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Medical Applications of Cerium.

Introduction

Oxidative stress is a causative factor of numerous human diseases including aging and age-related disorders [1,2]. Despite the development of several antioxidative therapies to minimise the reactive oxygen species (ROS) production involved in the pathogenesis of various diseases, such traditional agents have had limited success which has been attributed to enzymatic degradation, difficulty to reach the target, daily dosing requirements, and short half-life [3-6]. In the field of engineering, numerous attempts have been devoted to the reduction of oxidative stress at the materials science level. In this context, nanotechnology has provided numerous constructs that reduce oxidative damage in engineering applications with great efficiency. Recently, there has been a growing interest in the development application of cerium oxide nanoparticles (nanoceria) as potential catalytic antioxidants in biology and medicine.

Physical Properties

Cerium is a rare earth metal belonging to the lanthanide series of elements. In general, cerium exhibits dual oxidation states: [Ce.sup.3+] and [Ce.sup.4+] ; as such there two different oxide forms of cerium dioxide, Ce[O.sub.2] ([Ce.sup.4+]) or [Ce.sub.2][O.sub.3] ([Ce.sup.3+]), in bulk material [7]. Cerium has the ability to recycle between two oxidation states depending on its environment and due to this property, cerium exhibits unique physical and chemical properties and are also excellent oxygen buffers [8,9]. In the nanoparticulate form, cerium adopts a fluorite crystalline structure with both [Ce.sup.3+] and [Ce.sup.4+] coexisting on its surface and hence, the interconversion of oxidation states generates greater number of oxygen vacancies on the surface of nanoceria which are actually sites of catalytic reactions [10,11]. Further, studies have also shown that with decrease in nanoceria particle size, the formation of oxygen vacancies in the crystal structure is also enhanced [12,13]. Therefore, nanoceria has improved redox properties as compared to the bulk materials. Most importantly, the presence of a dual valance state imparts nanoceria with an important role in scavenging reactive oxygen and nitrogen species. Due to this property, nanoceria is considered to be highly effective against disorders associated with oxidative stress and inflammation. Further, nanoceria has also been shown to have multienzyme mimetic activities such as superoxide dismutase, superoxide oxidase, catalase and oxidase and because of this property, nanoceria are capable of regenerating their antioxidant activity [11,14-16]. Further, nanoceria has also emerged as a lucrative material in biological fields, such as in bioanalysis, biomedicine and drug delivery [17-22]. In formulating nanoceria for therapeutic applications, the synthesis method is one of the major determinants of the biological effectiveness of nanoceria [23]. However, coating the nanoceria with biocompatible/ organic polymers have also been shown to enhance dispersion/ stability, reduces nonspecific interactions with cells and proteins, facilitates blood circulation time and minimises the toxicity of the nanoceria [24].

Industrial Applications

Ce[O.sub.2] (ceria) is commonly used for chemical-mechanical polishing of surfaces, including microelectronic device wafers, electronic displays, eye-glass lenses and other optical materials [25]. The commercial applications of ceria also include catalytic converters and diesel oxidation catalysts, intermediate temperature solid oxide fuel cells and sensors. Its potential future uses include chemical looping combustion, photolytic and thermolytic water splitting for hydrogen production and environmental chemistry [26,27].

Applications in Neurodegenerative Disorders

Several neurodegenerative diseases, such as Parkinson's disease, trauma, ischemic stroke, Alzheimer's disease (AD) and aging are known to be mediated by oxidative stress and ROS [28]. In this regard, numerous reports have elucidated the therapeutic candidacy of nanoceria to mitigate oxidative stress associated with such disorders. The neuroprotective effect of nanoceria was reported for the first time, in 2003 by Ellison and coworkers [29]. Most recently, a study also shows that conjugated nanoceria inhibits neuronal death and decreases reactive gliosis and mitochondrial damage in an AD model [30]. In ameliorating the pathology associated with AD, nanoceria has been shown to directly or indirectly affect the signal transduction pathways involved in neuronal death and neuroprotection such as the brain-derived neurotrophic factor (BDNF) pathway in human AD models [31]. Similarly, the neuroprotective effect of nanoceria has also been demonstrated in vivo in rat ischemic stroke model [32.33]. These reports therefore suggest the therapeutic importance of nanoceria in the treatment of neurodegenerative disorders.

Applications in Ophthalmological Disorders

Oxidative damage due to excessive production of ROS is correlated with diabetic retinopathy (DR), age-related macular degeneration (AMD), and glaucoma [34-36]. Therefore, targeting ROS with catalytic antioxidant nanoparticles can suppress pathology in both induced and heritable models of retinal degeneration. A novel approach for scavenging ROS prominent in retinal degenerative diseases was conducted by Chen and coworkers [37,38]. Their work demonstrated that intravitreal injection of nanoceria reduces light-induced photoreceptor damage in rodents. Similarly, other studies also show that nanoceria protects photoreceptor cells from degeneration and exerts anti-angiogenic effects in rodent models [39-44]. Nanoceria has also been demonstrated to inhibit neovascular lesions, accompanied with the upregulation of growth factor genes (neuroprotective) or antiangiogenic or anti-inflammatory genesin the retina of Vldlr null mice [43]. When introduced into the blood stream via intracardial injection, nanoceria has been shown to cross the blood retinal barrier and protect the photoreceptor neurons in the tubby mouse, a photoreceptor degeneration model by reducing ROS, upregulating neuroprotectionassociated gene expression and inhibition of caspase-induced apoptosis [40]. Further, intravitreally delivered nanoceria is rapidly taken up by retinal cells within one hour and ~50% of the injected nanoparticles are still retained in the retina after a year without any non-toxic effect and without any alteration in the retinal structure and function [45,46]. Similarly, nanoceria also delays rod cell degeneration, downregulates apoptosis, and decreases lipid peroxidation in the retina of retinitis pigmentosa model [37,47,48]. Further, nanoceria functionalized with hCAII inhibitors have also been explored as an ophthalmic drug-delivery tool for glaucoma [49]. Similarly, nanoceria is also highly effective in treating conditions associated with oxidative damage such as age-related macular degeneration, diabetic retinopathy. Taken together, these reports strongly suggest the role of nanoceria as a novel broad spectrum therapeutic agent for a number of ocular disorders [50-53].

Application in Cancer Therapy

The application of nanoceria in cancer therapy is also promising. The hypothesised mode of action of nanoceria in cancer treatment has been attributed to the acidic nature of cancer cells. Nanoceria could increase the oxidative stress and trigger apoptosis in the acidic cancer cells resulting in their destruction. The acidic environment of the cancer cells is also ideal for the catalase-like activity of nanoceria thus leaving the surrounding tissues unharmed [54]. Further experiments have demonstrated that generation of nanoceria with a negative surface charge can induce preferential accumulation in acidic lysosomes within the cell resulting in increased toxicity selectively in cancer cells [55]. This property of nanoceria also enhances their application in colorimetric ELISA for detecting cancer biomarkers [56]. Nanoceria also minimises the side effects of radiation therapy by protecting the normal cells from radiation induced damage and therefore serves as radio-protecting as well as radio-sensitizing agent [57-59]. The radioprotective effect of nanoceria has been demonstrated in the head and neck cancer therapy [60]. Nanoceria also plays a vital role in the treatment of ovarian cancer by inhibiting different growth factor like vascular endothelial growth factor [61]. Polymer (dextran) coated nanoceria has also been shown to combat malignant melanoma at concentrations which are nontoxic to normal cells [62]. In addition, nanoceria treatment has been shown to induce glutathione oxidation, lipid peroxidation, and membrane damage in lung cancer cells and also suppress malignant activity of gastric cancer by increasing the expression of DHX15 [63,64].

Other Applications

Nanonoceria has also been explored in the treatment of endometriosis, diabetes-associated oxidative stress and in combating obesity [65-67]. Nanoceria has also been shown to have potential anti-inflammatory and wound healing properties [68-70]. Recent studies also show their potential application in glucose and cholesterol biosensors and bio grafting field [71-74].

The antibacterial activity of nanoceria toward both gram-negative and gram-positive bacteria is well documented [75-77]. Studies have also linked the antibacterial effect of nanoceria particles to their surface charge and redox ability of cerium ions [78,79]. Nanoceria particles with a lower [Ce.sup.+3]/[Ce.sup.+4] ratios have more catalase mimetic activity and these particles possess more anticancer and antibacterial properties [80]. Further, recent study also demonstrates the antibacterial efficacy of nanoceria to be pH-dependent [81]. These reports therefore suggest a wide range of anti-bacterial applications of nanoceria without resorting to the use of antibiotics.

Nanoceria Toxicity

Reports on the toxicological effects of nanoceria are quite limited and the mechanisms involved are still not clear [82]. In vitro studies have shown that nanoceria is toxic to bronchial epithelial lung fibroblasts, but non-toxic to other cell types including mammary epithelial cells, macrophages, immortalized keratinocytes, or immortalized pancreatic epithelial cells [58,68,83-85]. When introduced prior to ROS insult, nanoceria exerts protective effects from oxidative stress related damage in vitro and in vivo [86,87]. Nasal exposure of rats with nanoceria in the size ranging from 15-30 nm for 4 hr has been found to induce pulmonary toxicity whereas nanoceria with size between 1 and 5 im do not show any significant cytotoxicity in vitro [88,89]. Recent report also establishes the relationship between the toxicity and shape of nanoceria. Rod-like nanoparticles enhance lactate dehydrogenase (LDH) release and tumor necrosis factor alpha (TNF-[alpha]) production in vitro [90]. Hence, from these reports, the toxicological effects of nanoceria still remain inconclusive. Hence more studies are warranted to fully understand the potential of nanoceria application and its toxicological effects.

Nanoceria has shown positive therapeutic results for antioxidant therapy of various neurodegenerative diseases, cancer, drug delivery and diagnostics. Moreover, due to their regenerative antioxidant property, a small amount of nanoceria is sufficient for extended time periods. The biological activity of nanoceria is modulated by method of preparation, particle size and shape, nature and level of dopant, and surface chemistry. Further studies should also emphasize on different nanoceria in order to establish nontoxic formulations with enhanced catalytic activity for medical applications. Finally, the long-term effects of nanoceria using large animal models are also needed.

Financial support and sponsorship: This article is a part of the research project no. BMB/2015/56, funded by Department of Biotechnology, Ministry of Science and Technology, Government of India.

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Barilin Dkhar, Abhijeet Bhatia

Dept of ENT, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences (NEIGRIHMS), Shillong 793018, Meghalaya

Received 5 October 2017; Accepted 11 November 2017; Published online 31 December 2017

* Coresponding author: Dr Abhijeet Bhatia; E-mail: abhijeetbhatia77@gmail.com
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Author:Dkhar, Barilin; Bhatia, Abhijeet
Publication:Trends in Biomaterials and Artificial Organs
Date:Jul 1, 2017
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