Encapsulation of food bioactives and nutraceuticals by various chitosan-based nanocarriers

Journal Pre-proof Encapsulation of food bioactives and nutraceuticals by various chitosan-based nanocarriers

Safoura Akbari-Alavijeh, Rezvan Shaddel, Seid Mahdi Jafari PII:

S0268-005X(19)32650-5

DOI:

https://doi.org/10.1016/j.foodhyd.2020.105774

Reference:

FOOHYD 105774

To appear in:

Food Hydrocolloids

Received Date:

10 November 2019

Accepted Date:

13 February 2020

Please cite this article as: Safoura Akbari-Alavijeh, Rezvan Shaddel, Seid Mahdi Jafari, Encapsulation of food bioactives and nutraceuticals by various chitosan-based nanocarriers, Food Hydrocolloids (2020), https://doi.org/10.1016/j.foodhyd.2020.105774

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Journal Pre-proof Encapsulation of food bioactives and nutraceuticals by various chitosan-based nanocarriers Running title: Encapsulation of food bioactives by chitosan nanocarriers Safoura Akbari-Alavijeh1, Rezvan Shaddel1, Seid Mahdi Jafari2*

1Department

of Food Science and Technology, Faculty of Agriculture and Natural Resources,

University of Mohaghegh Ardabili, P.O. Box 56199-11367 Ardabil, Iran 2Department

of Food Materials and Process Design Engineering, Gorgan University of Agricultural

Sciences and Natural Resources, Gorgan, Iran *Corresponding

author, E-mail address: [email protected]

Abstract Nowadays, nanoencapsulation as a leading technique using nanostructures, can considerably enhance the bioavailability and durability of bioactive food components. For this purpose, chitosan as a bioactive polysaccharide has been widely utilized as carrier, due to its unique chemical and biological characteristics, for example polycationicity, biocompatibility, and biodegradability. In this review, various approaches and techniques for development of chitosan-based nanodelivery systems with an overview of the related studies will be discussed. Nutritional and functional properties of the nanostructures and relevant safety issues are also highlighted. Scientists have developed various nanostructures such as nanoparticles, nanohydrogels, nanofibers, and nanocomposites from chitosan which have been successfully applied as nanocarriers for encapsulation of a diverse range of bioactive compounds including phenolic compounds, essential oils, carotenoids, vitamins, etc. This review gives a new insight into the investigation of potent uses of chitosan-based nanostructures in the food and pharmaceutical manufacturing sectors.

Keywords: Nutraceuticals; Encapsulation; Chitosan nanocarriers; Food applications; Preparation.

1

Journal Pre-proof 1. Introduction Nanotechnology manipulates materials to create novel nanoscale materials with various properties which could be used in different fields like medicine, agriculture, and food (Augustin and Oliver, 2012). Food industry uses nanotechnology to develop new functional foods with improved nutritional value and food quality. Nanoencapsulation as the main branch of nanotechnology has been notably used in food industries to protect bioactive food ingredients against processing and environmental stresses (Abaee, Mohammadian, & Jafari, 2017; Katouzian, Faridi Esfanjani, Jafari, & Akhavan, 2017; Jafari & McClements 2017; Akhavan, Assadpour, Katouzian, & Jafari, 2018; Yousefi, Ehsani, & Jafari, 2019). From the commercial point of view, there are some marketed nano based products in the food industry including 24Hr Microactive® CoQ10 (nanosized coenzyme Q10 and ß-cyclodextrin matrix) (Genceutic Naturals, USA), Nanoceuticals™ Slim Shake Chocolate from RBC Life Sciences in the USA (pure cocoa infused “Nanoclusters”), NanoCurcuminoids™ from Life Enhancement in the USA (curcuminoids encapsulated with solidlipid nanospheres) (Dasgupta, & Ranjan, 2018), as well as Aquanova NovaSol® (nanoemulsions fabricated by ω-3 fatty acids and liposoluble vitamins), Asia Food beverage® in Thailand (manufacturing food-grade nanoliposomes) and Curcosome® (quercetin-bearing nanoliposomes) (Akhavan

et al., 2018). The novel approach in utilization of nanoencapsulation in food

manufacturing sectors is using food grade natural biodegradable polymers as shell material (Jafari, Fathi, & Mandala, 2015; Katouzian & Jafari, 2019; Mokhtari, Jafari, & Assadpour, 2017; Rostamabadi, Falsafi, & Jafari, 2019; Taheri & Jafari, 2019). The unique characteristics of polysaccharides including high modifiability, solubility and binding ability via their functional groups make them suitable for this purpose (Akbari-alavijeh et al. 2018; Assadpour & Jafari, 2019b; Rostami, Yousefi, Khezerlou, Aman Mohammadi, & Jafari, 2019). Chitosan is a chitin derivative biopolymer composed of N-cetyl-D-glucosamine units jointed by β(1,4)- glycosidic linkages (Luo & Wang 2013; Azevedo 2013; Hosseinnejad & Jafari, 2016). Moreover, the exclusive characteristic of chitosan, due to the presence of positive-charge amino 2

Journal Pre-proof groups, creates the water-soluble cationic biopolymer which is commercially available (Hamed et al., 2016). Chitosan is pH sensitive because of D-glucosamine in its structure, so that it is soluble at pH under 6; however, it is insoluble at neutral pH (Hamed et al., 2016; Fathi et al., 2014). Furthermore, the protonation rate of amino groups by acids through the chitosan chain increases its polarity and determines its solubility level (Azevedo, 2013). The wide range of Molecular weight (3.8-2000 kDa) and percentage of deacetylation (40-98%) of chitosan can definitely affect its application in different industries (Sundar et al., 2010; Mourya and Inamdar, 2008). Some other applicable attributes of chitosan are high mucoadhesive and adsorption activity, antifungal capacity, film-forming, metabolic functions, and forming micro/nanostructures (Fathi et al., 2014; Azevedo, 2013). The presence of amino and hydroxyl groups and the cationicity in chitosan structure provide many manipulation methods (Mourya and Inamdar, 2008; Harish Prashanth and Tharanathan, 2007), as shown in Fig. 1. In this regard, there are three main categories including depolymerization (chitonolysis), substitution and chain elongation. Fig. 1 Depolymerizaton has been proposed to get low molecular weight chitosan called chitooligomers which possess lower viscosity and extra functional characteristics exemplary more bioavailability, antitumor, antimicrobial and antifungal capacities (Mao et al., 2004; Harish Prashanth and Tharanathan, 2007; Mourya and Inamdar, 2008). Depolymerization process can be carried out by acid hydrolysis, deamination, heating and enzymatic methods. Among above-mentioned methods, enzymatic depolymerization is controllable by temperature and pH which makes it the preferred one (Mourya and Inamdar, 2008; Mao et al., 2004; Harish Prashanth and Tharanathan, 2007). In substitution category, quaternization or methylation has been used to enhance the cationicity and mucoadhesiveness, antibacterial and antifungal properties of chitosan (Rúnarsson et al., 2007; Mourya and Inamdar, 2008; Guo et al., 2007). Acylation or alkylation may help to produce acylated or hydroxyalkyl/carboxyalkyl chitosans with super porous, cross-linked and pH-sensitive properties with a wider range of solubility in organic solvents for acyl chitosans and in water for alkyl chitosan 3

Journal Pre-proof (Muzzarelli 1988; Chen et al. 2004; Lin et al. 2005; Teng, Luo & Wang 2013; Hamed et al. 2016; Mourya & Inamdar 2008). Thiolation or sulfation substitutes the primary amino groups by thiol or sulfate to develop efficient controlled release delivery systems with notable biological, polyelectrolyte, cohesive and gelling properties (Mourya & Inamdar 2008; Ngo et al. 2015; Jayakumar et al. 2007; Ngo et al. 2015; Hamed et al. 2016). Sugar-bound chitosan can also be synthesized by reductive N-alkylation of chitosan to form carriers with exclusive rheological properties and biological effects due to the potential of sugar for assessment of cells, viruses, and bacteria (Ngo et al., 2015; Mourya and Inamdar, 2008). Chain elongation as another strategy to develop modified chitosan includes crosslinking and graft copolymerization methods. The conformational alterations in molecular structure and higher degree of crystallinity are the main outcomes of crosslinking process (Harish Prashanth and Tharanathan, 2007). Grafted chitosans have also more water solubility and bioactivity (Jayakumar et al., 2005; Ngo et al., 2015). This review gives a new insight into the processing, functional features, and utilizations of chitosan nanocarriers for nanoencapsulation of food bioactive ingredients 2. Different nanocarriers prepared with chitosan Nanostructures are materials exhibiting new physical and chemical features with nanoscale size of 1–1000 nm in at least one dimension; more specifically, they are commonly defined to be of diameter in the range of 1 to 100 nm (Akhavan et al., 2018; Jeevanandam et al., 2018; Samiei et al., 2016). They are categorized into nanoparticles, nanoclusters, nanotubes, films, and nanocomposites (Jafari, 2017a, 2017b; Pathakoti et al., 2017; Peters et al., 2016). Changes in surface to volume ratio and electronic characteristics of the nanostructures greatly enhances their functional and technological applications (Jafari and McClements, 2017; Shukla et al., 2013). Food scientists aim to develop the targeted food-based nanostructures while keeping their natural origin (Dickinson, 2003). Among all food components, polysaccharides like chitosan are widely used due to their functional groups with broad range of binding and entrapment potentials 4

Journal Pre-proof (Liang et al., 2017). Fig. 2 presents a schematic overview of chitosan-based nanostructures with related preparation techniques. Fig. 2 2.1. Nanoparticles of chitosan Generally, nanoparticles are particulate dispersions or solid particles commonly ranging from 1–100 nm in diameter (Liang et al., 2017). As shown in Fig. 2, the preparation methods proposed for development of chitosan nanoparticles are ionic gelation, reverse micelles, emulsification, coacervation, self-assembly, nano spray drying, and nanoprecipitation (Zhao et al., 2011; Jafari, 2017a). The ionic gelation technique has been widely used for nanoencapsulation of food components by chitosan (Rajabi, Jafari, Rajabzadeh, Sarfarazi, & Sedaghati, 2019). This procedure is based on the interaction of opposite-charge macromolecules. In this regard, a nontoxic and multivalent material such as tripolyphosphate (TPP) is needed to provide the charge density. Concentration, ratios of ingredients, way of mixing, and pH are the affective factors in gelation process. Although the large size of the obtained nanoparticles (200-1000 nm) provides high loading capacity (up to 80% for bovine serum albumin), the particle sizes, pH sensitivity, and high polydispersity are considered as the drawbacks of this method (Katouzian and Jafari, 2016; Orellano et al., 2017; Rupareliya et al., 2015; Shukla et al., 2013; Yang et al., 2015; Zhao et al., 2011). Azevedo et al. (2014) nanoencapsulated vitamin B2 using nano-gelispheres by chitosan and alginate with encapsulation efficiency of 55.9% and loading capacity of 2.2%. Tan et al. (2018) fabricated nanoparticles to stabilize anthocyanins by the ionic gelation method of positively charged chitosan and negatively charged chondroitin sulfate (CS) with encapsulation efficiency of 88% which was driven by intermolecular electrostatic interaction. Jardim et al. (2015) used ionic gelation technique to develop chitosan nanocarriers for curcumin using CS with average size ranging from 175.7 to 710.2 nm. Reverse micelles can be fabricated via solving a surfactant in an organic solvent including chitosan, constantly agitated, centrifuged or sonicated which results in a limited size range (Rupareliya et al., 5

Journal Pre-proof 2015; Orellano et al., 2017; Zhao et al., 2011). The water dispersibility of chitosan is very low at physiological pH. Reverse micelles could be used to prepare chitosan nanoparticles (Ch-NPs) in order to improve the chitosan dispersibility in water (Orellano et al., 2017). In this method, Ch-NPs can be fabricated via cross-linking of chitosan and glutaraldehyde within n-heptane/sodium 1,4- bis2-ethylhexylsulfosuccinate (AOT)/water reverse micelles; in which, AOT act as surfactant. In this regard, glutaraldehyde is the most effective cross-linking agent which is used to covalently cross-link the chitosan. Reverse micelle aggregates can be formed by self-assembly using dispersed surfactants (AOT) in a nonpolar solvent. A broad range of surfactant molecules instead of AOT can also develop reverse micelles, including nonionic, anionic, cationic, and zwitterionic molecules (Orellano et al., 2017). Emulsification process needs a water-in-oil (W/O) emulsion with/without a cross-linking agent (e.g., glutaraldehyde). An W/O emulsion is obtained upon injection of an organic phase containing an emulsifier (i.e. Span 80) into a mixture of bioactive compound and chitosan solution under mechanical stirring, followed by sonication and then hardening by cross-linking agent (e.g., glutaraldehyde) (Grenha, 2012). By the addition of glutaraldehyde, its aldehyde groups are subjected to the amino groups of chitosan as a covalent cross-linking to form the emulsion and consequently the nanoparticles (Grenha, 2012). In this method, stirring speed directly affects the particle size and the progression of cross-linking. The toxicity of some cross-linking agents like glutaraldehyde is a limitation of the use of this method for nanoencapsulation of food components which should be replaced by safer ones like TPP ( Rupareliya et al., 2015; Katouzian and Jafari, 2016). Besides, the chitosan itself can be also cross-linked under sonication without using any cross-linking agent (Tan et al., 2019) or it can be used to coat on the emulsion via electrostatic adsorption without cross-linking agent (biopolymer-coated liposomes by electrostatic adsorption of chitosan (chitosomes)) (Tan et al., 2016) which could solve the mentioned limitation of using this method. Simple coacervation is made of the electrostatic forces between the opposite-charge molecules by a single biopolymer and complex coacervation is made by a complex set of electrostatic force between 6

Journal Pre-proof the negative-charge biopolymers (e.g., gum Arabic) and positive-charge biopolymers (e.g., Gelatin) (Butstraen and Salaün, 2014; Shaddel et al., 2018a, 2018b; Fathi et al., 2014). Min et al. (2016) proposed a complex coacervation method to produce chitosan nanoparticles immobilizing iron casein succinylate (ICS) for iron deficiency patients to increase the bioavailability of iron . Furthermore, Tan et al. (2016) proposed a new delivery system composed of chitosan and gum Arabic coacervates for curcumin with average diameter size of 863 nm and encapsulation efficiency of 90%. Self-assembly is the organization of a new structure from initial components which can be atoms, molecules, nanoparticles which is a reversible process due to the non-covalent interactions (Augustin and Oliver, 2012; Augustin and Sanguansri, 2009). Therefore, the process can be simply affected by environmental conditions (e.g., pH, mechanical stresses, temperature). In a study by Wang et al. (2019), quercetin-loaded nanomicelles were prepared through self-assembly method by using amphiphilic chitosan as wall-material and quercetin as core-material with average size of 363-579 nm and encapsulation efficiency of 84-90%. Furthermore, the self-assembly of nanomicelles of damnacanthal-loaded amphiphilic modified chitosan were used to fabricate the nanoparticles ranging from 144-253 nm in diameter with encapsulation efficiency of 27-53% (Sukamporn et al., 2017). In another study, the self-assembly of modified lecithin and chitosan were used to make the stable nanoparticles ranging from 123−350 nm in diameter with encapsulation efficiency of 9-63%. The electrostatic interaction between the NH3+ groups of chitosan and the phosphate groups of lecithin drive the self-assembly process (Chuah et al., 2009). Nano spray-drying is the atomization of a solution into a hot-air drying chamber to get the nanoparticles as dried powder within an electrostatic collector (Assadpour & Jafari, 2019a). The main challenge in this technique is the viscosity of biopolymer suspension which may block the atomizer and decrease the encapsulation yield (Jafari, 2017b). Application of modified chitosan like glycol chitosan has been proposed to obtain better nanoparticles by this method (Fathi et al., 2014). 2.2. Nanofibers of chitosan

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Journal Pre-proof Nanofibers are defined as solid fibers ranging from 1–1000 nm in diameter which are encouraging nanostructures for a plenty of applications i.e. pharmaceutical and bioactive delivery because of their unique characteristics such as superior porosity (Jafari & McClements, 2017; Rezaei, Fathi, & Jafari, 2019). The preparation methods include electrospinning, thermal oxidation, and chemical vapor deposition. However, electrospinning is the preferred method to fabricate nanofibers from natural biopolymers since it is continuous, profitable and no expensive equipment needed (Elsabee et al., 2012; Jafari, 2017a; Zhao et al., 2011). The complex chemical structures of biopolymers and wide distribution of molecular weights makes electrospinning process difficult. The electrospinability of chitosan is low due to its rigid structure, high crystallinity, and low solubility in common organic solvents (Schiffman and Schauer, 2008). So, using the mixture of polylactic acid and chitosan has been proposed to fabricate the electrospun nanofibers (Torres-Giner et al., 2008). Further, Schiffman and Schauer (2007) used 2.7% trifluoroacetic acid (TFA) and different molecular weight of chitosans to produce the nanofibers by electrospinning and uniform nanofibers were obtained ranging from 108-58 nm in diameter while the higher molecular weight caused larger fibers. In order to fabricate a new active food packaging, Ge et al. (2012) applied polyvinyl-alcohol/chitosan/tea-extract nanofibers to immobilize the glucose oxidase. Their obtained electrospun membrane exhibited ~73% deoxidization activity. Mendes et al. (2016) introduced chitosan-phospholipid nanofibers for controlled release and delivery of curcumin with the diameters ranging from 248 to 800 nm. The obtained nanofibers showed constant release behavior of curcumin which was around 75% at the end of 7 days (Mendes et al., 2016). In another work, Wongsasulak et al. (2014) developed zeinpolyethyleneoxide-chitosan composite electrospun nanofibers as a vehicle to entrap α-tocopherol with the size distribution of 449±126 nm, with improved targeted release and gastro-mucoadhesivity (Wongsasulak et al., 2014). 2.3.

Nanogels of chitosan

Nanogels present the features and characteristics of both nanoparticles and hydrogels, simultaneously (Hamidi et al., 2008). Chitosan is a potent hydrocolloid to from a hydrogel with no additives due to 8

Journal Pre-proof its polycationic nature and the charge density of hydrogels could be controlled by modification of the ionic strength and pH (Pereira et al., 2017). Self-assembly, radical polymerization, microemulsion (O/W and W/O), physical processing, ionic gelation, and emulsification are the preparation techniques suggested for development of chitosan nanohydrogels. Wang et al. (2004) used Schiff’s base reaction between the aldehyde groups of glutaraldehyde and the amino groups of chitosan to prepare chitosan hydrogels. The biological properties of chitosan nanohydrogels are enhanced bioavailability, adjustable dose, great permeability and stability through body defense mechanisms which make them an optimal carrier for functional components and their controlled delivery as well as the targeted one (Wang et al., 2017). good mechanical properties and thermal stability which make them an appropriate 2.4. Nanocomposites and nanocoatings of chitosan Basically, nanocomposites are composed of dispersed nanofillers such as nanoparticles, nanoplates, and nanofibers commonly with a mean size < 100 nm (Azeredo, 2009). Chitosan nanocomposites have shown good mechanical properties and thermal stability which make them an appropriate alternative for application in food and drug industries and also food packaging (Ali and Ahmed, 2018; Pathakoti et al., 2017). Superior film forming property of chitosan with selective permeability to oxygen and carbon dioxide has gained lots of attention to fabricate chitosan films and coatings. Nevertheless, the great permeability of chitosan coatings and films to water/gas restricts their application, since the control of water evaporation is a desirable characteristic for foods. So, some strategies have been proposed to enhance the hydrophobicity property by addition of organic (waxes, fatty acids) or inorganic (montmorillonite, silicate) ingredients and to improve the mechanical characteristics by the addition of cross-linking agents and ultrasonic and irradiation treatments (Elsabee and Abdou, 2013; Rhim et al., 2013). Hosseini et al. (2016) developed bioactive fish gelatin/chitosan nanoparticle composite films incorporated with Origanum vulgare L. essential oil (OEO). The obtained films showed superior mechanical properties with a decrease in water vapor permeability (WVP) and a distinctive antimicrobial activity. 9

Journal Pre-proof Furthermore, ionic gelation, supercritical fluid extraction of emulsions (SFEE), electrospinning, and emulsion-homogenization methods have been used to fabricate chitosan nanocomposites for nanoencapsulation of food bioactive ingredients (Abdollahi et al., 2012; Jamil et al., 2016). For instance, Abo-Elseoud et al. (2018) fabricated chitosan nanoparticle (CHNP)/cellulose nanocrystal (CNC) nanocomposites by ionotropic gelation method for the controlled release of repaglinide (RPG). CHNP was around 197 nm in diameter, while CHNP/CNC/RPG nanocomposite showed size ranging from 215 to 310 nm. The obtained nanocomposites showed a good drug release profile suitable for use as antidiabetic controlled-release drug systems. Now, there are some supercritical fluid encapsulation methods containing the supercritical fluid extraction of emulsions (SFEE) (Santos et al., 2012), rapid expansion of supercritical solutions (RESS) (Wang et al., 2002), and supercritical anti solvent (SAS) (Wang et al., 2004). Among them, SFEE is an appropriate technique to enhance the bioavailability of heat sensitive bioactive agents with ideal size distribution (~100 nm) (Fathi et al., 2014; Santos et al., 2012). In this method, initially, an O/W emulsion is prepared with dissolving the bioactive agent and the carrier material in the dispersed and aqueous phases, respectively. Consequently, formation of the nanoparticles is performed by putting it into contact with the supercritical fluid. To the best of our knowledge, although there are several studies on using supercritical fluid encapsulation methods to fabricate various nanocomposites, chitosan nanocarrier-based nanocomposites have not yet developed by these methods which could be a good research area for researchers. 3. Application of chitosan nanocarriers for various food bioactives Nanoencapsulation facilitates the controlled release and stability of bioactive food components at the proper time and the right place. For this purpose, using biopolymers due to their exclusive physicochemical characteristics, functional characteristics and biocompatibility with human body are preferred. However, in most of the studies, they have been utilized as a drug delivery vector. Tables 1 and 2 present a number of studies which have utilized chitosan nanocarriers for food bioactive ingredients categorized by the preparation techniques. 10

Journal Pre-proof Table 1 Table 2 3.1. Vitamins Low stability and high sensibility of vitamins to severe environmental conditions like freezing, heating, and oxidation are the principle challenges for their application in the food industries (Katouzian & Jafari, 2016). Use of chitosan-based nanoparticles has been proposed to overcome this challenge. In this regard, ionotropic gelatin is the preferred method for nanoencapsulation of vitamins due to the mild condition of the process. Azevedo et al. (2014) developed alginate/chitosan nanoparticles to encapsulate vitamin B2 by ionotropic polyelectrolyte pre-gelation method. They reported polydispersity index (PDI) and the mean size of nanoparticles 104.0 ± 67.2 nm and 0.319 ± 0.068, respectively with loading capacity and encapsulation efficiency of 2.2 ± 0.6% and 55.9 ± 5.6%, respectively. They also showed that the release profile of produced nanoparticles at different conditions is affected by polymeric relaxation and were stable at 4°C during 5 months in terms of particle size and PDI (Azevedo et al., 2014). Moreover, Vitamin C has been encapsulated using chitosan nanostructure by ionotropic gelation method. Alishahi et al. (2011) used sodium tripolyphosphate (STPP) to react with different molar masses of chitosan to prepare the nanoparticles as a carrier for vitamin C. Furthermore, the release rate of vitamin C was the fastest one at pH= 7.4 and the slowest one in 0.1 M HCl which was confirmed by in-vivo assay in rainbow trout digestive tract (Alishahi et al., 2011). Jiménez-Fernández et al. (2014) also introduced chitosan nanoparticles as ideal vehicles for delivering hydrosoluble compounds such as vitamin C with encapsulation efficiency > 15% in a nanosize range < 300 nm as a tool in aquaculture studies. In another study, de Britto et al. (2012) used a water soluble modified derivatives of chitosan (N,N,N-trimethyl chitosan, TMC) to develop nanoparticles with TPP anions by ionic gelation technique with the average size of 196 ± 8 nm and encapsulation efficiency of 95% for delivering vitamins B9, B12 and C.

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Journal Pre-proof α-tocopherol has also been encapsulated using chitosan-based nanoparticles and nanofibers. Lou et al. (2011) proposed chitosan nanoparticles coated via zein as a delivery system for α-tocopherol by ionic gelation technique followed by freeze drying. Their structural and physicochemical analysis elucidated that the hydrogen and electrostatic bonds were essentially responsible for the complex formation with a smooth surface. The particle size range was extended from 200 to 800 nm (Luo et al., 2011). Wongsasulak et al. (2014) used electrospinning for nanoencapsulation of α-tocopherol to form chitosan-based nanofibers. The nanofiber matrix was composed of zein, polyethylene oxide and chitosan with considerable gastro-mucoadhesive characteristics. 3.2. Antimicrobials Use of natural preservatives has recently been interested due to the proved adverse impact of synthetic preservatives on human health. To improve their resistance and functionality in food matrix, nanoencapsulation is a good strategy. Essential oils (EOs) are known antimicrobial agents, but their use is often restricted because of their volatile compounds which make them sensitive to heat, light, pressure, and oxygen (Mohammadi et al., 2015) (Vahedikia, Garavand, Tajeddin, Cacciotti, Jafari, Omidi, et al., 2019). Paula et al. (2010) proposed nanoencapsulation of Lippia sidoides EO by spray drying using Angico gum/chitosan as wall material ranging from 10 to 60 nm in diameter and encapsulation efficiency of 77.8%. They also proved the great larvicidal effect of the nanoparticles against larvae of Stegomyia aegypti or Aedes which is the dengue vehicle responsible for many diseases (Paula et al., 2010). Due to the harsh conditions of spray drying, most of further studies applied emulsification or ionic gelation techniques to nanoencapsulate EOs. Oregano EO, eugenol, carvacrol, Carum copticum EO, and Satureja hortensis L. EO, have been nanoencapsulated via TPP/STPP-Chitosan to form nanoparticles using emulsion- ionic gelation technique (Esmaeili and Asgari, 2015; Feyzioglu and Tornuk, 2016; Hosseini et al., 2013; Keawchaoon and Yoksan, 2011; Woranuch and Yoksan, 2013). These experiments cover a particle size range of 30 to 200 nm with a wide range of encapsulation efficiency from 14% to 47%. Antimicrobial and antioxidant effect and also the release profile of EOs were studied in all 12

Journal Pre-proof experiments which shows significant effect of the nanoencapsulation method on the stability of EOs. The highest encapsulation efficiency in this area has gained by Jamil et al. (2016) to encapsulate cardamom EO by TPP-chitosan using ionic gelation technique. They formed the nanocomposites in size range of 50 to 100 nm with a remarkable antimicrobial effect against S. aureus and E. coli (Jamil et al., 2016). 3.3. Phenolic compounds Phenolic compounds are secondary metabolites of plants commonly involved in the defense against pathogens or UV radiation. Phenolic compounds have been extensively utilized in the food sector due to their known functional, nutraceutical and medicinal properties (Caleja et al., 2017). Some phenolic compounds show high antioxidant activity, while others represent bioactive effects. Their unique chemical structure is responsible for the antioxidant activity mostly depending on hydroxyl groups’ number and position. They can be categorized as two major groups, flavonoids and nonflavonoids ( Faridi Esfanjani & Jafari, 2016; Faridi Esfanjani, Assadpour, & Jafari, 2018). Catechins, quercetin and anthocyanins have been nanoencapsulated via modified chitosan by means of ionic gelation technique (Dube et al., 2010; He et al., 2017; Zhang et al., 2016, 2008). Zhang et al. (2016) used β-chitosan to form nanoparticles ranging from 208 to 591 nm in diameter and encapsulation efficiency of 50-89%. Furthermore, they characterized its antibacterial activity against Listeria innocua and E. coli and showed that smaller particles have higher antibacterial activity than larger particles (Zhang et al., 2016). Quercetin-loaded nanoparticles via TPP- chitosan based on ionic gelation technique were prepared ranging from 40 to 100 nm in diameter and their antioxidant activity was evaluated in vitro through reducing power test and free radical scavenging activity test. The experiments demonstrated that encapsulation of quercetin in chitosan nanoparticles can be a useful strategy to improve the bioavailability of quercetin for development of pharmaceuticals (Zhang et al., 2008). Anthocyanin-loaded chitosan nanoparticles were also fabricated via carboxymethyl chitosan and chitosan hydrochloride with encapsulation efficiency of 63.15% and particle size distribution of 220 nm. Moreover, the release rate and stability of nanoparticles in simulated gastrointestinal fluid 13

Journal Pre-proof and a beverage model system was investigated compared with the free anthocyanin solution which proved the efficiency of nanoencapsulation by chitosan (He et al., 2017). Curcumin or its extracts as a well-known phenolic compound have been nanoencapsulated by chitosan derivatives using various encapsulation methods (Mendes et al., 2016; Sowasod et al., 2008; Tan et al., 2016; Yadav et al., 2012). Mendes et al. (2016) produced nanofibers using chitosanphospholipid by electrospinning with size range of 248 to 800 nm. The nanofibers were stable for at least up to 7 days in PBS and cytotoxicity assays exhibited suitable biocompatibility (Mendes et al., 2016). Yadav, et al. (2012) and Tan et al. (2016) achieved 90% encapsulation efficiency in fabrication of chitosan nanoparticles loaded by curcumin using emulsification and complex coacervation, respectively. Emulsification method resulted in nanoparticles < 50 nm while the size of nanoparticles by complex coacervation was ~860 nm. 3.4. Carotenoids Carotenoids such as lutein and astaxanthin have been encapsulated by TPP- low molecular weight chitosan and poly(ethylene oxide)-4-methoxycinnamoylphthaloyl chitosan (PCPLC), respectively. For instance, Arunkumar et al. (2013) applied ionotropic gelation method to develop lutein-loaded chitosan nanoparticles with a size range of 80 to 600 nm. They assayed the bioavailability of lutein both in vivo and in vitro using simulated gastrointestinal digestion and mice, respectively and showed that nanoencapsulation of lutein significantly increased (~50%) its bioavailability (Arunkumar et al., 2013). Tachaprutinun et al. (2009) formed nanospheres of PCPLC-chitosan loaded by astaxanthin with mean size of ~300 nm and a considerable encapsulation efficiency of 98'% to protect the pigment against thermal stresses. They demonstrated that the thermal stability of astaxanthin heated at 70◦C for 2 h was remarkably enhanced upon PCPLC nanoencapsulation, due to preventing the loss of olefinic functionality (Tachaprutinun et al., 2009). 3.5. Other bioactive compounds and nutraceuticals Iron has been encapsulated as chitosan- Iron Casein Succinylate (ICS) nanoparticles by complex coacervation with size range of 800 to 1000 nm to improve oral iron delivery system (Min et al., 14

Journal Pre-proof 2016). Some of enzymes like glucose oxidase and lipase have also been encapsulated by electrospinning method to develop nanofiber or nanocomposites (Ge et al., 2012; Huang et al., 2012; Siqueiraa et al., 2015). Lysosyme-loaded chitosan nanocomposites were formed by use of electrospinning and layer by layer assembly to enhance the preservation of pork against E. coli and S. aureus (Huang et al., 2012). To immobilize the lipase enzyme, polylactic acid- chitosan were used as nanofibers ranging from 200–1300 nm in diameter. Glucose oxidase was also encapsulated using polyvinyl-alcohol/chitosan/tea-extract to develop the nanofibers which can be applied in novel food packaging (Ge et al., 2012). 4. Gastrointestinal fate and safety of chitosan nanostructures Nanostructures may change both structurally and physicochemically passing through the gastrointestinal tract (GIT). At the first step of digestion, starch-based nanostructure will be degraded partly due to the release of salivary glands amylase in mouth. Afterwards, most of the polysaccharidebased nanostructures would be highly changed in the stomach due to the extreme circumstances of mechanical, acidic and ionic stresses. As soon as the nanostructures enter to the small intestine, their digestion starts by enhancing the pH and the encapsulated ingredients would be absorbed (Fathi et al., 2014; Vandamme et al., 2002). However, the nanostructures could be absorbed in various areas of GIT based on their particle size, stability, structure and surface features. Nanoparticles would pass across mucosal epithelial cells in the size range below 400 nm (Fathi et al., 2014). Accordingly, cationic and hydrophobic nanoparticles are efficiently absorbed via epithelium cells (Bouwmeester et al., 2009). This can cause distinct concerns like accumulation or excretion of nanoparticles to blood, lymph or adjacent organs, leading to inflammation, cytotoxicity, fibrosis, immunologic responses, and oxidative stress (De Jong et al., 2008; Greulich et al., 2011; Zhang & Chen, 2019). Given the above, it is essential to explore the action of all produced nanostructures including bioactive components transmitting across the GIT which has been restrictively done so far. Chitosan has shown antimicrobial and antioxidant activity. Moreover, it is a suitable option for dietary and healthy weight loss food products due to its high capacity to bind fat in the GIT (Liang et al., 15

Journal Pre-proof 2017; Fathi et al., 2014). Chitosan has some particular features (i.e., mucoadhesion, biocompatibility, transfection increment, in situ gelling, very low toxicity, efflux inhibitory property, and hydrophilic character) which make it a suitable vehicle to deliver the bioactive ingredients (Liang et al., 2017). Also, deacetylated chitosan has the primary role in most of the monitored biological activities due to its positive surface unlike most polysaccharides which boosts its binding to substances comprising negative charge (Liang et al., 2017). Negatively charged aspect of the mucus layer is the key for its interaction with positive-charge chitosan nanoparticles and promotes the cellular uptake. Conclusively, application of positive-charge chitosan nanoparticles would be an auspicious strategy to enhance bioavailability of nanoencapsulated food components (Dube et al., 2011). Dube et al. (2011) encapsulated green tea catechin (epigallocatechin gallate or EGCG) in chitosantripolyphosphate nanoparticles and measured the oral absorption of EGCG in Swiss Outbred mice. They showed that plasma exposure of EGCG elevated by 1.5 fold compared to free EGCG solution. They also represented that the improved exposure of EGCG to the jejunum was responsible for the enhanced EGCG plasma concentration (Dube et al., 2011). Accordingly, Dudhani and Kosaraju (2010) stabilized the catechin by chitosan nanoparticles via ionic gelation method and evaluated the mucoadhesive potential and oral bioavailability of catechin through the simulated GIT in vitro. The release rate of catechin from chitosan nanoparticles during 24 h was 32%. Mucoadhesivity for catechin-loaded chitosan nanoparticles and free chitosan nanoparticles with size range of 130 ± 5 nm and 110 ± 5 nm were 40% and 32%, respectively. Moreover, they declared that the fate of chitosan nanoparticles after reaching to the colon is unknown; further degradation by colon microflora and release of the residual encapsulated catechin is possible. Conclusively, their results exhibited that mucoadhesive chitosan nanoparticles is a promising technique for enhancement of the bioavailability of catechin via oral administration (Dudhani & Kosaraju, 2010). In another study, Ribeiro et al. (2019) encapsulated Pickering emulsions of roasted coffee oil by chitosan applying deprotonation and ionic gelation method. Subsequently, they evaluated the rate and extent of digestion and also bioaccessibility of total phenolic compounds. Their results showed that lower 16

Journal Pre-proof oil content and deprotonation method led to a better droplet stabilization and improved bioaccessibility of total phenolic compounds (Ribeiro et al., 2019). Although nanotechnology has plenty of potential advantages, there are still cautious attitude to the use of nanomaterials because of the unexplored degree of risks of exposure and even the life cycle analysis of the substances (Augustin and Sanguansri, 2009; FAO, 2010). The primary concern in nanomaterials usage is their probable migration from the nano coatings and films into food systems, which has not yet specified due to limited studies on nanoparticle migration and its possible toxicity. Obtained results in different studies revealed that pH of food matrix, temperature and time of storage are the main stimulants responsible for the migration of nanoparticles with various sizes and morphologies (Youssef et al., 2018; Huang et al., 2018). It should be noted that the complexity of food matrix makes the investigations and estimations difficult regarding the migration and toxicity of nanoparticles. In addition to the physiochemical features, applied dosage may influence on eventual fate and toxicity of nanostructures in food processing industries. Heavy metal release and allergy are two other main worries of nanomaterial exposure which could be diminished by use of natural biopolymeric nanomaterials (He and Hwang, 2016). Considering all above-mentioned issues about the applications of nanoparticles in foods such as cytotoxicity, migration from nanofilms into food, complexity of food matrix and unexpected interactions, definition of applied dosage and also the long-term consequences like allergies, more extensive studies are needed to get ensure about the consumption of chitosan-based nanoparticles; to achieve a manufacturing scale of production (Saboktakin et al., 2010). In general, some effective factors like the chemical formula, mass, particle size, surface charge features, and the agglomeration of individual nanoparticles can control the degree of nanotoxicity, which should be investigated both in vitro and in vivo (Ezhilarasi et al., 2013). In vitro toxicological studies investigate the cytotoxicity and its mechanisms. Cell lines obtained from intestine, liver, lung and skin of human and rodent are the most commonly used models for cytotoxicity assays (Zhang & Chen, 2019). In an in vitro study by Dura´n-Lobato et al. (2015), polymeric polylacticco-glycolic acid and lipid nanoparticles as oral nanocarriers for the cannabinoid 17

Journal Pre-proof derivative were successfully modified with chitosan and polyethylene glycol and comparatively assessed under the same experimental conditions. Zeta potential values of nanoparticles turned to positive and neutral values over coating by chitosan and polyethylene glycol, respectively. Imaging by electron microscopy displayed non-aggregated and spherical particles, with a well-defined core– shell structure after chitosan coating in the case of polymeric polylacticco-glycolic acid nanoparticles. Coating with chitosan resulted in a higher interaction with Caco-2 cells and a restricted uptake in THP1 cells, while coating with polyethylene glycol led to a limited uptake in Caco-2 cells and strongly inhibited THP1 cells uptake (Dura´n-Lobato et al., 2015). In another study, it has been announced that chitosan and its derivatives are potent to actuate human lymphocyte and macrophages proliferation with no inflammatory reaction because of cytokines’ inhibition (Jain & Jain, 2015). In vivo studies utilize more complicated organisms such as rodents, rabbits, dogs, and also volunteer humans to estimate the body response against nanoparticles (Zhang & Chen, 2019). In vivo experiments revealed that the hypodermic administration of chitosan from 5 to 50 mg/kg/day caused signs of cytotoxicity in dogs and rabbits, while orally given chitosan up to 6.75 g/day showed no clinical implications in human volunteers (Jain & Jain, 2015). Some state organizations have accomplished regulations via laws in order to prevent or at least decline the hazardous factors related to nanomaterials until reaching a comprehensive agreement. Nevertheless, there is no distinct internationally admitted regulation on legal explanation for manufacturing, labeling, in vivo and in vitro toxicity assays as well as environmental efficacy of nanoparticles (Jeevanandam et al., 2018; Zhang & Chen, 2019). Recently, some regulatory agencies in the USA such as the Food and Drug Administration (FDA), and scientific committees in the European Union (EU) like Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR), as well as some organic suppliers like the Biological Farmers of Australia and Canada General Standards Board have been formed to verify or estimate the potent risks of nanomaterials and even to ban the usage of manipulated nanomaterials in food processing industries. In addition, the European Union is continuously updating the list of 18

Journal Pre-proof substances that can be used to manufacture food packaging. The list makes part of an annex of the Regulation EU no. 10/2011 (https://eur-lex.europa.eu/eli/reg/2011/10/oj). In this list, some nanosized materials are already included although chitosan is still not part of the list. The consolidated version (the version that includes all the amendments done until now) of the Regulation EU no. 10/2011 can be found at https://eur-lex.europa.eu/legalcontent/EN/TXT/?uri=CELEX:02011R0010-20190829, which could be useful for interested readers. Similar to the list of substances that can be used to manufacture food packaging, there is a list of food additives in Annexes II and III to Regulation (EC) No 1333/2008 (https://eurlex.europa.eu/legal content/ EN/TXT/PDF/?uri=CELEX:32012R0231&qid = 1581371112970&from=EN) and its re-evaluated version with the Regulation EU no. 257/2010 (https://eur-lex.europa.eu/legal content /EN/TXT/PDF/?uri=CELEX :32010R0257&qid= 1581426929081 & from=EN), in which chitosan is not part of the list. Totally, it is recently admitted that nanomaterials

are not inherently hazardous and toxic, even have positive health benefits in most cases; Nevertheless, the evaluation of risk factors is certainly needed in the future to scale-up chitosan nano based food products (Ezhilarasi et al., 2013; Jeevanandam et al., 2018). 5. Conclusion and further remarks Today, the stability and bioavailability of food bioactive compounds are known as the main issues in development of nano-delivery systems. In this regard, chitosan can be an ideal nanocarrier due to its modification capability. Current review investigates the proposed chitosan-based nanostructures and their preparation techniques as well as their potential application in food industries. However, most of the available reports on chitosan nanostructures have been in biomedical area; their utilization in food still has been in lab-scale. Moreover, the evaluation of their toxicity, nutritional value, functionality and biological fate is needed. To conclude, in spite of all safety reports and regulations, chitosan-based nanostructures are promising nanocarriers in functional food development. References

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Journal Pre-proof Preparation and application of chitosan nanoparticles and nanofibers. Brazilian Journal of Chemical Engineering, 28(3), 353–362.

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Journal Pre-proof All authors declare that there is no conflict of interest.

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Fig. 1. Native and modified forms of chitosan; adapted from (Harish Prashanth and Tharanathan, 2007; Mourya and Inamdar, 2008).

1

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Fig. 2. Chitosan nanostructures and their preparation methods; adapted from (Augustin & Oliver, 2012; Jafari, 2017b; Zhao et al., 2011).

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Journal Pre-proof Highlights: 

Different properties of chitosan make it an ideal candidate for bioactive delivery systems.



Various methods for preparation of chitosan-based nanocarriers can be applied.



Chitosan nanostructures enhances bioavailability and stability of bioactive ingredients.



Positively charged chitosan nanoparticles facilitates cellular uptake by epithelial cells.

Table 1. Nanoencapsulation of bioactive ingredients by ionic gelation, coacervation and electrospinning of chitosan Nanoencapsulation process

Ionic gelation

Core Vitamin B2

Alginate/chitosan

Type of nanocarrier Nanoparticles

Vitamin C

Chitosan

Nanoparticles

< 300

>15

Vitamin C

STPP-Chitosan

Nanoparticles

238

70

Vitamins B9, B12, C

TPP-TMC

Nanoparticles

196

95

Zataria multiflora EO

Chitosan

Nanoparticles

125–175

45.24

Satureja hortensis L. EO

STPP-Chitosan

Nanoparticles

140-238

35-41

Lippia sidoides EO

Chitosan/cashew gum TPP-Chitosan

Nanogels

335–558

70

Nanocomposites

50–100

> 90

Lutein

TPP- LMW Chitosan

Nanoparticles

80-600

85

Protein: Bovine serum albumin

TPP- Chitosan

Nanoparticles

200–580

38-88

Curcumin

Chitosan

Nanoparticles

863

90

Iron

Chitosan-ICS

Nanoparticles

830–1070

_

Lipase

Polylactic acidchitosan Polyvinylalcohol/chitosan/ tea-extract

Nanofibers

200-1300

_

Nanofibers

_

_

Cardamom EO

Coacervation

Electrospinning

Glucose oxidase

Shell

Carrier size (nm) 104

Encapsulation efficiency (%) 56

1

Purpose of study Encapsulation efficiency and controlled release Nutritional value of nanoparticles in marine organisms Shelf life and release rate of vitamin C Size, morphology, spectroscopic and zeta potential properties Antifungal activity and stability against Botrytis cinerea Pers. Antimicrobial and antioxidant activity and enhancement of stability against environmental conditions Characterization and in vitro release profiles Characterization and cytotoxicity analysis Bioavailability of encapsulated lutein in vitro and in vivo Optimized conditions of fabrication for efficacious loading and release Characterization and antioxidant activity Development of liquid oral iron delivery system Immobilization of lipase enzyme Development of a novel food packaging system

Reference Azevedo et al., 2014 JiménezFernández et al., 2014 Alishahi et al., 2011 de Britto et al., 2012 Mohammadi, Hashemi & Hosseini, 2015 Feyzioglu & Tornuk, 2016 Abreu et al., 2012 Jamil et al., 2016 Arunkumar, Prashanth & Baskaran, 2013 Gan & Wang, 2007 Tan et al., 2016 Min et al., 2016 Siqueiraa et al., 2015 Ge et al., 2012

α-tocopherol Curcumin

zeinpolyethyleneoxide -chitosan Chitosanphospholipid

Nanofibers

449

_

Nanofibers

248-800

_

Enhancement of gastromucoadhesivity and targeted release To deliver curcumin with controlled release Coating of fish fillets with nanofibers to delay spoilage

Wongsasulak et al., 2014

Mendes et al., 2016 Liquid smoke/ Nanofibers 72-132 _ Ceylan, Unal thymol combination Sengor & Yilmaz, 2018 TPP: Trypolyphosphate; STPP: sodium Trypolyphosphate; LMW: Low Molecular Weight; TMC: N,N,Ntrimethyl Chitosan; EO: Essential oil; HMP: Sodium hexametaphosphte; ICS: Iron Casein Succinylate.

2

Table 2. Combined processes for nanoencapsulation of food ingredients by chitosan nanocarriers Nanoencapsulation process

Core

Shell

Type of nanocarrier

Carrier size (nm)

Encapsulation efficiency (%)

Purpose of study

Reference

Emulsion–ionic gelation

Oregano EO

TPP-Chitosan

Nanoparticles

40–80

21–47

Preparation, characterization and in vitro release study

Hosseini et al., 2013

Emulsion–ionic gelation

Eugenol

TPP-Chitosan

Nanoparticles

< 100

20

Thermal stability improvement and antioxidant activity

Woranuch & Yoksan, 2013

Emulsion–ionic gelation

Carvacrol

STPP-Chitosan

Nanoparticles

40–80

14–31

In vitro release profiles and antimicrobial activity against S.aureus, B. cereus and E. coli

Keawchaoon & Yoksan, 2011

Emulsion–ionic gelation

Carum copticum EO

STPP-Chitosan

Nanoparticles

30–80

36

In vitro release studies and antioxidant activity

Esmaeili & Asgari, 2015

Ionic gelation and freeze drying

Catechins

TPP- Chitosan

Nanoparticles

163

_

Evaluation of nanoparticles stability in an alkaline medium

Dube et al., 2010

High-pressure homogenized emulsions and layerby-layer shell assembly

Oil: Mediumchain triglyceride

Modified starchchitosan-lambdacarrageenan

Polyelectrolyte nanocapsules

130

_

Preparation and characterization of nanocapsules for food and pharmaceutical industries

Preetz et al., 2008

Emulsion- solvent evaporation

Curcumin extract

TPP- Chitosan

Nanocapsules

254-415

18-96

Preparation and characterization

Sowasod et al., 2008

Emulsionhomogenization

Rosemary EO

Chitosan

Nanocomposite films

_

_

Characterization and antimicrobial properties

Abdollahi, Rezaei & Farzi, 2012

Emulsificationfreeze drying

Curcumin

chitosan

Nanoparticles

< 50

> 90

Development of a stable detoxifying agent for arsenic poisoning

(Yadav et al. 2012)

ElectrospinningLayer by layer assembly

Lysozyme

Chitosan

Nanocomposites

500-700

_

Pork preservation against Escherichia coli and Staphylococcus aureus

Huang et al., 2012

Spray drying

Lippia sidoides EO

Angico gum/Chitosan

Nanoparticles

10-60

78

Characterization and release studies

Paula et al., 2010

HMP-Chitosan

23

3

Freeze drying

α-tocopherol

Zein-chitosan

Nanoparticles

200-800

75-88

Enhancement of stability and protection against environmental conditions

Luo et al., 2011

Nanoprecipitation by method of LuqueAlcaraz et al., 2012

Lime EO

Chitosan

Nanoparticles

6-18 and 60-900

_

Characterization and antibacterial activity against food-borne pathogens

Sotelo-Boyás et al., 2017

Nanoprecipitation by solvent displacement

Astaxanthin

PCPLC

Nanospheres

300–320

98

Characterization and thermal stability

Tachaprutinun et al., 2009

TPP: Trypolyphosphate; STPP: sodium Trypolyphosphate; TMC: N,N,Ntrimethyl Chitosan; EO: Essential oil; HMP: Sodium hexametaphosphte; PCPLC: poly(ethylene oxide)-4methoxycinnamoylphthaloyl chitosan.

4