines: (J774, LLC and CT26) incubated for 24 h with fullerenes and illuminated with white light. The order of effectiveness as PS was inversely proportional to the degree of substitution of the fullerene nucleus for both the neutral and cationic series. The monopyrrolidinium fullerene was the most active PS against all cell lines and induced apoptosis 4-6 hours after illumination. It produced diffuse intracellular fluorescence when dichlorodihydrofluorescein was added as an ROS probe suggesting a Type I mechanism for phototoxicity. We conclude that certain functionalized fullerenes have potential as novel PDT agents and phototoxicity may be mediated both by superoxide and by singlet oxygen.