Chapter 8
Artificial Nanoparticle Antioxidants Downloaded by PENNSYLVANIA STATE UNIV on June 4, 2012 | http://pubs.acs.org Publication Date (Web): November 17, 2011 | doi: 10.1021/bk-2011-1083.ch008
Erica Sharpe, Daniel Andreescu, and Silvana Andreescu* Department of Chemistry and Biomolecular Science, Clarkson University, Potsdam, New York 13699-5810 *E-mail:
[email protected] Nanoparticle antioxidants constitute a new wave of antioxidant therapies for disease prevention and treatment in the field of oxidative stress. These ‘artificial’ antioxidants have demonstrated free radical scavenging activity, reducing the concentration of reactive oxygen and nitrogen species, thus acting as antioxidants by themselves. This review chapter discusses recent advances in the preparation, characterization and functionalization of these artificial nanoparticle antioxidants, the mechanism of their antioxidant activity and their use in the field of oxidative stress. These artificial antioxidants include inorganic nanoparticles possessing intrinsic antioxidant properties and nanoparticles functionalized with natural antioxidants or antioxidant enzymes to perform as an antioxidant delivery system. The antioxidant properties of these nanoparticles are discussed in relation to the structure, physicochemical properties and composition of these particles, parameters that are responsible for their redox activity and antioxidant action. Toxicity and potential applications of nanoparticles with antioxidant properties are also discussed. Antioxidant nanoparticles must be used with careful awareness of all their properties in order to achieve therapeutic results and balance antioxidant versus deleterious pro-oxidant effects.
© 2011 American Chemical Society In Oxidative Stress: Diagnostics, Prevention, and Therapy; Andreescu, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2011.
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1. Introduction Antioxidants have drawn much attention in recent years, due to their ability to fight oxidative stress, which has been linked to cancer, aging, and a wide variety of neurodegenerative diseases. Oxidative stress is created by highly reactive oxygen (ROS) and nitrogen (RNS) species, which are induced by environmental stress (e.g. ionizing radiation, redox and heavy metals, excess UV-radiation) or metabolism (e.g. secretion by macrophages, as well as by-product formation by the electron transport chain). ROS and RNS cause damage to lipids, cell membranes, proteins and DNA, leading to mutations, apoptosis, and failure within these systems. The main function of an antioxidant is to prevent and repair the effects of ROS and RNS, which are thought to be one of the causes of diseases such as atherosclerosis, Alzheimer’s and Parkinson’s, along with many cancers and other resulting effects of aging. Antioxidants function through two primary pathways: prevention of ROS/RNS formation, and scavenging or neutralization of ROS/RNS (1). Antioxidants like quercetin, and citric acid have been found to have significant reducing properties, preventing molecular mechanisms that are responsible for ROS formation (2, 3). A wide variety of antioxidants have been seen to primarily function as scavengers of existing free radicals (4). Other antioxidants, primarily enzymatic compounds, are responsible for decomposition of reactive oxygen/nitrogen species into less harmful or neutral products (4). An emerging area of research in the field of oxidative stress is the use of nanoparticles, possessing redox properties, which act as effective free radical scavengers. Several recent studies demonstrated that several types of nanoparticles have antioxidant properties (5, 6). These ‘artificial’ antioxidants can be engineered at the nanoscale level (1-100 nm), have very high reactivity and can act as antioxidants by themselves. The antioxidant capacity depends on the nature, chemical composition, surface charge, surface to volume ratio and surface coating of the inorganic nanoparticles. A number of studies indicated that several redox active nanoparticles such as ceria and yttria act by mimicking the activity of oxidative enzymes, superoxide dismutase (SOD) and catalase (CAT) (7, 8). Available literature data show that many of these nanoparticulate antioxidant systems protect cells against oxidative stress and are relatively nontoxic to cultured cells. On the other hand, inert nanoparticles such as gold can be used as carriers for antioxidant molecules. In this case, natural antioxidants can be attached onto the nanoparticle surface, providing a new class of supported antioxidants with increased antioxidant capacity. Using this strategy, it is possible to enhance efficiency and provide targeted delivery of certain natural antioxidants that are difficult to cross cell membranes and be internalized into cells. Such small particles of several nanometers are able to enter cells and cross cell membrane through pinocytosis. Supported antioxidants can be delivered into the cytoplasm and mitochondria where they can neutralize ROS and RNS. As an example, nanoparticles loaded with glutathione (GSH) have been shown to penetrate cell membranes and to successfully deliver and release drug molecules in living cells (9). Recent developments in this field demonstrate the potential of this technology for designing new powerful antioxidants based on inorganic nanoparticles for disease prevention and therapy. 236 In Oxidative Stress: Diagnostics, Prevention, and Therapy; Andreescu, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2011.
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This review chapter provides an overview of the different classes of antioxidant nanoparticles derived from inorganic materials including those with intrinsic antioxidant capacity and those that can be functionalized to become potent antioxidants. The chapter discusses recent advances in the preparation, characterization and functionalization of these particles, the mechanism of their antioxidant activity and their use in the field of oxidative stress. The antioxidant properties of these nanoparticles are discussed in relation to their structure, physicochemical properties and composition; parameters that are responsible for their redox activity and antioxidant action. Toxicity and physiological effects of nanoparticles with antioxidant properties are also discussed.
2. Classes of Nanoparticle Antioxidants 2.1. Inorganic Nanoparticles with Intrinsic Antioxidant Properties as Free Radical Scavengers Several types of inorganic nanoparticles have demonstrated intrinsic free radical scavenging activity, decreasing concentrations of ROS and RNS, and thus acting as antioxidants (10). Their effectiveness in mitigating oxidative stress has been demonstrated in complex biological systems including cell cultures and in in vivo conditions. This interesting characteristic has been related to their redox and catalytic properties, electronic configuration, high surface-to-volume ratio and biocompatibility. Therefore, potential use of these nanoparticles to reduce oxidative stress in biological systems and treat oxidative stress related diseases is increasingly being explored. Classes of inorganic nanoparticles possessing intrinsic antioxidant activity range from metal (gold and platinum) to several types of metal oxides (e.g. ceria, yttria, and iron oxide). Gold, platinum and nickel oxide (11, 12) have been found to have ROS neutralizing abilities. Platinum has been found to be particularly effective in reducing smoke-induced respiratory inflammation in the respiratory system, which has been associated with high levels of ROS and depletion of the normal antioxidant function (13, 14). Experimental results showed that mice, which received platinum nanoparticles stabilized with poly(acrylate) prior to exposure to smoke, experienced less inflammation and decreased cell death than those in a control group which received a saline solution. Platinum nanoparticles (2.4 nm) have also been shown to scavenge superoxide and hydrogen peroxide in a dose-dependent manner, and to prolong the lifespan of Caenorhabditis elegans (12). In another study, 50 nm gold nanoparticles were found to inhibit oxidative stress mediated diabetic progression during hyperglycemia in mice, demonstrating therapeutic potential in diabetic treatment (15). No toxic effects were observed when the mice were injected with the particles at a dosage of 2.5 mg/kg.b.wt/day for 15 days. The mechanism of action has been attributed to either the inhibition of the stress signaling pathways or to the interaction of gold with the cysteine residues of a thioreductase, thioredoxin, which is involved in the antioxidative mechanism in hyperglycemic conditions. Chitosan-stabilized gold nanoparticles with diameters ranging between 6 and 16 nm have shown antioxidant action against hydroxyl radicals formed in a hydrogen peroxide/FeSO4 system (16). 237 In Oxidative Stress: Diagnostics, Prevention, and Therapy; Andreescu, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2011.
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In addition to gold and platinum, nickel oxide nanoparticles have been shown to have radical scavenging properties through in vitro testing using the DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging activity assay. However, at high doses, nickel is toxic and can have adverse cytotoxic effects when used in a biological environment. In other studies, iron oxide nanoparticles have been shown to possess antioxidant properties (17). Diamond nanoparticles (4 nm diameter) decorated with gold and platinum nanoparticles (
