Review

1.

Introduction

2.

ROS/RNS and oxidative stress

3.

Antioxidant compounds of

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therapeutic interest 4.

Nanocarriers for antioxidant compound delivery

5.

Nanoparticles with intrinsic antioxidant properties

6.

Advanced nanoscience-based antioxidant systems

7.

Mitigation of oxidative stress in drug delivery

8.

Conclusion

9.

Expert opinion

New concepts to fight oxidative stress: nanosized threedimensional supramolecular antioxidant assemblies Pascal U Richard, Jason T Duskey, Svetlana Stolarov, Mariana Spulber & Cornelia G Palivan† †

University of Basel, Department of Chemistry, Basel, Switzerland

Introduction: Misregulation of reactive oxygen species and reactive nitrogen species by the body’s antioxidant system results in oxidative stress, which is known to be associated with aging, and involved in various pathologies including cancer, neurodegenerative and cardiovascular diseases. A large variety of low-molecular-weight (LMW) antioxidant compounds and antioxidant enzymes have been proposed to alleviate oxidative stress, but their therapeutic efficacy is limited by their solubility, stability or bioavailability. In this respect, nanoscience-based systems are expected to provide more efficient mitigation of oxidative stress. Areas covered: The main nanoscience-based three-dimensional (3D) supramolecular assemblies, decorated with, or entrapping antioxidant compounds, or which possess intrinsic antioxidant activity are discussed and illustrated with recent examples. Assemblies with different architectures and sizes in the nanometer range serve: i) to deliver LMW antioxidant compounds or enzymes; ii) as antioxidant systems due to their intrinsic activity; and recently iii) to provide a confined space where catalytic antioxidant reactions take place in situ (nanoreactors and artificial organelles). A few insights into the role of antioxidants in mitigating oxidative stress caused by therapeutic compounds or drug carriers are also discussed. Expert opinion: Several challenges must still be overcome in the development of 3D supramolecular assemblies to efficiently fight oxidative stress. First, an improvement of the assemblies’ properties and stability in biological conditions has to be addressed. Second, new systems based on the combination of biomolecules or mimics in supramolecular assemblies should provide multifunctionality, stimuli-responsiveness and targeting properties for a more efficient therapeutic effect. Third, comparative studies are necessary to evaluate these systems in a standardized manner both in vitro and in vivo. Keywords: antioxidant delivery, antioxidant enzymes, artificial organelles, nanocarriers, nanoparticles, nanoreactors, oxidative stress, polymersomes, solid lipid nanoparticles Expert Opin. Drug Deliv. [Early Online]

1.

Introduction

Medicine today faces various challenges in understanding and finding solutions to imbalances that are involved in pathological conditions, such as the misregulation of proteins or the unregulated accumulation of toxic compounds. One critical imbalance is oxidative stress, which arises from the misregulation between processes involved in the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) with those that ensure their degradation/conversion into nontoxic

10.1517/17425247.2015.1036738 © 2015 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted

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P. U. Richard et al.

Article highlights. .

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Oxidative stress, the imbalance of reactive oxygen species (ROS) and reactive nitrogen species (RNS) levels, is described in biological systems (sources and effects of ROS/RNS, natural defense mechanisms). Antioxidant compounds (natural and synthetic), and their limitations upon direct administration, are described. Nanocarriers for antioxidant delivery based on lipids (liposomes, solid lipid nanoparticles and nanostructured lipid carriers), polymers (dendrimers, micelles, vesicles, and solid polymer nanoparticles) and inorganic nanoparticles are presented with recent relevant examples. Advanced nanoscience-based antioxidant systems (nanoreactors and artificial organelles) are introduced as concepts by their first reported examples. The effectiveness of using antioxidant molecules to mitigate ROS generation induced by drugs or nanocarriers is described.

This box summarizes key points contained in the article.

products [1,2]. The terms ROS and RNS refer to free radicals, containing one or more unpaired electrons, derived from molecular oxygen (e.g., superoxide anion, hydroxyl radical and nitric oxide) and non-radical intermediates involved in free-radical generation (e.g., reactive aldehydes, hypochlorous acid, peroxynitrite and hydrogen peroxide) [1,3,4]. ROS are critical and necessary for the proper maintenance of cell signaling pathways as they act as regulators of physiological responses such as cell and platelet adhesion, cell growth and differentiation, apoptosis, protein folding, vascular tone and immunological response [5-9]. Oxidative stress increases when high amounts of ROS and RNS are not detoxified by the antioxidant defense system [1]. In high amounts, oxidative stress is toxic and can result in apoptosis from the induction of macromolecular damage (DNA, proteins, lipids) or from the stimulation of stress-activated protein kinases [10-12]. This imbalance has been reported to be associated with aging [13] or as a major factor in, or directly causing, various pathologies including neurodegenerative diseases, cardiovascular diseases, cancer and chronic inflammation [14-18]. How are ROS and RNS regulated in biological systems, what are the consequences of their misregulation, and, in which respects can nanoscience propose new solutions to fight oxidative stress by overcoming the limitations of a direct administration of antioxidant compounds? Here, the key points in efficiently fighting oxidative stress will be examined by providing an overview of recent nanoscience-based strategies. The focus will be on supramolecular assemblies with sizes in the nanometer range that are used both as carriers for antioxidant molecule delivery, and as confined spaces for in situ antioxidant reactions intended to directly detoxify ROS and RNS. The interest is to present the concept of using threedimensional supramolecular assemblies such as micelles, 2

particles or vesicles, as opposed to surfaces or films, by selecting very recent and relevant examples (from the extended literature in the domain) in order to provide a critical overview indicating the advantages, limitations and possible future nanoscience-based solutions to overcome oxidative stress. This review will present state-of-the-art developments in the design of nanoscience-based antioxidant assemblies as an essential first step for non-topical therapeutic applications, but without focusing on a particular pathology. 2.

ROS/RNS and oxidative stress

ROS and RNS are generated by the single electron reduction of molecular oxygen to superoxide anion, which is further converted to hydrogen peroxide or reacts with nitric oxide resulting in the formation of peroxynitrite [1,19]. Hydrogen peroxide can then react with various metallic centers, or their complexes by a Fenton or Fenton-like reaction, which generates the highly reactive hydroxyl radical [2,20,21]. ROS and RNS are produced endogenously through various pathways, including phagocytosis, peroxisomal b-oxidation of fatty acids and aerobic respiration [22]. Mitochondria are also a major site for the accumulation of low-molecular-weight (LMW) iron complexes able to participate in the Fenton reaction [23]. Furthermore, free radicals can be generated from the exposure to exogenous factors, including pollution and irradiation, the intake of particular drugs (e.g., anticancer and analgesics), dietary consumption (e.g., alcohol, unsaturated fats) or heavy metal exposure [13,21,24]. Damages caused by ROS and RNS in vivo ROS and RNS, when not detoxified, lead to intracellular damage, by being key components in the oxidation of membrane lipids, amino acids, DNA or thiol-containing molecules [20,23]. Lipid peroxidation of polyunsaturated lipids is a radical chain reaction induced by ROS and consists of three main stages: initiation, propagation and termination [20,21,25]. The initiation stage involves ROS-induced hydrogen abstraction from the methylene groups of lipids, especially those adjacent to double bonds in unsaturated lipids. It results in the formation of lipid radicals, also called fatty acid radicals, which are converted in the presence of oxygen to lipo-peroxyl radicals that can further abstract hydrogen from fatty acid molecules to form lipid hydroperoxides and new lipid radicals, thus propagating the chain reaction [25]. This continues until the recombination of radical species, thus terminating the chain reaction. Lipid peroxidation has been shown to influence the fluidity of the cell membrane [26], and to be involved in diseases such as sickle-cell anemia [27]. Protein damage is based on the oxidation of the protein backbone, its amino acid side chains, or protein--protein cross-linking [28]. Oxidation and nitration of amino acid side chains lead to the formation of various oxidation products. Oxidation of the protein backbone undergoes a similar mechanism as lipid oxidation starting with hydrogen 2.1

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New concepts to fight oxidative stress: nanosized three-dimensional supramolecular antioxidant assemblies

abstraction by ROS and formation of an alkyl radical (initiation). Alkyl radicals react with molecular oxygen and induce the formation of alkylperoxyl radicals that decompose to alkoxy radicals. Alkoxy radicals can further attack the neighboring amino acids in the protein backbone forming alkyl radicals that initiate another attack, leading to chain propagation. The termination phase involves either the recombination of different alkyl radicals leading to protein--protein cross-linking or cleavage of the protein [29]. The accumulation of oxidized proteins enhances cellular dysfunction [29] and has been associated with pathologies, such as neurodegenerative diseases [22]. DNA oxidation in the presence of ROS and RNS can lead to single- and double-strand breaks or the mispairing of purines and pyrimidines during DNA replication [30,31]. ROS and RNS react by addition to the double bonds of DNA bases or by abstraction of a proton from the methyl group of thymine, resulting in the formation of nucleobase radicals. These radicals can then interact with aromatic amino acids of neighboring proteins leading to DNAprotein cross-linking [30]. Activation of stress-activated protein kinases by ROS is known to induce cell apoptosis by the oxidation of thiol groups in thioredoxin, which leads to the release of apoptosis-regulating signal kinase 1 [12,32]. The balance between beneficial and toxic ROS levels is a very fragile equilibrium. Various factors lead to continuous shifts in the production of ROS that, if not properly controlled, can lead to any combinations of damages detailed above. These damages have been associated with > 60 different pathologies including type 2 diabetes [19], neurodegenerative diseases [22], cardiovascular diseases [15], chronic inflammation and cancer [16]. Therefore, to maintain the balance of limiting toxic effects while still allowing the necessary beneficial properties, living organisms have evolved a wide array of natural defense mechanisms to maintain proper ROS and RNS concentrations. Natural defense mechanisms against ROS/RNS Living organisms control the production and degradation of ROS and RNS through natural antioxidant defense mechanisms which are regulated individually depending on the cell compartment [33]. Generally, ROS and RNS levels are regulated by four major mechanisms: enzymatic conversion, the cytochrome c oxidation-reduction cycle, spontaneous dismutation of superoxide anions and detoxification by non-enzymatic compounds. Enzymatic conversion involves various enzymes, which participate in the complete conversion of ROS/RNS into nontoxic compounds [34]. For example, superoxide dismutase (SOD) catalyzes the conversion of superoxide radicals to hydrogen peroxide and molecular oxygen [35]. While this dismutation occurs spontaneously, it is a second-order reaction which results in an exceedingly long half-life at lower concentrations, which would be insufficient for proper regulation 2.2

without the assistance of SOD [36]. Hydrogen peroxide is further decomposed by enzymes, such as catalase, and glutathione (GSH) peroxidase, while phospholipid-hydroperoxide GSH peroxidase converts the lipid peroxides back to lipids [34,37]. These enzymes can be found in the cytosol or in various organelles. Among these is the peroxisome, a spherical structure formed by a single membrane that encloses various enzymes including oxidases, catalase and SOD [38,39]. The cytochrome c oxidation-reduction cycle involves the reduction of cytochrome c by superoxide anions that are oxidized to molecular oxygen. Reduced cytochrome c is further oxidized by cytochrome oxidase. In this way, electrons that escaped the respiratory chain contribute to an overall energy production [40]. Spontaneous dismutation of superoxide anions is favored in mitochondria by the presence of the proton-rich inner membrane [41]. Detoxification by various non-enzymatic electron carriers involves the neutralization of free radicals or free-radical precursors by LMW antioxidant compounds. Various antioxidants accept or donate unpaired electron(s) from/to the radical species, which become less active, and can be further neutralized [42]. Although organisms have evolved multiple mechanisms to regulate ROS and RNS, they are quite often exceeded, as is the case in various pathologies. Various therapeutic strategies can be considered to alleviate oxidative stress. One approach is to inhibit known cellular ROS sources such as the hydrogen peroxide producing xanthine oxidase or the superoxide producing isoforms of NADPH oxidase [43,44]. However, the most direct method to mitigate oxidative stress is the supplementation of antioxidant molecules or enzymes.

Antioxidant compounds of therapeutic interest

3.

Natural compounds with antioxidant activity present in the human body can be endogenous or exogenous. Endogenous antioxidants include both LMW compounds (e.g., GSH, coenzyme Q10, uric acid, melatonin, bilirubin, biliverdin, methionine) and enzymes (e.g., SOD, catalase, lactoperoxidase [LPO] and GSH peroxidase). A large variety of exogenous antioxidants also exist: among them are various polyphenols (e.g., hydroxycinamic acid, gallic acid [GA], resveratrol, curcumin, the flavonoids rutin, quercetin, catechin and epigallocatechingallate [EGCG]) and vitamins A (retinoids, carotenes), C (ascorbic acid) and E (tocopherols) [45]. Various synthetic antioxidants have also been developed over the years including N-acetyl cysteine (NAC), idebenone (IDB) -- an analogue of coenzyme Q10 -- as well as various enzyme mimics, such as Mn-metalloporphyrins and salenes [46,47]. All these antioxidant compounds have been tested for the treatment of pathological conditions in which oxidative stress is involved. However, their direct administration as pharmacological compounds suffers from numerous limitations. Most of

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the LMW compounds are not water soluble, requiring a specific formulation prior to therapeutic use. They further have a poor bioavailability and/or stability, resulting in very limited therapeutic effects [43,48]. Enzymes such as catalase and SOD are water soluble but they suffer from rapid proteolysis, limited cellular uptake or low permeability through cell membranes. The limitations of LMW antioxidants or antioxidant enzymes could be overcome by the development of synthetic analogues and mimics, respectively. However, even if a compound was optimally designed, it would lack the ability to distinguish between physiological and pathological ROS/RNS levels. Another strategy is the use of delivery systems, which not only allow overcoming the main limitations of direct administration of antioxidant compounds but also can be designed to target tissues with oxidative stress and release their payload in a controllable manner, thus limiting off-target effects. Towards this goal, multiple nanosized drug delivery systems (DDS) have been developed. The literature covering nanocarriers for LMW antioxidants delivery and their applications has been extensively reviewed [49-52]. Therefore, only the most commonly studied compounds are presented here (Table 1). 4. Nanocarriers for antioxidant compound delivery

Numerous supramolecular assemblies, with sizes in the nanometer range, have been developed for antioxidant compound delivery from a large variety of natural and synthetic molecules, including lipids, polymers and inorganic compounds. They are either self-assembled structures that entrap an antioxidant molecule, or nanoparticles whose surface is functionalized with therapeutic compounds [53]. The characteristics, production and application of such systems for drug delivery have been extensively reviewed; therefore, only a brief description of each systems and recent examples relative to antioxidant delivery will be presented for the most relevant nanostructures. Lipid-based nanocarriers Lipids are well-known molecules that compose the membrane of cells and their organelles. Lipids have been used to produce various nanostructures that are of interest as DDS. In the case of non-topical antioxidant delivery, the supramolecular assemblies of interest are: liposomes, solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). 4.1

Liposomes Liposomes (Figure 1A), the simplest biocompatible model of biological membranes and compartments, are spherical assemblies (composed of one or more lipid bilayers enclosing an aqueous core) ranging from 20 to 30 nanometers up to micrometers (giant unilamellar vesicles), with membrane thicknesses of 3 -- 6 nm [54]. Based on their architecture, the membrane of liposomes can be loaded with LMW lipophilic 4.1.1

4

antioxidants (e.g., retinoids, carotenoids, vitamin E, ubiquinones, quercetin or hesperitin), or their core can accommodate water-soluble small molecules (e.g., vitamin C, GSH) and enzymes (e.g., SOD, catalase) [55]. Their composition, properties, production methods and applications have been extensively reviewed [53-59]. Liposomes have been shown to improve the solubility, stability and bioavailability of both LMW antioxidants and water-soluble enzymes. Loading phosphatidylcholine (PC) liposomes with curcumin with a 65% entrapment efficiency (EE) showed a twofold increase of SOD activity in lipopolysaccharide (LPS) treated macrophages compared to free curcumin [60]. Similarly, the encapsulation of vanillin in liposomes composed of egg yolk PC and cholesterol (2:1) resulted in a 50% increase in scavenging of 2,2-diphenyl1-picrylhydrazyl (DPPH) compared to free vanillin. The scavenging efficiency was further improved by 50% by addition of 1-O-decylglycerol to the liposome preparation solution (2:1:0.2) without affecting the encapsulation efficiency [61]. Due to their architecture, liposomes allow for the coencapsulation of hydrophilic and hydrophobic compounds providing dual functionality; it has been suggested that the co-encapsulation of vitamin C and a-tocopherol would exhibit a synergistic improvement in antioxidant potency based on the ability of vitamin C to regenerate tocopheryl radicals to a-tocopherol [55]. The co-encapsulation of a-tocopherol with b-lactoglobulin in liposomes composed of PC:cholesterol (2:1 molar ratio) considerably improved both the loading efficiency of a-tocopherol (reaching nearly 97%) and the stability of the liposomes. The increased encapsulation efficiency is explained by the ability of b-lactoglobulin to bind to hydrophobic molecules, increasing their solubility in the liposome’s core, whereas the enhanced stability resulted from a-tocopherol binding to the lipid bilayer [62]. The same lipids (9:1 ratio) have also been used to co-encapsulate the lipophilic flavonoid quercetin and its hydrophilic b-cyclodextrin inclusion complex. This resulted in a 90% drug loading efficiency and a twofold increase in protection against iron-sulfate-induced lipid peroxidation in rat liver homogenate [63]. Although liposomes can increase the solubility and bioavailability of various antioxidant compounds, they generally suffer from rapid first-pass clearance by the liver and spleen [57]. This limitation has only been partially overcome by surface modifications with molecules such as PEG. For example, coating liposomes with PEG2000-distearoly phosphatidyl ethanolamine resulted in a 15% increase in curcumin encapsulation efficiency, reaching 85%. Biodistribution studies in rats over 96 h after a single intragastric dose showed a threefold improvement in its circulatory half-life compared to non-coated liposomes and, a considerable increase of quercetin concentrations in the brain and heart, with a decrease in the liver, lungs and kidneys were observed [64]. Antioxidant enzymes such as SOD and catalase have also been encapsulated in liposomes, but their activity was limited

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New concepts to fight oxidative stress: nanosized three-dimensional supramolecular antioxidant assemblies

Table 1. Structures and recent reviews of the most common antioxidants. Name/ class

Structure

Recent reviews and their topic

Flavonoids O

Ref.

Flavonoid delivery in solid tumors Rutin : delivery and therapeutic potential Quercetin: bioavailability: problems and promises

[175] [176] [177]

Tocopheryl succinate nanoparticles as DDS for cancer therapy

[178]

Nanocarriers for curcumin delivery Curcumin nanoformulations for cancer therapy Curcumin delivery methods (formulation and carriers) Curcumin: towards nanomedicine Neuroprotective effect of curcumin in Alzheimer’s disease Curcumin: current and future clinical applications Curcumin pharmacokinetics/-dynamics in relation to cancer Recent developments in curcumin delivery Nanocurcumin: advancement over native curcumin Novel DDS to improve curcumin bioavailability

[179] [180] [181] [182] [183] [184] [185] [186] [187] [188]

New DDS to improve resveratrol bioavailabilty Therapeutic potential and advances in resveratrol delivery

[189] [190]

New uses of retinoids by innovative DDS

[191]

Delivery systems for idebenone

[192]

O Flavone backbone

Tocopherols Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Kainan University on 04/21/15 For personal use only.

HO O α-tocopherol

Curcumin

HO

OH

O

O O

OH

HO

OH

O

O O

O

Curcumin in its enol and keto forms OH

Resveratrol HO

OH

Retinoids (Vitamin A)

R retinol R = CH 2OH retinal R = CHO all-trans-retinoids

Idebenone

O

retinoic acid R = COOH OH

O

O O DDS: Drug delivery systems.

by the low permeability of the membrane for ROS [65]. In order to overcome this limitation, hydrophobic SOD derivatives, such as acylated SOD (Ac-SOD) have been entrapped near the external surface in the liposome membrane [66]. In an adjuvant arthritis rat model, PEG-coated liposomes, loaded with either SOD or Ac-SOD, showed a superior therapeutic effect compared to the non-coated systems. The therapeutic effect of Ac-SOD-loaded liposomes was shown to occur faster when compared to encapsulated SOD [67]. Another approach

in the design of long-circulating systems is to covalently bind SOD to the distal termini of PEG-coated liposomes, resulting in a system with good storage stability (32 days at 4 C and 96 h at 37 C) and a biodistribution comparable to SOD-loaded liposomes [68]. In order to further improve the therapeutic efficiency of liposomal systems, surface functionalization with targeting groups has been considered. PEG-coated liposomes have been loaded with EUK-134, a potent SOD/ catalase mimetic, and functionalized with anti-PECAM

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A.

B.

Lipid

PEGylation moiety

C.

Targeting moiety

Surfactant

Lipophilic drug and

enzyme

Hydrophilic drug and

enzyme

Figure 1. Schematic cross-section of the lipid-based nanostructures: (A) Liposome; showing a lipid bilayer functionalized with targeting moieties or PEG coating. (B) Solid lipid nanoparticle coated in surfactant. (C) Nanostructured lipid carrier; the blending of different lipids results in a bigger loading capacity due to a decreased density of the crystalline matrix.

antibodies for endothelial targeting. In mice, this system provided efficient delivery of the mimic to the lungs showing both a twofold increase in protection against LPS-induced acute pulmonary inflammation and a 12-fold more potent protection against pulmonary edema compared to nontargeted liposomes [69]. SLNs and NLCs SLNs are composed of a solid lipid core (i.e., having a higher melting point than the body temperature), which are stabilized by a surfactant coating (Figure 1B). The structure of SLNs confers them several advantages over liposomes, such as easier large-scale production, better long-term stability, and a more constant release. Their composition, properties and applications have been extensively reviewed [59,70-73]. One example of application to antioxidant delivery is the entrapment of IDB into a SLN. Here, a steady release of IDB over 8 h, followed by a rapid release resulting from a polymorphic transition of the lipid matrix, was observed. This system, however, efficiently protected astrocytes from 2,2¢-azobis-(2-amidinopropane) dihydrochloride induced oxidative stress in vitro [74]. The loading capacity of SLNs for lipophilic antioxidant molecules is limited by the solubility of the compound in the melted lipid and by the structure of the lipid matrix. Furthermore, the matrix can suffer polymorphic transitions upon storage or circulation causing a sudden discharge of the drug [70-72]. In order to overcome these limitations, NLCs have been developed by blending lipids with different physical properties in a matrix with a tunable structure (Figure 1C). The packing of the lipids within the particle’s matrix is much less dense than in the case of SLNs increasing the amount of loadable drug [71,75-77]. For example, resveratrol has been loaded in both SLNs and NLCs with maximal EE of 73 and 91%, respectively. Both systems showed no 4.1.2

6

cytotoxicity to human dermal fibroblast cells and efficiently prevented H2O2-induced oxidative stress [78]. However, NLCs do not always provide a better EE, as was reported for the loading of a-lipoic acid into SLNs and NLCs with comparably high EE (> 70%), and stability (> 90 days at room temperature) [79]. SLNs and NLCs appear to be interesting delivery systems for LMW antioxidants because they have higher stability, encapsulation efficiency of lipophilic compounds and easier large-scale production than liposomes. However, they present intrinsic limitations in terms of encapsulation of enzymes, functionalization for targeted delivery and triggered release. Therefore, their use is limited to systemic administration of LMW compounds with passive targeting or topical applications. Polymer-based nanocarriers Both natural and synthetic polymers are used to prepare nanocarriers for antioxidant compound delivery [53]. Polymers present numerous advantages over lipids because they can be designed to include stimuli-responsive functional groups for triggered release or can easily be decorated with a variety of targeting groups for site-specific delivery [59]. The main structures of interest for antioxidant delivery are: i) dendrimers, ii) micelles, iii) vesicles and iv) solid polymer nanoparticles. 4.2

Dendrimers Dendrimers are highly branched polymeric macromolecules (Figure 2A) that can be produced by reacting a molecule containing multiple functional groups with monomers, yielding a first-generation (G1) dendrimer, which subsequently participates in further reaction steps with monomers, yielding higher generation dendrimers [80]. Dendrimers have the ability to accommodate LMW antioxidant compounds in their core. For example, the flavonoid daidzein has been loaded within the hydrophobic core of both G3 poly(amidoamine) 4.2.1

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New concepts to fight oxidative stress: nanosized three-dimensional supramolecular antioxidant assemblies

(PAMAM) and G4 poly(propylene imine) (PPI) dendrimers, resulting in a 190- and 650-fold increase in aqueous solubility, respectively. PPI dendrimers, however, were cytotoxic when dosed in two cell lines (MCF-7 and A549) while PAMAM dendrimers were not. The protective effect of daidzein against H2O2-induced oxidative stress in both cell lines was preserved upon inclusion in PAMAM dendrimers [81]. Another approach is the conjugation of LMW antioxidant molecules to the polymer chains in the external corona of the dendrimer. As an example, NAC was linked to PAMAM dendrimers (G4) through disulfide bonds that can be cleaved through GSH-induced exchange reactions. In vitro experiments indicated no release of the payload at plasma GSH levels, but a release of 60% within 1 h at intracellular GSH levels. NAC-bound PAMAM dendrimers, compared to free NAC, exhibited significant uptake into mouse microglial cells within 4 h, no cytotoxicity, and a log decrease in LPS-induced oxidative stress compared to free NAC [82]. Dendrimers show much promise in advancing antioxidant delivery; however, to the best of our knowledge, dendrimers have not been used to entrap or bind antioxidant enzymes. This is probably because their architecture prevents them from shielding the enzymes and preserving their bio-activity for longer periods of time. Micelles Polymeric micelles (Figure 2B) are filamentous or spherical (diameter from 1 to 100 nm) supramolecular structures, resulting from the self-assembly of amphiphilic block copolymers and are usually composed of a hydrophilic shell surrounding a hydrophobic core [83-85]. Their production, properties and applications have been reviewed in detail elsewhere [83]. Micelles, generated by a polymer based on a natural linear polyfructose (inulin) reacted with D-a-tocopherol succinate -a derivative of vitamin E -- showed no cytotoxicity on fibroblast cells. When these micelles were loaded with the antioxidant curcumin (58% EE), their payload was released over 250 h in PBS buffer [86]. Delivery of antioxidant compounds with micelles can be further enhanced by functionalization of their outer shell with targeting moieties. For example, by modifying the distal termini of the block copolymer poloxamer 105 (PEG-b-poly(propylene glycol)-b-PEG) with the liverspecific moiety lactobionic acid, the micellar delivery of the encapsulated flavonoid silybin in rat liver resulted in threefold increase in tissue-to-plasma concentrations compared to the same system without targeting [87]. Micelles can also be applied to enzyme delivery. Catalase was entrapped in micelles based on block copolymers of PEG and poly-(L-lysine) cross-linked through disulfide bonds. Cross-linking allowed for the disruption of the micelle and the release of the active enzyme in reductive environments [88]. Enzymes can also be conjugated to the outer shell of micelles to form enzyme-polymer supramolecular structures. For example, poly(propylene sulfide) and PEG copolymer micelles terminated with vinyl sulfones were conjugated with SOD without affecting the enzyme’s 4.2.2

activity. The polymer itself was further able to scavenge hydrogen peroxide in vitro [89]. However, the conjugation approach can only be used for very stable biomacromolecules, because it does not shield them from proteolytic attack. Vesicles Polymer vesicles -- also named polymersomes -- are hollow spherical structures formed by the self-assembly of amphiphilic block copolymers in dilute aqueous solutions (Figure 2C) [90]. Their size ranges from around 50 nm to several micrometers [91,92] and their membrane thickness ranges from 6 to 21 nm [93,94]. Polymersomes have been widely used for stimuli-responsive and targeted drug delivery [95-97], but reports of their use in LMW antioxidant delivery are quite limited. This could originate from the fact that the main LMW antioxidants are hydrophobic and thus, not soluble in the aqueous core of vesicles. Therefore, hydrophobic LMW antioxidant compounds can only be entrapped in the membrane of polymersomes, limiting their controlled release. Polymer vesicles are, however, still of great interest in oxidative stress therapy because encapsulated antioxidant enzymes, such as SOD and catalase, maintain their activity within the cavity. They can be designed so that the enzyme remains encapsulated inside the cavity to act in situ as nanoreactors or artificial organelles (further discussed in Section 6) or for the enzyme to be released in the appropriate biocompartment if a DDS approach is intended [98]. For DDS applications, polymersome membranes must allow the release of the payload. This can be accomplished either by degradation of the membrane or by a change in its architecture resulting from a stimulus (physical, chemical or enzymatic). 4.2.3

Solid polymer nanoparticles Solid polymer nanoparticles are spherical supramolecular assemblies in which a hydrophobic core is surrounded by a hydrophilic shell (Figure 2D). Various types of solid polymer nanoparticles have been developed for antioxidant compound delivery [99]. For example, GA loaded (> 90% EE) in NPs formed by cross-linking chitosan with tri-polyphosphate pentasodium was released in a burst manner (~ 60% GA) over 2 h followed by a steady release reaching 80% after 24 h. Coating of these particles with the surfactant polysorbate 80 slightly reduced the release rate (10%), but significantly improved the antioxidant activity of the system as shown by a decrease in lipid peroxidation and increase of catalase activity in rat brains upon intraperitoneal injection [100]. Similarly, SOD was encapsulated in poly(D,L-lactic-co-glycolic acid) (PLGA) NPs and the system was more efficient than free SOD in a rat focal cerebral ischemia-reperfusion model. Administration of this system resulted in a 65% infarct volume reduction, protection of neuronal cells against apoptosis and improved survival (75 vs 0%) of the treated animals [101]. More recently, new types of systems have been designed by incorporating antioxidant moieties in the polymeric 4.2.4

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A.

B.

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Triblock and

diblock copolymers

C.

Targeting moiety

D.

Lipophilic drug and

enzyme

Hydrophilic drug and

enzyme

Figure 2. Schematic cross-section of the polymer-based nanostructures: (A) Dendrimer of generation 3 (G3). (B) Micelle showing conjugation to enzymes and functionalization with targeting moieties. (C) Polymer vesicle. (D) Solid polymer nanoparticle.

backbone. Nanoparticles composed of a polymer obtained by esterification of trolox (a synthetic vitamin E analogue) showed little to no cytotoxicity in mouse pulmonary microvascular endothelial cells. Enzymatic degradation of the polymer allows the release of active trolox which resulted in up to 50% protection against copper nanoparticles-induced oxidative stress in U937 cells [102]. Poly(vanillin oxalate) nanoparticles have been developed by acetalization of vanillin with trimethyloethane and subsequent polymerization with oxalyl chloride. The resulting inflammation responsive polymer scavenges hydrogen peroxide and can subsequently be hydrolyzed to release the antioxidant vanillin (Figure 3A). These particles showed a high efficiency in scavenging hydrogen peroxide (90% after 36 h) in vitro, no cytotoxicity on RAW 264.7 cells, and a dose-dependent protection on LPS-stimulated cells [103]. Similarly, hydroxybenzyl alcohol incorporated polyoxalate polymers were designed to release hydroxybenzyl alcohol upon reaction with H2O2 (Figure 3B). These nanoparticles significantly reduced the generation of intracellular ROS in stimulated macrophages, making them of interest as a system for the treatment of airway inflammatory diseases [104]. Polymer nanoparticles containing nitroxide groups have also been proposed to fight oxidative stress. For example, nanoparticles based on pH-sensitive poly(ethylene glycol)b-poly[4-(2,2,6,6-tetramethylpiperidine-1-oxyl)aminomethy lstyrene] and pH inert poly(ethylene glycol)-b-poly[4(2,2,6,6-tetramethylpiperidine-1-oxyl)oxymethylstyrene] were reported as ROS scavenger systems with high therapeutic potential [105]. By covalently binding nitroxide groups on the polymer chain, the nitroxide-containing nanoparticles minimized the common adverse side effects of LMW nitroxides (e.g., mitochondrial dysfunction or hypertension), while still preserving their ROS scavenging properties [105]. These redox inert particles have been shown to accumulate preferentially in mucosa and in the inflamed gastrointestinal tract with no 8

uptake in the blood stream upon oral administration, making them of interest as therapeutic systems for gastrointestinal inflammation [106]. The redox-sensitive particles could be used as a treatment for cancer or ischemia as they disassemble at low pH, exposing polymer chains containing nitroxide radicals able to scavenge ROS [107]. Polymeric nanocarriers are of interest for the delivery of both LMW antioxidants and enzymes as they can be designed to incorporate chemical moieties for triggered release and targeted delivery. However, their efficiency can be limited by the amount of active compound they can encapsulate. Nanoparticles composed of a polymer containing antioxidant moieties in its backbone present the advantage of allowing the delivery of higher doses of active compounds but their route of administration should be considered carefully and their design should include targeting moieties such as to minimize deleterious off-target effects resulting from the scavenging of physiological ROS in healthy tissue. Inorganic nanoparticles Inorganic nanoparticles (especially Au and SiO2 nanoparticles) are of interest for drug delivery because they can be conjugated to various antioxidant compounds and can be functionalized with targeting moieties [108-113]. 4.3

Gold nanoparticles The synthesis, functionalization and applications of gold nanoparticles (AuNPs) have been extensively reviewed [111-113]. They can be functionalized with antioxidant compounds, and, in some cases, have also been shown to increase their potency [114]. For example, AuNPs functionalized with trolox, exhibited a DPPH radical scavenging rate constant eight times higher than free trolox [114]. Similarly, the conjugation of the flavonoid EGCG to AuNPs resulted in a fourfold increase in antioxidant activity over the free compound. These particles also showed good stability at lower pH, which supports their 4.3.1

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New concepts to fight oxidative stress: nanosized three-dimensional supramolecular antioxidant assemblies

A. O

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O O

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2 CO2

OH HPOX

OH HBA

Figure 3. (A) Structure, hydrolytic decomposition, and H2O2 scavenging capabilities of poly(vanillin oxalate) (PVO), and (B) Structure and H2O2-induced decomposition of hydroxybenzyl alcohol (HBA) incorporated polyoxalate (HPOX).

oral administration [115]. AuNPs coated with three repeating units of ethylene glycol linked to the phenolic antioxidant salvianic acid A (SA) exhibited a DPPH scavenging rate constant nine times higher than free SA, a low cytotoxicity and a twofold increase in ROS scavenging in both RAW 264.7 cells and Caenorhabditis elegans [116]. Citrate-capped AuNPs, hydrogen bonded to the flavonoid quercetin were reported to internalize into human red blood cells, making them viable candidates for therapeutic applications [117]. An early report of the functionalization of AuNPs with antioxidant enzymes aimed to compare two methods for the coupling of catalase to mercapto-undecanoic acid (MUDA) stabilized AuNPs. The first approach made use of carbodiimide chemistry to form an amide bond directly between MUDA and a free amine group on the enzyme, whereas the second approach consisted in biotinylation of both the AuNPs and catalase and subsequent coupling using streptavidin as cross-linker. Whereas both methods allowed efficient coupling of catalase without affecting its activity, the carbodiimide approach resulted in increased aggregation over time and the biotin approach suffered from a short half-life (6 min) in the blood of mice, likely due to fast uptake by the liver, spleen and lungs [118]. In addition, AuNP only allow for surface functionalization resulting in limited protection of enzymes against proteolysis.

85% after 120 h. DPPH scavenging assays showed that the antioxidant activity of the released GA was preserved for at least 96 h [119]. Silica nanoparticles can also be engineered to possess a mesoporous structure (Figure 4A), allowing them to be loaded with small molecules. For example, GA has been loaded into mesoporous silica nanoparticles (MSN) that were efficiently internalized through endocytosis in Caco-2 cells. These particles showed a dose-dependent cytotoxicity, which indicated that the antitumor activity of GA was preserved [120]. The surface of MSN, loaded with the dye fluorescein isothiocyanate, was also functionalized with nickel nitrilotriacetic acid (Ni-NTA) and subsequently linked to a genetically engineered His-tagged TAT-SOD fusion protein. Treatment of HeLa cells against LPS-induced oxidative stress with this system, after denaturation of the protein, showed that the cell penetrating peptide TAT led to non-endocytotic uptake of the particles and SOD could refold to its active form in the cytosol (Figure 4B) [121]. Whereas the surface of silica nanoparticles can be functionalized with LMW antioxidants and targeting moieties, their functionalization with enzymes is limited as it does not offer protection against proteolysis. This limitation can, however, be overcome by loading the enzyme in MSN of specific structure [122].

Silica nanoparticles The production, surface functionalization and applications of silica nanoparticles in drug delivery have been widely reviewed [108-110]. They have also been applied to antioxidant delivery, as illustrated by the fact that the polyphenol GA was chemically bound to silica nanoparticles by esterification, in order to be released in acidic conditions, through hydrolysis of the ester linkage. Release experiments in simulated gastric juice (HCl, pH = 1.2) showed ~ 30% release of GA within the first hour followed by a continuous release reaching

5.

4.3.2

Nanoparticles with intrinsic antioxidant properties

Some assemblies based on inorganic/metallic compounds, usually smaller than 100 nm, exhibit catalytic antioxidant activity, making them potential therapeutic candidates [123]. There are various methods for the production of such nanoparticles ranging from physical methods such as grinding, to synthetic routes such as vapor-, liquid- or solid-phase synthesis [124].

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Figure 4. (A) Transmission electron microscopy image of fluorescent mesoporous silica nanoparticles (MSNs) functionalized with TAT-SOD. (B) Confocal microscopy analysis of fluorescent MSNs (green) in endosomes (red). MSNs are uptaken in endosomes (top), whereas functionalization with TAT-SOD favors a non-endocytotic uptake (bottom). Adapted with permission from [121]. Copyright 2013 American Chemical Society. SOD: Superoxide dismutase.

5.1

Ceria nanoparticles

Ceria nanoparticles (CeNPs), composed of cerium oxide, can reduce oxidative stress due to their ability to cycle between Ce4+ and Ce3+ with very little required energy [125,126]. CeNPs display both SOD and catalase-mimetic activity [125] and are further able to scavenge peroxynitrites [127]. While many reports show the beneficial in vitro and in vivo protective effects of CeNPs in the fight against oxidative stress [128], recent papers indicate that high doses of CeNPs can also lead to oxidative stress and DNA damage [129,130]. Various factors, including synthetic routes, composition, purity, particle size, surface charge and aggregation, were identified as possible causes of in vivo CeNP toxicity at high doses [129,131]. Therefore, researchers are exploring different combinations of these factors in order to maximize their antioxidant effectiveness while minimizing their toxicity. Platinum nanoparticles Platinum nanoparticles (PtNPs) are promising structures in nanotechnology due to their negative surface potential, which prevents aggregation by electrostatic repulsion. PtNPs are produced by the sol-gel method involving the reduction of platinum ions by alcohol (methanol, ethanol) in the presence of protective agents (citrate, poly(N-vinyl-2-pyrrolidone), poly(N-isopropylacrylamide) or sodium polyacrylate) [132-135]. PtNPs act as SOD/catalase mimics and efficiently scavenge superoxide anion radicals, hydroxyl radicals, and hydrogen peroxide [136,137]. In vitro cell studies showed that PtNPs reduced cell damage and cell death caused by oxidative stress [136,138]. PtNPs were shown to be effective at extending the lifetime of C. elegans exposed to elevated levels of oxidative stress [138]. However, the therapeutic dose of PtNPs should be further investigated because harmful effects (acute and chronic nephrotoxicity, allergies and inflammation, decreased 5.2

10

GSH levels and impaired DNA integrity in colon carcinoma cells) are observed at increased PtNP concentrations [139-141].

Advanced nanoscience-based antioxidant systems

6.

Nanoreactors Nanoreactors are nanosized assemblies containing an active species in a confined space, which acts in situ, and is protected from harmful environmental agents. Various structures such as dendrimers, capsosomes, liposomes and polymersomes have been used in the design of nanoreactors [142-144]. However, nanoreactors developed to fight oxidative stress are only based on polymersomes, as they possess an aqueous core suitable for the encapsulation of catalytic compounds, high mechanical stability and allow a high degree of functionalization. An important factor in the successful detoxification of ROS and RNS in situ is the permeability of the polymeric membrane for both substrates and products of the catalytic reaction. In this respect, there are various strategies to permeabilize the nanoreactor membrane: i) the use of copolymers that self-assemble in a membrane, whose hydrophobic domain is permeable to ROS and RNS [145,146]; ii) the use of polymers that generate porous membranes [147]; or iii) the insertion of channel proteins to serve as gates for molecules of the appropriate size [148-150]. The concept of an antioxidant nanoreactor was first introduced by the encapsulation of SOD in vesicles comprised of the amphiphilic triblock copolymer poly(2-metyloxazoline)poly(dimethylsiloxane)-poly(2-metyloxazoline). Since the nanoreactors had an oxygen permeable membrane, they were able to efficiently detoxify superoxide radicals in situ, and the activity of the enzyme was preserved for up to 3 weeks when stored at 4 C [151]. By changing the encapsulated biomacromolecule to hemoglobin, the resulting nanoreactor 6.1

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: O2

Figure 5. (A) Schematic representation of a nanoreactor containing a dual superoxide dismutase/catalase mimic and superoxide permeable membrane. (B) Confocal microscopy images of THP-1 cells after 24 h incubation with vesicles coencapsulating sulforhodamine B and the mimic CuIIENZm. (a) Internalized CuIIENZm and sulfo-rhodamine B-containing vesicles (red channel). (b) THP-1 cell membranes stained with Deep Red (green channel). (c) THP-1 cell nuclei stained with DAPI (blue channel). (d) Overlay of all channels. Adapted from [153] by permission of The Royal Society of Chemistry.

served to detoxify peroxynitrites in situ in addition to its role in oxygen storage. In this case, the permeabilization of the membrane was achieved by insertion of the channel protein OmpF, allowing the diffusion of molecules up to 600 Da through the pore [152]. Besides the encapsulation of enzymes or proteins, antioxidant nanoreactors have been loaded with mimics or nanoparticles with intrinsic ROS scavenging activity. For example, a metal complex serving as a SOD and catalase mimic was encapsulated in a nanoreactor to combine the detoxification of both superoxide and H2O2 (Figure 5), inducing a 23% increase of cell viability after exposure to oxidative stress [153]. Nanoreactors encapsulating CeNPs have also been designed, which resulted in a decrease of CeNP toxicity (increase of cell viability from 50 to 90%), while preserving their freeradical scavenging activity [154]. Artificial organelles An artificial organelle represents a nanoreactor which simulates the natural function of an organelle and is active for prolonged periods of time upon uptake into cells [155-157]. The first example of a synthetic organelle was generated by the co-encapsulation of SOD and either LPO or catalase, in polymersomes with a membrane permeabilized by insertion of the porin OmpF. These enzymes are involved in a cascade reaction which detoxifies both superoxide and H2O2 allowing them to mimic the function of natural peroxisomes (Figure 6). Artificial peroxisomes showed no toxicity, and effectively decreased ROS for > 48 h in cells pre-exposed to oxidative stress [158]. While the development of artificial organelles is in an early stage, further research is being performed with promising outcomes in terms of cascade reactions intended to simultaneously decrease ROS and RNS in vivo. 6.2

Mitigation of oxidative stress in drug delivery

7.

Mitigation of drug-induced oxidative stress Recently, the use of antioxidants has surpassed being used only for the direct treatment of ROS related diseases by being utilized to mitigate the toxicity of the delivered drugs. A prime example of this is with chemotherapy. Current chemotherapeutics mainly rely on the natural increased uptake and toxicity of the drugs into rapidly dividing cells. However, these drugs are often highly toxic not only to tumor cells but also to rapidly dividing healthy tissues, partially arising from the formation of excess ROS [159]. Therefore, it is possible that antioxidant compounds could alleviate the ROS-induced stress produced by chemotherapeutics on healthy cells. Bleomycin, etoposide and cisplatin used for the treatment of testicular cancer lead to gonadotoxicity, weight loss and complete sterilization in rats due to a decrease in sperm number and motility. By incorporating a mixture of a-tocopherol, L-ascorbic acid, Zn and Se to the formulation solution, a 60% increase of sperm motility and a twofold increase in the number of fertile rats was observed compared to the chemotherapeutic drugs alone [160]. This concept has also been shown with nanoparticles that exhibit natural antioxidant properties by combining the delivery of the chemotherapeutic drug doxorubicin with CeNPs to treat both A375 melanoma and stromal cells. CeNPs were toxic to the tumor cells but had little toxic effect on healthy cells. In addition, they induced a decrease in toxicity of doxorubicin upon pre-treatment of the stromal cells [161]. Another example, showed the benefits of co-encapsulating the antioxidant fisetin with cyclophosphamide in liposomes based on DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) and 7.1

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Cu/Zn SOD

nt me ge

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2H2O + O2

Figure 6. (A) Schematic representation of a) a cell, with various organelles b) peroxisome, a spherical nanometer sized organelle that plays a significant role in ROS regulation, c) an artificial peroxisome (AP), based on the co-encapsulation of a set of superoxide dismutase (SOD) and lactoperoxidase (LPO) or catalase (CAT) in a vesicle rendered permeable with channel proteins, (d) enzymatic cascade reaction occurring inside the AP. (B) Confocal microscopy image of a HeLa cell incubated for 24 h with APs (blue: nucleus, green: endosome/lysosome, red: artificial peroxisomes) (scale bar = 5 µm). Adapted with permission from [158]. Copyright 2013 American Chemical Society. ROS: Reactive oxygen species.

pegylated DODA (dioctadecyldimethylammonium chloride) by increasing the effect of the chemotherapeutic drug [162]. The combination of these results exemplifies the potential of how effectively antioxidants can be used to treat a disease, while simultaneously lowering the toxicity of the drugs to healthy cells. Antioxidants have also been applied to mitigate the toxicity of non-chemotherapeutic drugs such as iloperidone (ILO), an antipsychotic drug known to increase oxidative stress upon long-term administration. Intranasal administration to rats of NLCs co-loaded with ILO and the antioxidant IDB resulted in a 9- and 10-fold increase of drug concentrations in the brain when compared to the free drug. Repeated administration over 28 days of pure ILO or ILO-loaded NLCs resulted in a net decrease of the activity of various antioxidant enzyme, and an increase in lipid peroxidation, indicating oxidative stress. However, the coloading of NLCs with IDB allowed maintaining a normal ROS level [163]. Mitigation of nanocarrier-induced oxidative stress

7.2

ROS production and toxicity of the drug carrier is a desired effect to help kill cancer cells, but this is often not the case for delivery to other diseases. One limiting factor when using DDS is the ROS-induced toxicity by the carrier, often necessitating a complete redesign of the system. The effects on ROS by many nanocarriers in regards to toxicity have been extensively reviewed [164,165]. Also, various studies have described nanoparticles that show ROS toxicity such as, but not limited to: SiO2 [166], cationic SLNs [167], PAMAM 12

dendrimers [168], gold, silver, iron oxide and zinc oxide nanoparticles [169-172]. If successful, attempts to use antioxidants to limit the toxicity of these types of particles could dramatically increase the number of possible nanocarriers that would make acceptable drug delivery candidates and lower the number of failed projects due to ROS toxicity. While AuNPs have beneficial characteristics making them popular delivery vehicles [111-113], the literature is divided as to the extent of their ROS-dependent toxicity [173]. Cui et al. recently showed that ~ 2.5 nm tiopronin-AuNPs induced a fourfold increase in ROS toxicity in multiple cell lines. In this respect, co-delivery with antioxidants decreased ROS levels twofold when dosed with NAC and reduced L-cysteine, and completely inhibited ROS toxicity to cells when delivered with GSH or excess tiopronin [169]. Another example includes the delivery of antioxidant poly(trolox ester) nanoparticles in combination with iron oxide, a ROS producing MRI imaging agent. The system led to a reversal of toxicity and a 100% cell viability [171]. This concept has also been applied to improve gene delivery. Polyethyleneinimine (PEI), a gold standard for in vitro gene transfection, is cell toxic and was shown to lead to an increase of ROS. Therefore, PEIPLGA micelles were co-loaded with DNA and the antioxidant a-tocopherol, thus lowering the production of ROS in multiple cell types and improving gene expression multiple orders of magnitude. Treating cells with PEI-PLGA DNA micelles and free a-tocopherol showed only minor improvements in gene expression compared to PEI-PLGA micelles alone. This effect was attributed to the localization of the antioxidant within the ROS-producing micelles, increasing its scavenging

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New concepts to fight oxidative stress: nanosized three-dimensional supramolecular antioxidant assemblies

efficiency [174]. The increase in gene expression by antioxidants could have long-lasting effects in gene therapy research.

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8.

Conclusion

Nanoscience proposes new solutions to fight oxidative stress in a more efficient manner than the conventional administration of antioxidant compounds. This is accomplished by the design and development of supramolecular assemblies that possess intrinsic antioxidant activity or are combined with antioxidant compounds (LMW compounds or enzymes). The majority of these nanoscience-based systems are at an early stage of research (preclinical studies). Significant efforts are necessary to further characterize and optimize their properties to reach clinical applications. In addition to conventional nanocarrier-based DDS, antioxidant nanoreactors and artificial organelles were very recently introduced as an elegant manner for antioxidant assemblies to avoid the limitations of DDS to obtain an efficient and localized, long-lasting, therapeutic effect against oxidative stress. New research directions are needed to improve antioxidant systems by: i) inducing multifunctionality, which results from the co-encapsulation of biomolecules working in tandem; ii) chemical modification of the assemblies to support targeted approaches; iii) introducing stimuli-responsive properties; and iv) combining compounds for the detection and treatment of pathologies in one assembly for theragnostic approaches. However, while these improvements are critical for successful antioxidant therapies, there will be no single therapeutic system effective against all ROS-related disease states as a consequence of the very complex nature of the mechanisms linking oxidative stress to pathologies. Therefore, effective nanosized antioxidant assemblies must be designed on a case by case basis. 9.

Expert opinion

Nanoscience-based solutions against oxidative stress intend to overcome the limitations of direct administration of antioxidant compounds, such as their instability, low solubility, bioavailability or permeability through cellular membranes. In this respect, supramolecular assemblies, with different morphologies and properties, are designed to deliver antioxidant compounds or to be used as antioxidant systems themselves, based on their catalytic activity. Even if these nanosciencebased systems proved to be effective at detoxifying ROS and RNS in vitro or in preclinical studies, there are still several challenges that need to be solved in order to translate their effectiveness into clinical therapeutics. First, it is necessary to improve the biocompatibility of antioxidant assemblies. Inorganic nanoparticles (CeNP and PtNP) and nitroxide-containing polymer nanoparticles were reported to efficiently scavenge ROS and RNS in vitro and in vivo. However, they are far from therapeutic applications because they become toxic at high concentrations. To prevent

their toxicity while maintaining their antioxidant activity, they can either be coated in nontoxic polymers or encapsulated to act in situ as nanoreactors. A large variety of lipidand polymer-based nanocarriers were proposed for the delivery of antioxidant compounds. Whereas first-generation lipid-based nanocarriers, namely micelles and liposomes, allow for increased bioavailability of antioxidants, they suffer numerous drawbacks including poor long-term stability and uncontrolled release. Newer lipid-based structures such as SLNs and NLCs are more stable than liposomes, but they are limited in the nature of their payload because they do not allow for the entrapment of biomacromolecules, such as enzymes. The use of polymers in the design of antioxidant assemblies further advanced the field of antioxidant therapy. Natural polymers are of high interest because of their biocompatibility, but their chemical functionalization can be quite difficult. On the other hand, synthetic polymers are easy to produce and their properties can be tuned to design various nanostructures. However, the requirements of low toxicity and high biocompatibility represent factors limiting the use of a large variety of synthetic polymers. Therefore, new directions in the development of polymeric nanocarriers for antioxidant therapy should favor low toxicity combined with long-term stability in vivo. Second, it is necessary to design assemblies with combinations of different biomolecules or mimics, and to introduce multifunctionality through targeting or stimuli responsive moieties. In this respect, the concept of antioxidant nanoreactors and artificial organelles could lead to efficient solutions for improved design, production and functionality. Two interesting developments leading to multifunctional ‘smart solutions’ include the encapsulation of enzymes working in tandem to simultaneously detoxify various ROS and RNS, and the co-encapsulation or entrapment of imaging agents and antioxidant compounds in one assembly for theragnostic approaches. In order to optimize the supramolecular assembly to the active compounds, its characteristics should be modulated in order to increase the antioxidant activity by increasing the encapsulation efficiency or by directly incorporating the active compound in the polymeric backbone. The use of polymers capable of scavenging ROS is also of interest to maximize the therapeutic effect, as they can be combined with stimuli responsive moieties to be degraded in oxidativestress-specific conditions. Furthermore, it is needed to improve the behavior of the nanostructure in vivo, by extending its circulation time and increasing its uptake in the desired regions through targeting. In addition, architectures such as vesicles, which allow simultaneous entrapment of different active compounds, should be favored compared to solid nanoparticles, especially when the antioxidant molecule is an enzyme. However, these new nanoscience concepts are in their very early stage of research, often with little more than preliminary in vitro evaluation. Therefore, significant efforts are necessary to fully characterize them in more bio-oriented conditions as an essential step towards clinical applications.

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Third, it is essential to provide comparative studies regarding the efficacy of different assemblies in a standardized manner. To the best of our knowledge, these kinds of studies have not been performed, making it difficult to compare the promising aspects of various systems tested in different bio-simulated conditions. It is clear that the complexity of fighting oxidative stress in pathological conditions cannot be addressed with only one type of supramolecular assembly. However, optimizing the properties of each type of antioxidant assemblies and determining and comparing the advantages and limitations of each of them, will give a more clear view towards the effectiveness of each system and lead to the design of a suitable Bibliography

treatment against oxidative stress in specific pathological conditions.

Declaration of interest PU Richard and S Stolarov are supported by SNF-Switzerland, CG Palivan is supported by the University of Basel. JT Duskey and M Spulber are supported by the University of Basel and NCCR-MSE Switzerland. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Affiliation Pascal U Richard1, Jason T Duskey1, Svetlana Stolarov1, Mariana Spulber1 & Cornelia G Palivan†2 † Author for correspondence 1 University of Basel, Department of Chemistry, Klingelbergstrasse 80, CH 4056 Basel, Switzerland 2 Professor, University of Basel, Department of Chemistry, Klingelbergstrasse 80, CH-4056 Basel, Switzerland Tel: +41 061 267 38 39; Fax: +41 061 267 38 55; E-mail: [email protected]

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New concepts to fight oxidative stress: nanosized three-dimensional supramolecular antioxidant assemblies.

Misregulation of reactive oxygen species and reactive nitrogen species by the body's antioxidant system results in oxidative stress, which is known to...
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