Accepted Manuscript

The biological activities, chemical stability, metabolism and delivery systems of

quercetin: A review

Weiyou Wang, Cuixia Sun, Like Mao, Peihua Ma, Fuguo Liu, Jie Yang, Yanxiang Gao

PII: S0924-2244(15)30170-9
DOI: 10.1016/j.tifs.2016.07.004
Reference: TIFS 1840

To appear in: Trends in Food Science & Technology

Received Date: 20 November 2015

Revised Date: 21 April 2016
Accepted Date: 11 July 2016

Please cite this article as: Wang, W., Sun, C., Mao, L., Ma, P., Liu, F., Yang, J., Gao, Y., The biological
activities, chemical stability, metabolism and delivery systems of quercetin: A review, Trends in Food
Science & Technology (2016), doi: 10.1016/j.tifs.2016.07.004.

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1 The biological activities, chemical stability, metabolism and delivery

2 systems of quercetin: A review

3 Weiyou Wang1, Cuixia Sun1, Like Mao, Peihua Ma, Fuguo Liu, Jie Yang, Yanxiang
4 Gao*

Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing

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6 Laboratory for Food Quality and Safety, Beijing Key Laboratory of Functional Food

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7 from Plant Resources, College of Food Science and Nutritional Engineering, China

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8 Agricultural University, Beijing, 100083, P.R. China

9 *Corresponding author.

10 Tel.: + 86-10-62737034
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11 Fax: + 86-10-62737986
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12 Address: Box 112, No.17 Qinghua East Road, Haidian District, Beijing 100083,

13 China
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14 E-mail: gyxcau@126.com
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15 The authors contributed equally to this work.
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17 Abstract:

18 Background: Quercetin, one of the most well-known flavonoids, has been included in

19 human diet for a long history. The use of quercetin has been widely associated with a

20 great number of health benefits, including antioxidant, anti-inflammatory, antiviral

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21 and anticancer as well as the function to ease some cardiovascular diseases (i.e., heart

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22 disease, hypertension, and high blood cholesterol). However, poor water solubility,

23 chemical instability and low bioavailability of quercetin greatly limit its applications.

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24 Utilization of delivery systems can improve its stability, efficacy and bioavailability.

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25 Scope and approach: In this review, biological activities, chemical stability,
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26 metabolism and toxicity of quercetin and different delivery systems for quercetin were

27 discussed.
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28 Key findings and conclusions: Quercetin digested in human body (e.g., mouth, small
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29 intestine, liver, kidneys) undergoes glucuronidation, sulfation or methylation. During

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30 the food processing and storage, many factors such as heat, pH, metal ions, could

31 affect the chemical stability (including oxidation and degradation) of quercetin.

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32 Utilization of delivery systems including lipid-based carriers, nanoparticles, inclusion

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33 complexes, micelles and conjugates-based encapsulation has the potential to improve

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34 both the stability and bioavailability and thus health benefits of quercetin. Each

35 delivery system has its unique advantages and shortcomings, and the specific

36 selection should be based on the application domains. Moreover, the exploration of

37 natural food-grade ingredients as main compositions of delivery systems for quercetin

38 might be required in the future.

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39 Keywords: Quercetin; Metabolic pathway; Chemical stability; Bioavailability;

40 Delivery system

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42 Contents
43 1. Introduction........................................................................................................................ 5
44 2. Chemical structures of quercetin and its derivatives ................................................. 8
45 3. Biological activities of quercetin ................................................................................... 9
46 3.1. Antioxidant activity................................................................................. 9
47 3.2. Anti-inflammatory activity.................................................................... 10
48 3.3. Anticancer activity ................................................................................ 11

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49 3.4. Prevention of cardiovascular diseases ................................................... 12
50 4. Chemical stability of quercetin: oxidation and degradation .................................. 13
51 5. Absorption, metabolism and bioavailability ............................................................. 15

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52 5.1. Absorption and metabolism .................................................................. 15
53 5.2. Bioavailability ....................................................................................... 18
5.3. Excretion ............................................................................................... 19

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54
55 6. Toxic effects ..................................................................................................................... 20
56 7. Delivery systems for quercetin .................................................................................... 22
57 7.1. Lipid-based delivery systems ............................................................... 23

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58 7.2. Polymer nanoparticles .......................................................................... 26
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59 7.3. Inclusion complex ................................................................................ 29
60 7.4. Micelles ................................................................................................ 30
61 7.5. Conjugates-based delivery carriers ...................................................... 31
7.6. Other types of delivery systems ........................................................... 32
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63 8. Conclusions and future trends ...................................................................................... 32
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65 1. Introduction

66 Quercetin (3,5,7-trihydroxy-2-(3,4-dihydroxyphenyl)-4Hchromen-4-one) is a

67 dietary flavonoid, which widely existed in caper, black chokeberry, onion, tomato and

lettuce (Bischoff, 2008). In plants, quercetin is usually in a bound form with sugars,

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69 ethers or phenolic acids and etc. Different forms of quercetin derivatives seem to

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70 influence their rate of absorption in the small intestine and stomach (Mullen et al.,

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71 2008; Walle, 2004). The content and form of its derivatives play a key role in their

72 absorption (Rahman, Biswas, & Kirkham, 2006; Wiczkowski & Piskuła, 2004).

73
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Quercetin has attracted increasing attention due to its antioxidant (Dueñas,
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74 González-Manzano, González-Paramás, & Santos-Buelga, 2010), anti-obesity
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75 (Nabavi, Russo, Daglia, & Nabavi, 2015), anti-carcinogenic (Kumari, Yadav, Pakade,

76 Singh, & Yadav, 2010), antiviral (Anandam, & Selvamuthukumar, 2014; Ganesan et
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77 al., 2012), antibacterial (Rattanachaikunsopon & Phumkhachorn, 2010) and

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78 anti-inflammatory effects (Kleemann et al., 2011). Moreover, quercetin has been

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79 reported to have a strong potential in the treatment of cancers. Globally, it is estimated

80 that about 1.68 million new cases of cancer are expected to be diagnosed in 2016
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81 (Siegel, Miller, & Jemal, 2015). As documented, quercetin can inhibit the proliferation

82 of different types of cancer cells (e.g. colorectal cancer cells, prostate cancer cells,

83 liver cancer cells, pancreatic cancer cells and lung cancer cells) by modulating their

84 cellular processes and restraining them from growning (Lee, Bode, & Dong, 2011;

85 Shan; Wang & Li, 2009: Kim et al., 2013). It is also reported that the anti-cancer

86 function of quercetin is essentially associated to its strong antioxidant capacity

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87 (Conklin, 2000). Due to its potential health benefits for human, quercetin has come

88 into the focus of utilization as a nutraceutical ingredient in food and pharmaceutical

89 industries. Stability of quercetin has been extensively studied to investigate its

90 chemical changes during food processing and storage. The content of quercetin or

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91 quercetin derivatives could be dramatically reduced as a result of oxidation and

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92 degradation during food processing and storage (Buchner, Krumbein, Rohn, & Kroh,

93 2006; Odriozola-Serrano, Soliva-Fortuny, & Martin-Belloso, 2008). The stability of

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94 quercetin in different food matrixes could be influenced by pH, temperature, metal

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95 ions, and also other compounds such as glutathione (GSH) (Boots Balk, Bast, &
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96 Haenen, 2005; Dehghan, & Khoshkam, 2012; Moon, Wang, DiCenzo, & Morris, 2008;

97 Price, Bacon, & Rhodes, 1997).

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98 However, quercetin has low water solubility and bioavailability, chemical

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99 instability and short biological half-life, which may reduce its efficacy when used in
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100 the food and pharmaceutical fileds (Cai, Fang, Dou, Yu, & Zhai, 2013). Quercetin is a

101 lipophilic compound, and it is moderately soluble in ethanol (4.0 mg/mL, 37 oC)
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102 (Priprem, Watanatorn, Sutthiparinyanont, Phachonpai, & Muchimapura, 2008), and

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103 highly soluble in dimethyl sulfoxide (150 mg/mL, 25 oC) (Ferry et al., 1996).
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104 However, its solubility in water is only approximately 0.01 mg/mL (25 oC) (Gao, Liu,

105 Wang, Liu, Xu, & Ma, 2011). It is therefore difficult to directly incorporate high

106 levels of quercetin into water-based food matrix.

107 Delivery systems are generally designed to efficiently encapsulate an appreciable

108 amount of the functional components to protect them against the chemical degradation

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109 (e.g. oxidation or degradation) during the processing and storage, and the

110 nutraceuticals incorporated can be released at a controlled rate and at particular site of

111 action or within a particular region of the gastrointestinal tract (GIT) (des Rieux,

112 Fievez, Garinot, Schneider, & Préat, 2006; McClements, Decker, Park, & Weiss, 2009;

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113 Joye & McClements, 2016). Many types of delivery systems such as polymeric

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114 nanoparticles (Ensign, Cone, & Hanes, 2012; Chang-Bravo, Lopez-Cordoba, &

115 Martino, 2014; Nayak, Tiyaboonchai, Patankar, Madhusudhan, & Souto, 2010),

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116 liposomes (Jeon, Yoo, & Park, 2015; Koudelka et al., 2015), microparticles (Soto &

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117 Ostroff, 2010; Wan, Sun, Sun, & Tan, 2012), and emulsions (McClements, 2011; Wei,
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118 Alan, & Song, 2016; Liu, Hou, Lei, Chang, & Gao, 2012) have been shown to

119 significantly enhance the therapeutic efficacy of many nutraceuticals by increasing

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120 their bioavailability. Moreover, delivery systems can also protect the bioactive
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121 compounds from being enzymatically metabolized and thermal- or light-degradation,

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122 thus, increasing its stability (Sharma, Sharma, Nam, Doss, Lee, & Chakraborty, 2015).

123 Moreover, the utilization of delivery systems has the potential to reduce side effects
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124 and control the release of bioactive compounds, which makes this approach more
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125 attractive (Grill, Johnston, Sadhukha, & Panyam, 2009; Mainardes, Urban , Cinto,
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126 Chaud, Evangelista, & Gremião, 2006). Many nutrients and bioactive agents (e.g.

127 resveratrol, luercetin, curcumin and vitamin C) have been loaded into delivery

128 systems, which improved water solubility, chemical stability and bioavailability (Chen,

129 Li, & Tang, 2015; Li, Zhao, Ma, Zhai, Li, & Lou, 2009; Matos, Gutiérrez, Coca, &

130 Pazos, 2014; Zhou et al., 2014). However, each of those delivery systems has its own

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131 weakness, such as high cost in preparation and the difficulty to scale up, and further

132 investigation is required for better application (Singh, Tiwari, & Tawaniya, 2013).

133 The objective of this article is to give an overview of recent findings regarding the

134 main biological properties and chemical stability of quercetin, as well as the different

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135 metabolic pathways. Special attention is paid to the development of delivery systems

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136 for the incorporation of quercetin to enhance its water solubility, chemical stability

137 and bioavailability.

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138 2. Chemical structures of quercetin and its derivatives

139
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Quercetin has a typical flavonoid structure and contains five hydroxyl groups. Fig.
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140 1 displays the structural characteristics of flavonoids: 2 benzene rings (A and B)
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141 connected by an oxygen-containing pyrene ring (C). Quercetin is commonly found in

142 its glycoside form, in which one or more hydroxyl group is replaced by different types
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143 of sugar groups. The main groups of quercetin derivatives are quercetin O-glycosides
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144 and some other common derivatives are summarized in Fig. 1. The molecular
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145 structure and some physicochemical properties of quercetin and its derivatives are

146 shown in Table 1. In general, all these compounds have poor solubility in water.
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147 Quercetin and its derivatives usually exist in the form of yellow colored powder or

148 crystals.

149 Quercetin O-glycosides are the derivatives with at least one O-glycosidic bond.

150 Many plants and vegetables contain quercetin O-glycosides and the most common

151 glycosylation site is located at the C-3 carbon. The associated monosaccharides may

152 include glucose, galactose and xylose. Quercetin 3-O-glucoside has been found in

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153 beans (Chang & Wong, 2004), salvia (Esmaeili & Sonboli, 2010) and buckwheat

154 (Kalinova, & Vrchotova, 2009). Quercetin 3-O-galactoside is found in lingonberry

155 (Heyman et al., 2014) and plum (Kim, Chun, Kim, Moon, & Lee, 2003), whereas

156 quercetin 3-O-xyloside is presented in mango fruit (Masibo, & He, 2008). Quercetin

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157 derivatives in the form of disaccharides are also widely existed in plants and

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158 vegetables. For example, rutin (quercetin 3-O-rhamnosylglucoside) has been founded

159 in abundance in cherries (Goncalves et al., 2004), spinaches (Kuti & Konuru, 2004),

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160 grapes (Iacopini, Baldi, Storchi, & Sebastiani, 2008) and prunes (Gallaher, & Gallaher,

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161 2009).Moreover, three, four or more saccharide groups have also been detected in
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162 quercetin 3-O-glycoside (Williams, & Grayer, 2004). Other glycosylation sites in

163 quercetin derivatives can be on the hydroxyl group at C-7 carbon and C-4 carbon. For
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164 examples, Quercetin 7-O-glucoside in beans (Chang & Wong, 2004) has the
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165 glycosylation site at C-7 carbon. The quercetin derivative with glycosylation site at
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166 C-4 carbon is only found in onion (Price, Bacon, & Rohdes, 1997).
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167 3.Biological activities of quercetin

168 In this section, a number of main biological activities for quercetin are reviewed
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169 (Table 2).

170 3.1. Antioxidant activity

171 Quercetin has been shown to be a strong antioxidant in vitro and is one of the most

172 powerful scavengers of reactive oxygen species, such as O2•− (Kukongviriyapan,

173 Sompamit, Pannangpetch, Kukongviriyapan, & Donpunha, 2012), NO•·(Luangaram,

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174 Kukongviriyapan, Pakdeechote, Kukongviriyapan, & Pannangpetch, 2007), and

ONOO− (Kim et al., 2013). Oxidative damage induced by O2 −, NO and ONOO− can
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176 create deleterious effects on cells and tissues in human body and may cause many

177 diseases such as cardiovascular diseases, diabetes and cancers (Valko et al., 2006;

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178 Waris, & Ahsan, 2006). Fortunately, peroxidation can be terminated by antioxidants,

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179 such as quercetin, which can interfer peroxidation by reacting with the radicals

180 formed (Hollman, & Katan, 1997). Its antioxidative activity is ascribed to: (a) a

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181 catechol group in the B ring; (b) a 2,3-double bond in conjugation with a 4-oxo

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182 function in the C ring; and (c) –OH group at positions 3 and 5 in heterocyclic ring
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183 (Heijnen, Haenen, Oostveen, Stalpers, & Bast, 2002; Silva, Santos, Caroço, Rocha,

184 Justino, & Mira, 2002). Moreover, quercetin could significantly enhance the
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185 endogenous antioxidant capacity of scavenging ABTS radicals by 6.2 folds compared
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186 to that of trolox, which can be ascribed to its contribution to the total antioxidant
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187 capacity of plasma (Arts, Dallinga, Voss, Haenen, & Bast, 2004).
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188 3.2. Anti-inflammatory activity

189 As noted by Rubió, Motilva & Romero (2013) and Ruma, Kumar & Prakash (2013),
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190 quercetin exhibites a strong anti-inflammatory capacity. Some researchers suggest that
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191 quercetin could suppress lipopolysaccharide (LPS)-induced cytokine production in

192 different cells. For example, quercetin can inhibit LPS-induced tumor necrosis factor

193 production in macrophages (Sah, Tirkey, Kuhad, & Chopra, 2011) and LPS-induced

194 interleukin (IL)-8 production in lung cells (Geraets, Moonen, Brauers, Wouters, Bast,

195 & Hageman, 2007). Furthermore, Bureau, Longpré & Martinoli (2008) reported that

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196 quercetin can inhibit LPS-induced mRNA levels of cytokines in colloid cells, such as

197 tumor necrosis factor (TNF)-α and IL-1α. They also found that the apoptosis of

198 neuronal cell was decreased in a microglial–neuronal coculture by the addition of

199 quercetin.

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200 The anti-inflammatory effect of quercetin is associated with its antioxidantive and

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201 free radical scavenging properties in some reports (Comalada et al., 2005; Nijveldt,

202 Van Nood, Van Hoorn, Boelens, Van Norren, & Van Leeuwen, 2001). Reactive

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203 oxygen species not only exist in the oxidation process, but are also involved in

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204 inflammatory response by activation of transfer factors such as nuclear factor-κ-gene
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205 binding (NF-κB) (MacNee, 2001). Moreover, NF-κB could induce the production of

206 TNF-α cytokines (Xu et al., 2007). Therefore, eliminating reactive oxygen species
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207 could prevent oxidation and inhibit inflammation simultaneously. Furthermore, Nair
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208 et al. (2006) interpreted that quercetin could inhibit the gene expression of TNF-α by
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209 adjustment of NF-κB in peripheral blood mononuclear cells.

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210 3.3. Anticancer activity

211 Quercetin has been proven to be a strong anticancer agent from in vitro studies in
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212 various cancer cells, e.g. U138MG, Hep-2 cells and A549 lung cancer cells, and also
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213 from in vivo tests (Dajas, 2012; Gibellini et al., 2011). Quercetin can prevent cancer

214 induced by oxidative stress due to its antioxidant activity and suppression of many

215 kinases involved in the growth of cancer cells, proliferation and metastasis (Baghel,

216 Shrivastava, Baghel, Agrawal, & Rajput, 2012; Gibellini et al., 2011). In terms of

217 human breast carcinoma cells, such as SK-Br3 and MDA-MB cells, a low dose of

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218 quercetin inhibited their proliferation (Jeong, An, Kwon, Rhee, & Lee, 2009).

219 Quercetin was also found to induce the death receptor-mediated apoptosis in ascite

220 cells of Dalton’s lymphoma-bearing rats (Li, Wang, Zhang, Xuan, Su, & Wang, 2016).

221 Moreover, quercetin restrained the activity of protein kinase C, which contributed to

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222 cancer progression (Maurya & Vinayak, 2015).

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223 3.4. Prevention of cardiovascular diseases

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224 Recently, some studies reported that regular intake of flavonoids in foods can

225 decrease the risk of coronary artery disease (Hooper et al., 2008; Wang, Ouyang, Liu,

226
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& Zhao, 2014; Yamagata, Tagami, & Yamori, 2015). Results from some studies also
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227 indicated the effect of quercetin on inhibiting cardiovascular diseases. For
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228 hypertensive patients, the intake of quercetin (730 mg/day, 4 weeks) was found to

229 reduce systolic pressure (by 7 mm Hg), diastolic pressure (by 5 mm Hg) and mean
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230 arterial pressure (by 5 mm Hg) (Edward, Lyon, Litwin, Rabovsky, Symons, & Jalili,
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231 2007). In a similar study, the systolic pressure and atherogenic LDL level were
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232 reduced for some obese subjects with metabolic syndrome symptoms after being

233 supplemented with 150 mg quercetin/day for 42 days. However, the supplementation
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234 of quercetin scarcely affects the level of TNF-α and C-reactive proteins, even though
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235 fasting plasma quercetin concentration was increased from 71 to 269 nmol/L (Egert et

236 al., 2009).

237 In order to evaluate the beneficial effect of quercetin supplementation on heart

238 disease and elucidate a potential mechanism for this protective action, some studies

239 were performed using cells and animal models. Treating macrophagocytes with

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240 quercetin could decrease the basic expression of inflammatory genes, including

241 TNF-α, IL-6, IL-8, IL-10 and epoxidase-2 (a marker of prostaglandin production)

242 (Overman, Chuang, & McIntosh, 2011). In human adipose cells, quercetin inhibited

243 the expression of inflammatory genes and reduced the secretion of IL-6, IL-8 and

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244 monocyte chemoattractant protein-1. At the same time, it suppressed the NF-κB

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245 transcriptional activity induced by TNF-α (Chuang et al., 2010). In the animal model,

246 Wistar rats were administered orally with quercetin (10 mg/kg) for one week. The

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247 results revealed that quercetin protected the rats from myocardial infarction (induced

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248 by hypodermic injection of isoprenaline) by reducing the lipid peroxidation products
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249 such as lipid hydroperoxides and conjugated dienes in heart and plasma (Prince &

250 Sathya, 2010). Cardiovascular disease of human model was also investigated.
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251 Cultured human intracutaneous cells incubated with quercetin (0.1%, w/w in diet)
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252 were testified to have a lower level of H2O2-induced lipid peroxidation and attenuated
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253 atherosclerosis by 40% in ApoE*3-Leiden mice (Kleemann et al., 2011).

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254 4. Chemical stability of quercetin: oxidation and degradation

255 Quercetin undergoes many chemical changes such as oxidation, during food
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256 processing and storage. Chemical stability of quercetin is influenced by oxygen

257 concentration, pH value, temperature, concentration of other antioxidants, as well as

258 the presence of metal ions. Table 3 summarizes the effects of heat treatment, pH and

259 storage condition on quercetin degradation.

260 Quercetin can be oxidized into various oxidation products, namely

261 quercetin-quinones, which contain one ortho-quinone and three quinon methides. The

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262 reversible change between quercetin and quercetin-quinones is illustrated in Fig. 2. A

263 cleavage of quercetin leading to protocatechuic acid is also existent.

264 Quercetin-quinones are highly reactive towards mercaptans and can immediately react

265 with GSH, which is the most abundant endogenous mercaptans (Awad et al., 2002;

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266 Pocernich, & Butterfield, 2012). Boots and co-workers (2005) reported that at a low

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267 GSH concentration, quercetin-quinone reacted with protein sulfhydryls (protein-SH)

268 to form protein-quercetin adducts namely glutathionyl-quercetin (GSQ). They also

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269 found that GSQ was not stable, and could continuously dissociate into

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270 quercetin-quinones and GSH. At a high GSH concentration, the dissociated
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271 quercetin-quinones reacted again with GSH and turned into GSQ. However, at a low

272 GSH concentration the dissociated quercetin-quinones would react with other
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273 mercaptans, e.g. protein-SH (Boots, Balk, Bast, & Haenen, 2005).
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274 The stability of quercetin is pH and temperature dependent. Quercetin is very

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275 unstable in organic solutions (e.g. acetonitrile and methanol) at pH>7 (Moon, Wang,

276 DiCenzo, & Morris, 2008; Buchner, Krumbein, Rohn, & Kroh, 2006). Buchner et al.
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277 (2006) and Moon et al. (2008) showed that degradation rate of quercetin was higher
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278 under alkaline conditions. Storage temperature also affects the stability of quercetin
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279 significantly. Atmospheric (100 oC, 50 min) or pressure boiling (121 oC, 10 min) could

280 induce a 70% losse of quercetin in Phaseolus vulgaris L. beans (Ranilla et al., 2009).

281 Conventional pasteurization treatment (80 oC, 91 s) reduced approximately 17% of

282 quercetin in grapefruit juice (Igual et al., 2011).

283 The stability of quercetin is also influenced by storage time. Storage at 4 oC in

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284 darkness for 24 weeks resulted in 100% loss of quercetin in onion (Allium cepa)

285 (Price, Bacon, & Rhodes, 1997). At 4 oC in darkness for 56 days, quercetin in

286 strawberry juice was reported to decrease by 46.1% (Odriozola-Serrano,

287 Soliva-Fortuny, & Martin-Belloso, 2008). Storage in darkness at 20 oC for 180 days

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288 induced a 40% loss of quercetin conjugate in raspberry jam (Zafrilla et al., 2001).

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289 Quercetin can react with metal ions to form quercetin-metal complexes, and metal

290 ions bound to quercetin changed the quercetin oxidation potential (Ravichandran,

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291 Rajendran, & Devapiriam, 2014). According to reports in literatures, DPPH radical

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292 scavenging activity of quercetin increased in the presence of Cu2+ (Pękal, A., Biesaga,
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293 M., & Pyrzynska, 2011) and Cr3+ (Chen, Sun, Liang, & Song, 2009). However, Sn2+

294 (Dehghan, & Khoshkam, 2012) and Cd2+ (Ravichandran, Rajendran, & Devapiriam,
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295 2014) reduced this activity of quercetin. Pękal, Biesaga & Pyrzynska (2011) reported
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296 that metal ions were more likely bound to the carbonyl oxygen and 3-OH group (in C
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297 ring) of quercetin leading to its decrease of radical scavenging activity.

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298 5. Absorption, metabolism and bioavailability

299 5.1. Absorption and metabolism

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300 The in vivo absorption, distribution, metabolism, and bioavailability of quercetin

301 have been extensively studied in animal models and in human. Schematic illustration

302 of the absorption and metabolism of quercetin is shown in Fig. 3.

303 In the mouth, quercetin released from the food can interact with salivary proteins,

304 and form soluble quercetin-protein binary aggregates (Manach, Scalbert, Morand,

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305 Rémésy, & Jiménez, 2004). However, it was reported that the absorption of quercetin

306 hardly changed despite the formation of the binary aggregates (Cai & Bennick, 2006).

307 In the stomach, quercetin is exposed to the strong acidic condition, and may be

308 degraded to phenolic acids (e.g. protocatechuic acid) by bacterial ring fission, leading

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309 to the breakdown of the skeleton structure of quercetin (Weldin, Jack, Dugaw, &

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310 Kapur, 2003). Furthermore, phenolic acids could also be absorbed in the stomach

311 (Farrell et al., 2012; Konishi, Zhao, & Shimizu, 2006).

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312 In the small intestine, there is an efficient glucuronidation of quercetin by the action

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313 of uridine diphosphate glucuronosyltransferases and extensive O-methylation of
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314 quercetin by the action of catechol-O-methyltransferase. In addition, quercetin

315 glycosides (e.g. quercetin glucosides and quercetin galactoside) can be deglycosylated
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316 to quercetin in the small intestine, which is mediated by microbiota-derived

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317 β-glucosidase (Nemeth et al., 2003). Subsequently, those quercetin and quercetin
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318 derivatives are transported by the hepatic portal vein to the liver. In the liver, quercetin

319 is further metabolized, including O-methylation, sulfation and glucuronidation

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320 (Murota & Terao, 2005; Spencer, 2003). The conjugation of quercetin with sulfate is
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321 carried out by sulfotransferases. When quercetin is O-methylated, its major product is
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322 3′-O-methylquercetin (isorhamnetin) and 4′-O-methylquercetin (tamaraxetin) to a

323 lesser extent. The resulted quercetin derivatives and the un-metabolized quercetin are

324 released into blood circulation via the portal vein of liver. Subsequently, quercetin and

325 its derivatives can be conjugated in the liver, resulting in the formation of sulfate or

326 glucuronide (Boersma et al., 2002; Shali, Curtis, Powell, & Roy, 1991). Moreover, the

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327 catechol-O-methyl transferase in the liver and kidney could also take part in further

328 methylation of quercetin and its derivatives (De Santi, Pietrabissa, Mosca, & Pacifici,

329 2002).

330 The adsorption of quercetin and its conjugates takes place in the large intestine,

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331 where colonic microorganisms can disassimilate those compounds. For example,

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332 Clostridium orbiscindens plays a key role in executing the fission of the C-ring in

333 quercetin (Aura, 2008). The metabolites formed by the colonic microorganisms are

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334 absorbed and transported via the portal vein to the liver and undergo the conjugation

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335 reactions.
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336 A recent study estimates the distribution of quercetin after the intravenous and oral

337 administration in rats. After an oral administration of quercetin to male

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338 Sprague-Dawley rats, about 93% of quercetin was metabolized in the intestine before
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339 being absorbed, whereas only 3.1% was metabolized in the liver (Chen, Yin, Zuo,
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340 Chow, 2005). The report also revealed that about 59.1% of total quercetin including

341 free and conjugated quercetin as well as its metabolites was adsorbed after an oral
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342 administration of a single dose of 10 mg quercetin/kg body weight in rats. A long-term

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343 treatment (11 weeks) of rats with quercetin fed in diet (500 mg/kg BW rat)
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344 demonstrated that quercetin and its metabolites were distributed in several organs (e.g.,

345 lung, kidney, heart and liver), with the highest level of quercetin in the lung and the

346 lowest level in the brain and spleen. It implies that the intake of quercetin from daily

347 diet can lead to the accumulation of quercetin throughout the body (de Boer et al.,

348 2005).

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349 5.2. Bioavailability

350 In human, the total plasma concentration of free and conjugated quercetin as well

351 as its metabolites was in the range of 72 and 193 nmol/L, following the short-term

352 intake of quercetin-rich foods (Petersen et al., 2016; Pfeuffer et al., 2013; Nguyen,

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353 Staubach, Wolffram, & Langguth, 2015). This result implys that a short-term

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354 treatment of quercetin could not reach the threshold plasma concentration of quercetin

355 that is effective in inhibiting cancerin cells (Dajas, 2012). However, a long-term

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356 supplement of quercetin could be a different situation. Guo et al. (2014) interpreted

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357 that a daily ingestion of 1095 mg quercetin for 3 days led to a total plasma quercetin
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358 concentration of 1430 nmol/L. Similarly, approximately 2317 nmol/L of plasma

359 quercetin concentration is detected after an oral administration of Hypericum

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360 perforatum extract for a period of 9 days (Paulke, Nöldner, Schubert-Zsilavecz, &
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361 Wurglics, 2008). When 600 mg/kg of Ginkgo biloba extract is administered orally to
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362 rats, a mean plasma quercetin concentration of 582 nmol/L is detected, whereas a
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363 repeated adminstration of the same dose resulted in a 4.6-fold increase

364 (Rangel-Ordóñez, Nöldner, Schubert-Zsilavecz, & Wurglics, 2010). A good deal of

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365 literatures showed that a repeated quercetin administration obviously increased its
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366 bioavailability (Guo et al., 2014; Paulke, Nöldner, Schubert-Zsilavecz, & Wurglics,

367 2008; Rangel-Ordóñez, Nöldner, Schubert-Zsilavecz, & Wurglics, 2010). However,

368 Bieger et al. (2008) reported that the long-term dietary intake of quercetin did not lead

369 to its plasma accumulation.

370 Following a single-dose administration of 10 mg quercetin/70 kg of body weight

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371 dissolved in three beverages, i.e. vegetable homogenate, grape juice and white wine,

372 the subsequent serum quercetin concentrations were 10.8, 25.3 and 12.7 ng/L,

373 respectively (Goldberg, Yan, & Soleas, 2003). Supplementation of the capsule

374 containing 22 mg quercetin resulted in 109 nmol/L plasma concentration of quercetin

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375 (Petersen et al., 2016). Therefore, food matrix also seems to play an important role in

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376 the bioavailability of quercetin.

377 In this context, the fact that plasma levels of quercetin can be enhanced upon a

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378 long-term supplementation is interesting. Although abundant studies both in vitro and

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379 in vivo provide the evidence that the supplementation of quercetin could prevent
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380 cardiovascular diseases and cancers, little information about the effect of quercetin on

381 the treatment of human cardiovascular diseases and cancer is available.

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382 5.3. Excretion

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383 The absorbed quercetin and its derivatives were excreted in the urine (Nishijima,
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384 Takida, Saito, Ikeda, & Iwai, 2015) or excreted into the bile and eliminated in the
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385 excrement (Shi, & Williamson, 2015). In the other case, quercetin was suffered from

386 bacterial ring fission and decomposed into phenolic acids and CO2, which was
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387 excreted through feces and breath (Abrahamse, Kloots, & van Amelsvoort, 2005; Guo,
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388 & Bruno, 2015). In human experiments following an oral administration, absorbed

389 quercetin was excreted via CO2, urine or the feces as glucuronide or sulfate

390 conjugates, and accounted for 52.1%, 4.6% and 1.9%, respectively (Walle, Walle, &

391 Halushka, 2001). Although quercetin underwent extensive metabolism and was

392 mostly recovered in the form of metabolic products, Moon, Wang, DiCenzo & Morris

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393 (2008) demonstrated that a trace level of unchanged quercetin (varied from 0.25 to 18

394 µg within 10 healthy subjects) also existed in the urine after the ingestion of 500 mg

395 Quercetin 500-Plus® capsules.

396 6. Toxic effects

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397 Many reports showed that the oxidation products such as semiquinone and quinones

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398 displayed several toxic effects, because the oxidated products could alter redox

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399 homeostasis and deplete cellular protein-SH by arylation (Russo, Spagnuolo, Tedesco,

400 Bilotto, & Russo, 2012; Metodiewa, Jaiswal, Cenas, Dickancaite, & Segura Aguilar,

401
U
1999). By reacting with free radical of human body, quercetin can form toxic
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402 oxidation products, namely quercetin-quinine which is highly reactive with thiols and
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403 GSH might be the principal reactant (Boots, Kubben, Haenen, & Bast, 2003). Boots,

404 Haenen, & Bast (2008) has proven that if the GSH concentration was high enough, it
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405 could trap quercetin-quinine as GSQ. However, at low concentration of GSH, it might
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406 be ineffective to trap quercetin-quinine which could react with other sulfhydryl
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407 compounds such as protein-SH. Once it happened, it might produce toxic effects, e.g.

408 causing cell injury by destroying the integrity of cell membrane and proteins (Wagner
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409 et al., 2010; Yen, Duh, Tsai, & Huang, 2003), or destroying the function of enzymes

410 containing sulfhydryl structure (Kalyanaraman et al., 1987). In a model system of

411 isolated mice liver nuclei, quercetin decreased the nuclear GSH content in a

412 dose-dependent manner and might lead to DNA damage (Sahu & Gray, 1996). Ramos

413 & Aller (2008) used quercetin cooperating with arsenic to induce apoptosis in human

414 leukemia cell lines (THP-1, HL-60) and found that GSH content was decreased during

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415 the process. Considering that arsenic is highly reactive towards GSH, reduction of

416 GSH may increase the free arsenic concentration, and hence resulted in DNA and

417 cellular damage.

418 There are also numerous reports about the mutagenic/genotoxic effect of quercetin.

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419 In vitro, quercetin was tested positively for mutagenic effects in bacteria (Joseph &

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420 Priya, 2011). It could also induce reverse mutations (Resende, Vilegas, Dos Santos, &

421 Varanda, 2012), and prevent DNA strand breakage (Özyurt et al., 2014). The

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422 mutagenicity of quercetin was observed in hamster ovary cell, at concentrations

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423 ranging from 0.2 µM to 1 mM (Engen et al., 2015). Quercetin induced significant
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424 frequencies of sister chromatid exchange in ovary cells compared to spontaneous

425 occurrences. However, the mutagenicity/genotoxicity effect of quercetin has not been
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426 full confirmed in vivo. Supplementation of quercetin consistently resulted in no

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427 significant change in several genotoxicity endpoints (e.g. micronuclei and

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428 chromosomal aberrations) in bone marrow cells of rats (Cierniak, Papiez, &

429 Kapiszewska, 2004). However, it is recently reported that female rats intraperitoneally
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430 supplemented with quercetin suggested a protective effect of quercetin against

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431 genotoxic damage induced by Cr (VI) (del Carmen García-Rodríguez,

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432 Nicolás-Méndez, Montaño-Rodríguez, & Altamirano-Lozano, 2014). While positive

433 results were also obtained in some in vivo mutagenicity/genotoxicity assays, following

434 up a treatment with quercetin (da Silva, 2002). Because of the discrepancy in different

435 studies, further research work is required to better understand the potential risk or

436 safety of dietary quercetin.

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437 7. Delivery systems for quercetin

438 In the past decades, most efforts have been undertaken to improve the

439 bioavailability of poorly water-soluble bioactive compounds (Cai, Fang, Dou, Yu, &

440 Zhai, 2013; Lu, Kelly, & Miao, 2016). Different delivery systems were developed to

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441 incorporate the bioactive compounds to modify the dispersed states, improve their

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442 chemical stabilities, and finally fulfill their health benefits (McClements, Decker, Park,

& Weiss, 2009). Currently available delivery systems can be classified into five types:

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443

444 (i) lipid-based carriers (Fathi, Mozafari, & Mohebbi, 2012; Yao, Xiao, & McClements,

U
445 2014), (ii) Polymer nanoparticles (Kumari, Yadav, & Yadav, 2010; Jones &
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446 McClements, 2010; Parveen, Misra, & Sahoo, 2012; Wilczewska, Niemirowicz,

Markiewicz, & Car, 2012; Lee, Yun, & Park, 2015); (iii) inclusion complexes (Joye,
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447

448 Davidov-Pardo, & McClements, 2014; McClements, 2015); (iv) micelles (Kim, Chun,
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449 Kim, Moon, & Lee, 2003; Munin & Edwards-Lévy, 2011) and (v) conjugates-based
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450 capsulations (Weiss, Takhistov, & McClements, 2006; McClements, Decker, Park, &
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451 Weiss, 2009; Kim, Park, Lee, Park, Choo, & Chong, 2010; Kim, Park, Choo, &

452 Chong, 2015). These systems exhibited individual advantages, yet disadvantages were
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453 also identified in terms of limited physical stability, low loading capacity, leakage
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454 during the storage, organic solvent residue issues, complexity of manufacturing, lack

455 of cost-effective large-scale production, difficulty in the regulatory acceptance of

456 certain constituent materials, cytotoxicity and/or unpredictable safety issues. A

457 detailed description of these carriers is provided below, a variety of carriers are shown

458 schematically in Fig. 4, and the advantages and disadvantages of different delivery

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459 systems for quercetin are presented in Table 4.

460 7.1. Lipid-based delivery systems

461 Lipid-based formulations, such as solid lipid nanoparticles (SLNs), nanostructure

lipid carriers (NLCs), nanoemulsions (NEs) and liposomes, have been applied to

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462

463 enhance the oral absorption and bioavailability of lipophilic and hydrophilic bioactive

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464 compounds (Pouton, 2000; Hauss, 2007).

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465 7.1.1 NEs

466 Emulsion-based encapsulation is one of the most promising techniques for the

467
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protection and delivery of polyphenols, particularly nano-emulsions (NEs) (Lu, Kelly,
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468 & Miao, 2016). NEs (O/W) consist of spherical lipid particles dispersed within an
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469 aqueous medium, with the particles having a core-shell structure. The hydrophobic

470 core consists of oil molecules and the nonpolar parts of emulsifiers, whereas the polar
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471 shell consists of the polar parts of the emulsifiers (Davidov-Pardo, & McClements,
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472 2014). Lipophilic bioactive components could be encapsulated within the

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473 hydrophobic core of the lipid particles in emulsions (Donsì, Sessa, Mediouni, Mgaidi,

474 & Ferrari, 2011). Compared with conventional emulsions, NEs have been reported to
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475 show better stability against particle aggregation and gravitational separation, higher

476 optical transparency, and increased bioavailability of the encapsulated components

477 (McClements, 2010; 2013). NEs were utilized to improve the bioavailability of

478 quercetin. The solubility of quercetin in NEs was increased markedly to 4.138 mg/mL,

479 compared with 0.17-7.7 µg/mL in water, and a significant absorption enhancing effect

480 of NEs was implicated (Gao et al., 2009).

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481 7.1.2 SLNs

482 SLNs are composed of lipids that are solid at ambient temperature

483 (Schäfer-Korting, Mehnert, & Korting, 2007), and usually created by preparing an

484 O/W nanoemulsion at a temperature above the melting point of the lipid phase, and

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485 then cooling it down to induce lipid crystallization (Mehnert & Mader, 2012; Joye,

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486 Davidov-Pardo, & McClements, 2014). As a type of submicron particulate drug

487 delivery system, SLNs possess the advantages of high biocompatibility, high

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488 bioavailability, controlled release and minimal problems with multiple routes of

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489 administration, such as oral, intravenous, pulmonary and transdermal administration
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490 (Mehnert & Mäder, 2001). SLNs have been applied to enhance gastrointestinal

491 absorption of quercetin by Li, Zhao, Ma, Zhai, Li, & Lou (2009) who reported that the
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492 bioavailability of quercetin-loaded SLNs was 5.71-fold greater than that of the
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493 quercetin-loaded suspension in 4% CMC-Na (sodium carboxymethyl cellulose) in rats.

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494 Bose & Michniak-Kohn (2013) developed a solvent-free solid lipid based nanosystem,

495 which was evaluated for topical delivery of quercetin, and in vitro release studies
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496 showed the biphasic release of quercetin from the SLNs formulation, with an initial
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497 burst release followed by prolonged release for up to 24 h. In spite of the distinct
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498 advantages like high encapsulation efficiency and slower degradation rate for

499 quercetin, it has to be noted that SLNs also display some shortcomings such as the

500 potential for aggregation, recrystallization risk and possibility of explusion (Fathi,

501 Mozafari, & Mohebbi, 2012).

502 7.1.3 NLCs

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503 NLCs are the second-generation lipid-based nanoparticles and composed of a

504 solid matrix entrapping variable oils in the nanocompartments as solubilizing medium

505 for lipophilic bioactive compounds (Müller, Radtke, & Wissing, 2002). Sun, Nie, Pan,

506 Zhang, Fan, & Wang (2014) synthesized biocompatible and biodegradable

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507 quercetin-nanostructured lipid carriers (quercetin-NLCs) by using the phase

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508 inversion-based process method, and found that quercetin-NLCs exhibited a good

509 thermal stability and a sustained release pattern. The study also indicated that

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510 solubility of quercetin in water was improved by at least 1000 folds and the activity to

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511 inhibit breat cancer was dramatically enhanced. In vitro and in vivo investigations
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512 performed by Tan, Liu, Guo, & Zhai, (2011) interpreted that quercetin-NLCs could

513 promote the permeation of quercetin into the cell, increase the level of quercetin
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514 retention in epidermis and dermis, and enhance anti-oxidation and anti-inflammation
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515 functions. Liu et al. (2014) formulated a novel quercetin-loaded cationic

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516 nanostructured lipid carriers consisting of desired amounts of quercetin, lipids (the

517 compound of glycerol monostearate and medium chain triglycerides) and soy lecithin,
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518 which exhibited an average particle size of 126.6 nm, a zeta potential of 40.5 mV and
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519 89.3% entrapment efficiency of quercetin with slower release in vitro during the
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520 digestion compared with those of quercetin suspended in 0.5% (w/v) sodium

521 carboxymethylcellulose aqueous solution.

522 7.1.4 Lipsomes

523 Liposomes are mainly composed of phospholipids and steroids or other

524 surfactants (Wilczewska, Niemirowicz, Markiewicz, & Car, 2012). They are

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525 biocompatible spherical vehicles with a 80-300 nm size range and can entrap

526 water-soluble, lipid-soluble, and amphiphilic materials (Landi-Librandi, Chrysostomo,

527 Caleiro Seixas Azzolini, Marzocchi-Machado, de Oliveira, & Lucisano-Valim, 2012;

528 Mignet et al., 2012). Lipsomes could improve the water solubility, reduce the toxic

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529 effects and control the release of the entrapped drugs. Moreover, Liposemes are also

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530 reported to possibly protect the encapsulated compounds from external stimuli, such

531 as light, enzymes, extreme temperature, and pH fluctuations (Xia, Hu, Jin, Zhao, &

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532 Liang, 2012). Gang et al. (2012) explored the application of

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533 polyethyleneglycol-2000-distearoyl phosphatidyl ethanolamine (PEG2000-DSPE) to
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534 prepare quercetin-loaded nanoliposomes (PEG-DSPE-Q-NLs). The results showed

535 that quercetin/PEG2000-DSPE formulation was more effective than pure quercetin in
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536 inhibiting the growth of glioma cancer cells, suggesting nanomaterials

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537 (PEG2000-DPSE) could be effective drug delivery vehicles as tumor-targeted drug

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538 carriers. According to the report of Jeon, Yoo, & Park (2015), multilayered liposomes

539 with up to 10 alternating layers were successfully developed using a layer-by-layer

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540 deposition technique. The results revealed that an increase in the number of layers
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541 resulted in a more sustained release of quercetin with improved skin permeation.
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542 7.2. Polymer nanoparticles

543 Polymer nanoparticles can be fabricated from a variety of ingredients, including

544 natural polymers such as proteins and polysaccharides, systhetic polymers like poly

545 lactide (PLA) and poly lactide co-glycolide (PLGA), and inorganic materials mainly

546 referring to the silica. The compositions of the nanoparticles have a pronounced

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547 influence on many of their functional attributes, for examples the protective properties

548 and release characteristics for bioactive components (Joye & McClements, 2013).

549 7.2.1 Natural polymers-based nanoparticles

550 7.2.1.1 Protein-based nanoparticles

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551 Proteins, of both plant and animal origins, are often used to prepare nanoparticles,

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552 due to their easy digestion within the human GIT (Joye & McClements, 2014). Fang,

553 Hao, Wu, Li, Leng, & Jing (2011) developed a nanoparticle using bovine serum

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554 albumin (BSA) as a matrix to encapsulate quercetin, and found that BSA

U
555 nanoparticles could maintain the bioactive properties of quercetin under both acidic
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556 and neutral conditions for a long period. Patel, Heussen, Hazekamp, Drost, & Velikov

557 (2012) developed quercetin-loaded zein nanoparticles with the average particle size
M

558 below 200 nm and they found that chemical stability of quercetin entrapped in the
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559 colloidal particles was improved under the alkaline condition and exposition to
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560 UV-light irradiation.

561 7.2.1.2 Polysaccharide-based nanoparticles

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562 Polysaccharides, same as proteins, are commonly applied to fabricate biopolymer

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563 particles. There are three major gelation mechanisms for polysaccharides, i.e.
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564 ionotropic, cold- and heat-set gelation (Burey, Bhandari, Howes & Gidley, 2008). He,

565 Kim, Lee, & Lee (2013) prepared quercetin-loaded linoleic acid (LA) modified

566 chitosan oligosaccharide/β-lactoglobulin (CSO-LA/β-lg) nanoparticles and suggested

567 that the encapsulation efficiency of quercetin was enhanced with increased charged

568 amount of LA. In comparison with pure quercetin solution, the quercetin-loaded

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569 lecithin-chitosan nanoparticles showed a higher cell permeation ability, and

570 significantly increased the accumulation of quercetin in the skin, especially in the

571 epidermis (Zhang, Yang, Tang, Hu, & Zou, 2008). Water solubility of quercetin was

572 also improved when it was entrapped in polymeric microparticulates formed by

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573 sodium alginate and chitosan through an ionic cross-linking method, as the embedded

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574 quercetin was present in the amorphous form instead of its original crystalline one.

575 The authors claimed that quercetin molecules were encapsulated or dispersed into the

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576 chitosan-alginate polymers during the ionic cross linking, and it was included in an

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577 amorphous complex with intermolecular interactions within the matrix (Xing, Zhang,
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578 & Tan, 2007; Hazra, Mandal, Mandal, Bhuniya, & Ghosh, 2015).

579 7.2.2 Synthetic polymer-based nanoparticles

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580 Being a FDA-approved biocompatible polymer, poly (lactic-co-glycolic acid)

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581 (PLGA) has been widely explored in different drug delivery applications. Jain, Thanki,
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582 & Jain (2013) prepared the orally administrable PLGA nanoparticles (NPs)

583 encapsulating quercetin, and confirmed that the free radical scavenging ability of
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584 quercetin was retained in freeze-dried NPs. Poly (caprolactone, PCL) nanoparticles
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585 formed by nano-precipitation method was able to improve the bioavailability of

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586 quercetin probably because of the submicron size of nanoparticles and the controlled

587 release of quercetin from the particles (Kumar, Verma, & Singh, 2015). Pandey, Patel,

588 Thakur, Mishra, Maiti, & Haldar (2015) utilized the emulsified nanoprecipitation

589 technique to synthesize quercetin embedded poly (lactic acid) (PLA) nanoparticles

590 (PLA-quercetin), and they found delayed diffusion and stronger interaction between

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591 PLA and quercetin resulted in the sustained delivery of quercetin from the polymer

592 matrix. Quercetin could react with glycerol diglycidyl ether (GDE) to form poly

593 (quercetin) particles (p(quercetin)) via a microemulsion polymerization/crosslinking

594 method. The formed p(quercetin) particles were more thermally stable in comparison

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595 to pure quercetin and the particles were found to have significant antioxidant capacity

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596 equal to that of 82.5 mg/L gallic acid (Sahiner, 2014).

597 7.2.3 Inorganic material-based nanoparticles

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598 Quercetin-loaded silica nanoparticles modified by cetyltrimethylammonium

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599 bromide prohibited quercetin degradation and decreased its cytotoxicity (Nday,
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600 Halevas, Jackson, & Salifoglou, 2015). Sapino et al. (2015) evaluated the potential of

601 aminopropyl functionalized mesoporous silica nanoparticles (NH2-MSN) as a topical

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602 carrier system for quercetin. They found that the complex with NH2-MSN at a
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603 concentration of 60 µM was more effective than quercetin alone and the cell
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604 proliferation was reduced to a 50% level. Kumar et al. (2014) confirmed that the

605 quercetin conjugated Fe3O4 nanoparticle was a promising anticancer agent for targeted
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606 drug delivery.

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607 7.3. Inclusion complex

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608 A great number of studies have shown that flavonoids and carotenoids can form

609 inclusion complexes with cyclodextrins (CD). CD has a truncated cone structure and

610 relatively hydrophobic internal cavity and hydrophilic external faces, which could

611 facilitate the formation of non-covalent inclusion complexes with different foreign

612 compounds (guest). The complexes were reported to improve stability, solubility

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613 and/or dissolution rate and ultimately the bioavailability of many bioactive

614 compounds (Borghetti, Lula, Sinisterra, & Bassani, 2009; Tsao et al., 2012). Jullian,

615 Moyano, Yanez, & Olea-Azar (2007) investigated the complexation of quercetin with

616 three types of cyclodextrins, i.e. β-cyclodextrin (β-CD),

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617 hydroxypropyl-β-cyclodextrin (HP-βCD) and sulfobutyl ether-β-cyclodextrin

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618 (SBE-βCD) .The results indicated that all complexes showed a higher scavenging

619 capability than that of quercetin in water, and quercetin-SBE-βCD complex was the

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620 most reactive form. Aytac, Kusku, Durgun, & Uyar (2016) found that the inclusion

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621 complex of β-CD and quercetin formed at the ratio of 1:1 exhibited its higher weight
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622 loading with a much lower release, and also improved its solubility, antioxidant

623 activity and photostability properties. Kale, Saraf, Juvekar, & Tayade (2006) reported
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624 a quercetin-CD inclusion complex using a kneading and co-evaporation method, with
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625 which quercetin showed enhanced aqueous solubility (90-120 µg/mL) and dissolution
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626 rate, and the complex exhibited significantly higher anti-cancer activity in vivo with a

627 much lower dose.

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628 7.4. Micelles

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629 Micelles are based on the colloidal assemblies of amphiphilic molecules, which

630 can form micelles with a size of 100 nm or smaller (Trautwein, Duchateau, Lin,

631 Mel'nikov, Molhuizen, & Ntanios, 2003). Micellar systems have significant

632 advantages as effective delivery systems, for example, they have very small particle

633 size, and usually thermodynamically stable (Boyd, 2008). Therefore, micelles were

634 well investigated for the solubilization, encapsulation efficiency, loading capacity and

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635 targeted delivery of hydrophobic drugs (Oerlemans, Bult, Bos, Storm, Nijsen, &

636 Hennink, 2010). Zhao, Shi, Zou, Sun, Li, & Zhai, (2011) developed quercetin-loaded

637 mixed micelles as delivery systems for quercetin, which were composed of Pluronic P

638 123 and D-α-tocopheryl polyethyleneglycol succinate (TPGS) at the ratio of 7:3. Zhou

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639 & Wang (2015) studied the interactions between quercetin and sodium cholate (NaC),

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640 and confirmed that quercetin could strongly bind with NaC aggregates through

641 hydrophobic forces. The binding constant of quercetin with NaC secondary micelles

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642 was found to be higher than that with NaC primary ones, which obviously enhanced

U
643 the radical scavenging ability of quercetin.
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644 7.5. Conjugates-based delivery carriers
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645 Polyphenol can be incorporated into the backbone of the polymer matrix, which

646 allowed a slow release of the guest polyphenol (Wattamwar et al., 2012). A
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647 single-phase reaction-precipitation method was developed to formulate quercetin

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648 conjugated poly (β-amino esters) nanogels, which had a quercetin loading of 25-38
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649 wt%. Quercetin in the conjugate presented a consistent release over 45-48 h, and its

650 antioxidant activity was retained over the extended period (Gupta, Authimoolam, Hilt,
C
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651 & Dziubla, 2015). Du, Liu, Yang, & Zhai (2015) developed GA (glycyrrhetinic acid)

652 -CMCA (O-carboxymethylated chitosan+ cholic acid) conjugates for the delivery of

653 quercetin, and they testified that quercetin-GA-CMCA carrier could alter the in vitro

654 release pattern of quercetin, enhance cell apoptosis rate and prolong quercetin

655 circulation time in rats. The bioactivity of quercetin could be improved when it was

656 conjugated with a hydrolysable pivaloxymethyl (POM) group. Quercetin-POM

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657 conjugate could enhance the multidrug resistance modulating effect of quercetin (Kim,

658 Park, Choo, & Chong, 2015).

659 7.6. Other types of delivery systems

It was reported that hydrogels and hyper-branched polymers could be used to

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660

661 improve the solubility of quercetin (Althans, Schrader, & Enders, 2014).

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662 Quercetin-loaded maltodextrin films were also confirmed to be able to enhance the

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663 oral bioavailability of quercetin (Lai et al., 2015). Quercetin nanocapsules, formed by

664 emulsion-diffusion-evaporation method, were demonstrated to notably reduce

665
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arsenic-induced oxidative damage in liver and brain tissues than unformulated free
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666 quercetin (Ghosh, Mandal, Sarkar, Panda, & Das, 2009). In another study, the
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667 anti-tumorigenic activity of quercetin was significantly enhanced when encapsulated

668 in lecithin-based cationic nanocarrier (Leciplex). The growth of mice (C57BL/6)

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669 tumor from subcutaneously injected B16F10 melanoma cells was more effectively
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670 suppressed by quercetin leciplex than that by quercetin suspension since the least
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671 tumor volumes were observed in all measurements (Date et al., 2011). Guazelli et al.

672 (2013) compared the efficacy of microencapsulated quercetin with its suspension, and
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673 found that the microencapsulated quercetin reduced the oxidative damage, and

674 prevented the inflammatory progress and microscopic damage score in the mice

675 model.

676 8. Conclusions and future trends

677 Quercetin is widely present in the human’s daily diet. Therefore, it is important to

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678 clearly understand the effects of quercetin on human health. From studies performed

679 so far, it has been proven that quercetin is an excellent antioxidant, and it has

680 anti-inflammatory, anti-cancer and anti-cardiovascular disease effects. Interestingly,

681 the anti-inflammatory effect of quercetin seems to be linked with its antioxidant

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682 activity. This indicates that the supplementation of quercetin might become a potential

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683 alternative to the treatments of diseases induced by inflammation and oxidative stress,

684 e.g. sarcoidosis.

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685 Oxidation was reported as the main cause of changes in quercetin during food

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686 production and storage. Avoiding high oxygen exposure, high temperature and
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687 alkaline conditions during processing and storage is important to minimize the

688 degradation of quercetin. Toxicity problems of quercetin arise particularly in the case
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689 of the formation of oxidation products namely quercetin-quinone, which has high
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690 reactivity with sulfydryl. Thereofore, it could influence the function of several critical
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691 enzymes in human body (e.g. coenzyme A) in the human metabolic process. As a

692 result, quercetin supplementation should be taken with caution because of its potential
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693 toxicity. In addition, the biological activities, stability and potential toxicity of
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694 quercetin are largely dependent on its transformation during the absorption and
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695 metabolism in GIT, which includes O-methylation, sulfation and glucuronidation.

696 In order to improve water solubility, chemical stability and bioavailability of

697 quercetin, different types of delivery systems were introduced in this review,

698 including lipid-based carriers, polymer nanoparticles, inclusion complexes, micelles

699 and conjugates-based delivery systems. Each delivery system has its own advantages

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700 and shortcomings, and the specific selection should be based on the application fields.

701 On the basis of the current review, the future development of novel delivery systems

702 for quercetin should focus on the following three aspects: (i) development of natural

703 food-grade ingredients as the main compositions of delivery systems for quercetin to

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704 obtain a higher encapsulation and retention efficiencies; (ii) the investigation into

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705 interactions between food matrix and encapsulated quercetin; (iii) the potential

706 application of co-encapsulation, where two or more bioactive ingredients may be

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707 combined to generate a synergistic effect.

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708 Acknowledgements
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709 We gratefully appreciate for financial support of this work by the National

710 Natural Science Foundation of China under Grant No.31371835. We also thank
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711 McClements for the contribution to the manuscript since Figure 2 is derived from his
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712 previous report.

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713 A List of Abbreviations

714 BSA: bovine serum albumin

715 CA: cholic acid

716 CD: cyclodextrins

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717 CMCA: O-carboxymethylated chitosan (OCMC) hydrophobically modified with

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718 cholic acid (CA)

719 CMC-Na: sodium carboxymethyl cellulose

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720 CSO-LA/β-lg: chitosan oligosaccharide/β-lactoglobulin:

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721 GA: glycyrrhetinic acid
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722 GIT: gastrointestinal tract

723 GSH: glutathione

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724 GSQ: qlutathionyl-quercetin:

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725 HP-βCD: hydroxypropyl-β-cyclodextrin:

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726 IL: interleukin

727 LA: linoleic acid

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728 LPS: lipopolysaccharide

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729 NaC: sodium cholate

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730 NEs: nanoemulsions

731 NH2-MSN: aminopropyl functionalized mesoporous silica nanoparticles:

732 NLCs: nanostructure lipid carriers

733 NPs: nanoparticles

734 NF-κB: nuclear factor-κ-gene binding

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735 OCMC: O-carboxymethylated chitosan

736 PCL: poly (caprolactone)

737 PEG2000-DSPE: polyethyleneglycol-2000-distearoyl phosphatidyl ethanolamine

738 PEG-DSPE-quercetin-NLs: quercetin-loaded nanoliposomes composed of

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739 polyethyleneglycol-2000-distearoyl phosphatidyl ethanolamine

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740 PLA: poly lactide

741 PLGA: poly lactide co-glycolide

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742 POM: pivaloxymethyl

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743 SBE-βCD: sulfobutyl ether-β-cyclodextrin
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744 SLNs: solid lipid nanoparticles

745 TPGS: D-α-tocopheryl polyethyleneglycol succinate

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746 TNF: tumor necrosis factor

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747 βCD: β-cyclodextrin

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748
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1358 Journal of Pharmacology, 43, 192.

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1395 Journal of Nutrition, 133, 3255-3261.
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1469 (Rubus idaeus) jams. Journal of Agricultural and Food Chemistry, 49,
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D

1487 stability and skin permeation of vitamin C liposomes improved by pectin coating.
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1488 Colloids and Surfaces B: Biointerfaces, 117, 330-337.

C EP
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Table 1 Summary of physicochemical properties of quercetin and its derivatives

Chemical Molecular Melting logP Water Physical UV-Vis Reported biological References

PT
structure weight point solubility state max(nm) activities
(℃) (mg/ml)

RI
OH 302.23 314-316 1.48 0.001 Yellow 258, 360 Antioxidant, Polychniatou
OH powder anti-inflammation, & Tzia, 2016;

SC
antiviral, anti-obesity, Lemańska et
HO O
antidepressant as well al., 2004;
as preventing cancer, D'Andrea,

U
OH
diabetes, asthma, 2015; Nabavi

AN
OH O
hypertension and et al., 2015;
Quercetin cardiovascular
Gao et al.,
diseases

M
2011
OH 448.38 174-179 0.90 0.024 Yellow 256, 346 Antioxidant, Peng et al.,,

D
OH powder anti-inflammation, 2003;Gonzales
anticancer as well as et al., 2015;

TE
HO O
inhibiting lipid Wattenberg et
O peroxidation al., 1968;
EP
OH O OH Shimoi, et al.,
O
2003;
C

OH Uppugundla et
OH al., 2009;
AC

Quercetin 3-O-rhamnoside Cincin et al.,

(quercitrin) 2014
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OH 464.38 188-189 0.83 0.095 Yellow 257, 362 Antioxidant, Kwon et al.,
OH powder anti-inflammatory, 201;Valentová

PT
antihypertensive, as et al.,
HO O
well as 2014;Gonzales

RI
cytoprotection; et al., 2015;
O
Inhibiting Ohguchi et al.,
OH O OH

SC
O melanogenesis and 2010;
Ca2+-induced lipid
OH peroxidation

U
OH OH

AN
Quercetin-3-O- glucoside
(isoquercitrin)
464.38 227-230 0.43 NA Yellow 256, 358 Antioxidant, Ola et al.,

M
OH
OH powder antimicrobial 2009;
OH anti-inflammation, as Khanavi, et

D
well as preventing al., 2013;

TE
HO O hypertension and Li et al., 2013;
cardiovascular Sujatha, &
diseases Kantida, 2012
EP
O
OH O OH
O
C

OH
AC

OH OH
Quercetin 3-O-galactoside
(Hyperoside)
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OH 610.52 190-192 -2.02 0.034 Faint 256, 351 Antioxidant, Calabro et al.,
yellow anticancer, 2005;

PT
HO O
OH powder anti-inflammation, Diniz et al.,
cardioprotection 2008;
O

RI
as well as Nassiri-Asl et
OH O OH
O anticonvulsive al., 208;

SC
O Hu et al., 2012
O
OH

OH

U
HO OH

AN
OH
Quercetin
3-O-rhamnozyl-(1→6)-glucoside

M
(rutin)
OH 316.26 305-307 2.79 0.037 Yellow 255, 356 Antioxidant, Hughey et al.,

D
crystal anti-tumor as well as 2012; Zhao et

TE
HO O preventing endothelial al., 2013;
O dysfunction, Igarashi et al.,
hypertension and 1995:
EP
OH
cardiovascular Ibarra et al.,
OH O diseases 2003
C

Quercetin 3’- methyl ether

AC

(isohramnetin)
NA: Not available
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Table 2 Main biological activities of quercetin.

Biological Study model Method Effective or tested Results References

PT
activities concentration of

RI
quercetin
Antioxidative ICR rats O2•− production was determined by 50 mg/kg and100 Quercetin (100mg/kg) reduced Kukongviri

SC
lucigenin-enhanced mg/kg the production rate of O2•− by yapan et al.,
chemiluminescence method 50% 2012

U
Sprague–Dawley rats Accumulation of NO2 and NO3 were 25 mg/kg and 50 Quercetin at doses of 25 mg/kg Luangarame

AN
measured mg/kg and 50 mg/kg suppressed plasma t al., 2007
NOx concentration 50.4 % and

M
45.5 %, respectively
−
Zymosan-induced Amounts of ONOO were measured 1, 3, 10 and Quercetin exhibited inhibitory Kim et al.,

D
murine macrophages as relative fluorescence units with 30µM activity on ONOO− with IC50= 2013

TE
emission at 530 nm and excitation at 8.6 µM
485 nm
EP
Zymosan-induced UV spectrophotometry: measured at 3, 10, 30 and 100 Quercetin exhibited inhibitory Kim et al.,
murine macrophages 517 nm using microplate reader µM activity on DPPH• with IC50= 2013
C

27.6 µM
AC

Anti-inflammat A549 lung epithelial IL-8 was measured using ELISA kits 10 µM Quercetin significantly reduced Geraets et
ory cells (CLB/Sanquin) IL-8 production al., 2007
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Macrophages of Cytokines were measured from brain 2 and 25 mg/kg Quercetin significantly Sah et al.,
Wistar albino rat lung homogenate using commercially decreased IL-6 and TNF-α levels 2011

PT
tissue available ELISAs for rat IL-1β, but no significant decrease was
TNF-α, and IL-6 observed in levels of IL-1β

RI
PC12 cells PCR products were analyzed by 0.1 µM Quercetin significantly Bureau et

SC
electrophoresis reduced LPS-induced IL-1α and al., 2008
TNFα gene expression;

U
Quercetin prevented the
apoptosis of neuronal cells

AN
caused by microglia activation
Peripheral blood TNF-α and NF-κB gene expressions 1, 5, 10, 25, and Quercetin inhibited the Nair et al.,

M
mononuclear cells were quantitated using real-time PCR 50 µM proinflammatory cytokine 2006

D
TNF-α via modulation of

TE
EP NF-κB

Anticancer Human breast Cell proliferation was assayed by cell 5 and 10 µM A low dose of quercetin inhibit Jeong et al.,
carcinoma SK-Br3, counts using a hemocytometer or Z1 proliferation of cancer cell and 2009
C

MDA-MB-453, and Coulter Counter this inhibition resulted from cell

MDA-MB-231 cycle arrest at the G1 phase
AC

Ascite cells of Total protein kinase C activity was 25, 50 and 75 Activity of protein kinase C Maurya &
Dalton’s measured using a PepTag mg/kg was downregulated after Vinayak,
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lymphoma-bearing non-radioactive assay kit quercetin treatment 2015

rats

PT
RI
Hypertensive patients Blood pressure was obtained by a 730 mg/day for 4 Quercetin was found to reduce 7 Edward et
Prevention of

SC
trained observer using an Omron weeks mm Hg systolic pressure, 5 mm al., 2007
random zero automatic blood pressure Hg diastolic pressure and 5 mm
cardiovascular

U
analyzer Hg mean arterial pressures
diseases

AN
M
Obese and Blood pressure measurements were 150 mg/day for Quercetin decreased systolic Egert et al.,
hypertensive subjects obtained with a standard manual 42 days blood pressure by 2·9 mmHg 2009

D
sphygmomanometer under

TE
standardized conditions;
LDL-cholesterol was measured using
EP
the Konelab 20i analyser with the
manufacturer’s assay kits
C

Wistar rats Not shown in detail 10 mg/kg for one Quercetin decreased the levels of Prince &
AC

week lipid peroxidation products in Sathya,

plasma and adtevak 2010
Human H2O2-induced lipid peroxidation was 0.1%, w/w in diet Quercetin protected against Kleemann et
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intracutaneous cells assessed with a fluorescence assay H2O2-induced lipid peroxidation al., 2011
and ApoE*3-Leiden using fluorophore C11-BODIPY581/591; in human intracutaneous cells, as

PT
mice Atherosclerosis was analyzed blindly well as significantly attenuated
in 4 cross-sections from each atherosclerosis by 40% in

RI
specimen ApoE*3-Leiden mice

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AN
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AC
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Table 3 Effects of heat treatment, pH and storage condition on quercetin content.

PT
Food processing Food product Processing condition Results References
o
Thermal Bean（Phaseolus Atmospheric (100 C) and pressure 70% degradation of quercetin Ranilla et al.,

RI
vulgaris L.） boiling 2009

SC
(121 oC) with and without soaking
Onion bulbs Atmospheric boiling (100 oC) for 60 min 43.2% degradation of quercetin Makris & Rossiter,

U
2001

AN
Solutions Heating at 97 oC for 240 min under pH 8 The presence of oxygen caused 100% Makris & Rossiter,
degradation of quercetin, while the 2000

M
degradation without oxygen was only
15%

D
Grapefruit juices Conventional thermal pasteurization 17% degradation of quercetin Igual et al., 2011

TE
o
heating at 80 C for 91 s
EP
Alkali or acid Solutions Treatment with different pH values (pH=5 Complete degradation of quercetin after Buchner et al., 2006
and 8) with air or nitrogen perfusion for 180 min at pH 8;
C

300 min The presence of oxygen accelerated the

AC

degradation of quercetin
Solutions Treatment with different pH values Complete degradation of quercetin after Moon et al., 2008
(pH=2.7, 7 and 10) for 96 h 120 min at pH 10
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Storage Onions (Allium cepa) Long-term storage (168 days, 20 oC) 100% degradation of quercetin Price et al., 1997

PT
Strawberry juice Storage in darkness (56 days, 4 oC) 46.1% degradation of quercetin Odriozola-Serrano
et al., 2008

RI
o
Raspberry jams Storage (180 days, 20 C) 40% degradation of quercetin Zafrilla et al., 2001

SC
3-glycoside

U
Metal ions Solutions Quercetin and CuCl2 solutions mixed in Increase the antioxidant activity Pękal et al., 2011
three ratios (0.5, 1 and 2)

AN
Solutions In the presence of Cr3+ Increase DPPH radical scavenging Chen et al., 2009
activity

M
2+
Solutions In the presence of Sn Reduced DPPH radical scavenging Dehghan &

D
activity Khoshkam 2012

TE
C EP
AC
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Table 4 Advantages and disadvantages of different delivery systems for enhancing bioavailability of quercetin
Delivery systems Advantages Disadvantages References

PT
Solid lipid Good tolerability an biodegradability Potential for aggregation Muller et al., 1997; Yang et al.,1999;

RI
nanoparticles High encapsulation efficiency Recrystallization risk Cavalli et al., 2002
(SLNs) Targetability Low encapsulation loading

SC
Nanostructure Smaller particle sizes than SLNs Slightly faster release in Fang, Fang, Liu, & Su, 2008; Zhuang,

U
lipid carriers High encapsulation loading comparison to SLNs et al., 2010; Fryd & Mason, 2012;

AN
(NLCs) High stability Ezhilarasi, Karthik, Chhanwal, &
Anandharamakrishnan, 2012
Nanoemulsions Stable system to gravitational Rapid release Gregoriadis, 2006; Takahashi et al.,

M
(NEs) separation and aggregation Low stability in gastric condition 2007

D
Small droplet size and higher liquid
droplet interface area

TE
High encapsulation efficiency
Targetability
EP
Lipsomes Carriers for both lipophilic and Low stability at acidic pH Fathi, Mozafari, & Mohebbi, 2012;
hydrophilic molecules High cost of raw materials Hauss, 2007
C

Targetability
AC

Biopolymer-partic Preparing from natural ingredients Poor stability against aggregation Sahoo & Labhasetwar,2003; Parveen &
-les Small size (10-1000 nm) and gravitational separation Sahoo, 2008; Dutta & Green, 2008
Effective penetration ability
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Prolonged release
Targetability

PT
Inclusion Thermo-oxidative stability Potential for disruption Kalogeropoulos et al. 2010;
complexes Strong photo-protectors Not stable in the presence of López-García, López, Maya, &

RI
Controlled release competitive compounds and in Fernández-Bolaños, 2010
polar solvents

SC
Micelles Small size (typically ＜10 nm) Limited solubilisation capacity Torchillin, 2007; Boyd, 2008; Sahu,
Thermodynamic stability High amount of surfactants or Kasoju, & Bora, 2008

U
Colloidal stability surface active agents

AN
Undesirable taste to the
formulation

M
Conjugates-based No surfactant Complex preparation methods Kim, Park, Choo, & Chong, 2015;
carriers High loading capacity Being sensitive to pH Gupta, et al., 2015

D
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AC
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Figure captions:

Fig. 1 Chemical structures of quercetin and its main derivatives.

Fig. 2 Oxidation and degradation pathways of quercetin (adapted from Boots et al.,

2003).

PT
Fig.3 Schematic illustration of the metabolism and absorption of quercetin. Q

RI
represents quercetin.

Fig. 4. Schematic representation of the different kinds of colloidal delivery systems.

SC
(adapted from McClements, 2010).

U
AN
M
D
TE
C EP
AC
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R4
3' R3
4'
1' B
R5 O 2 5'
7 R2
A C
3
R6 5 R1

PT
R7 O

Systematic name R1 R2 R3 R4 R5 R6 R7

RI
Quercetin OH OH OH H OH H OH
Quercetin 3-O-rhamnoside O-Rha OH OH H OH H OH

SC
(quercitrin)
Quercetin 3-O-rhamnozyl-(1→ O-RG OH OH H OH H OH
6)-glucoside (rutin)
Quercetin 3-O-glucoside O-Glu OH OH H OH H OH

U
(isoquercitrin)
AN
Quercetin 3-O-galactoside O-Gal OH OH H OH H OH
(Hyperoside)
Quercetin 7-O-glucoside OH OH OH H OH H O-Glu
M

Quercetin O-Rha OH OH O-Glu OH H OH

3-O-rhamnoside-7-O-glucoside
Quercetin 6-C- glucoside OH OH OH H OH Glu OH
D

Quercetin 3’- methyl ether OH O-Met OH H OH H OH

(isohramnetin)
TE

Quercetin 7- methyl ether OH OH OH H OH H O-Met

(rhamnetin)
Quercetin 4’- methyl ether OH OH O-Met H OH H OH
EP

(tamarixetin)
Gal: galactose; Glu: glucose; Rha: rhamnose; RG: rhamnosyl glucose; Met: methyl
C

Fig. 1 Chemical structures of quercetin and its main derivatives.

AC
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AN
Fig. 2 Oxidation and degradation pathways of quercetin (adapted from Boots et al.,
2003)
M
D
TE
C EP
AC
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PT
RI
U SC
AN
Fig.3 Schematic illustration of the metabolism and absorption of quercetin. Q
M

represents quercetin
D
TE
C EP
AC
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PT
RI
U SC
AN
M
D
TE

Fig. 4. Schematic representation of the different kinds of colloidal delivery systems.

EP

(adapted from McClements, 2010).

C
AC
 ACCEPTED MANUSCRIPT

Highlights

1. Biological properties, metabolic pathway, chemical stability and delivery systems of

quercetin are reviewed.

2. Delivery systems greatly improve stability and bioavailability of quercetin.

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3. The potential applications of these delivery systems as food antioxidants are discussed.

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