Food Hydrocolloids 43 (2015) 153e164

Contents lists available at ScienceDirect

Food Hydrocolloids
journal homepage: www.elsevier.com/locate/foodhyd

Review

A review: Using nanoparticles to enhance absorption and

bioavailability of phenolic phytochemicals
Zheng Li a, b, *, Hong Jiang c, Changmou Xu a, Liwei Gu a
a
Food Science and Human Nutrition Department, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL, 32611, United States
b
Huangshan Kehong Bio-avors CO., Ltd, Huangshan, Anhui, 245200, China
c
Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, 40202, United States

a r t i c l e i n f o a b s t r a c t

Article history: Phenolic phytochemicals have been of particular interests in food and pharmaceutical elds because they
Received 1 April 2014 have potential to reduce the incidences of coronary heart disease, diabetes, cancers, and other chronic
Accepted 10 May 2014 diseases. However, extremely low absorption rate of phenolic phytochemicals restricts their bioactivity
Available online 21 May 2014
in vivo. Such low absorption and bioavailability are due to their low water solubility, poor stability, passive
diffusion, and active efux in the gastrointestinal tract. Nanoparticle delivery system has been widely
Keywords:
applied in pharmaceutical eld to enhance absorption of bioactive compounds. This review explains ab-
Phenolic phytochemicals
sorption barriers of phenolic phytochemicals in the gastrointestinal tract. Nanoparticles delivery systems
Nanoparticles
Absorption
are emphasized regarding fabrication methods and their potential benets on phenolic phytochemical
Bioavailability absorption. Particularly, absorption mechanisms of nanoparticles by epithelial cells and biodistribution of
Endocytosis nanoparticles after absorption are mainly discussed. Moreover, the potential challenges of nanoparticles as
delivery system for phenolic phytochemicals in the gastrointestinal tract are also discussed.
2014 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
2. Phenolic phytochemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
2.1. Health benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
2.2. Low absorption rate of phenolic phytochemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
2.2.1. Low solubility and poor stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
2.2.2. Low permeation due to passive diffusion and active efflux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
3. Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
3.1. Nanoparticle fabrication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
3.2. Measurement technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
3.3. Nanoparticle system for delivery of phenolic phytochemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
3.3.1. Nanoparticles enhance solubility of low-water-soluble phenolic phytochemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
3.3.2. Nanoparticles prevent phenolic phytochemicals against degradation in the gastrointestinal tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
3.3.3. Nanoparticles enhance absorption of phenolic phytochemicals in epithelial cells via endocytotic cellular uptake . . . . . . . . . . . . . . . . 158
3.4. Potential challenges of nanoparticle application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
3.4.1. Effects of pH, ions, and enzymes in the gastrointestinal tract on stability of nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
3.4.2. Effect of mucus layer on stability of nanoparticles dispersion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

* Corresponding author. Food Science and Human Nutrition Department, Insti-

tute of Food and Agricultural Sciences, University of Florida, Gainesville, FL, 32611,
United States. Tel.: 1 352 392 1991x285.
E-mail address: jameslee0221@u.edu (Z. Li).

http://dx.doi.org/10.1016/j.foodhyd.2014.05.010
0268-005X/ 2014 Elsevier Ltd. All rights reserved.
154 Z. Li et al. / Food Hydrocolloids 43 (2015) 153e164
1. Introduction
Phenolic phytochemicals are widely present in plant kingdom
and easily extracted from vegetables and fruits (Ka hko nen et al.,
1999). They are formed in plant as secondary metabolites to show
multiple functions for plant growth, development, and defense.
Phenolic phytochemicals are main components that contribute to
avor and color to plant (Asen, Stewart, & Norris, 1972; Castan ~ eda-
Ovando, Pacheco-Herna ndez, P aez-Herna ndez, Rodrguez, &
Galan-Vidal, 2009; Jackman, Yada, Tung, & Speers, 1987). They are
particularly accumulated in response to different growth stages,
environmental changes to behave as signaling molecules to regu-
late physical function of plants (Lynn & Chang, 1990; Xu, Zhang,
Zhu, Huang, & Lu, 2011). Phenolic phytochemicals also protect
plant against insects, fungi, bacteria, and viruses (Farkas & Kiraaly,
1962). Both epidemiologic and experimental studies have
conrmed that consumption of phenolic phytochemical-rich foods
was positively correlated to healthy benets for human body (Cai,
Luo, Sun, & Corke, 2004; Frankel, German, Kinsella, Parks, &
Kanner, 1993; Labrecque et al., 2005; Rice-Evans, Miller, &
Paganga, 1997). Thus, phenolic phytochemicals have been signi-
cantly attracted in food, nutritional, and pharmaceutical sciences.
However, phenolic phytochemicals can be absorbed in human body
with extremely low absorption rate (Appeldoorn, Vincken,
Gruppen, & Hollman, 2009; Hollman & Katan, 1997; Kanaze,
Bounartzi, Georgarakis, & Niopas, 2006).
Nanoparticle delivery system is a system in which nanocarriers
are used to encapsulate bioactive compounds and deliver these
compounds to either enhance their absorption in the gastrointes-
tinal tract by active endocytosis or improve bioactivity in body
circulation by specic targeting (Mller, Ma der, & Gohla, 2000; des
Rieux, Fievez, Garinot, Schneider, & Pre at, 2006). In the present
review, phenolic phytochemicals are introduced in terms of health
benets and barriers that contribute to their low absorption.
Nanoparticles as delivery system for phenolic phytochemicals is
further emphasized regarding fabrication methods, measurement
instruments, and unique properties to enhance phenolic phyto-
chemical absorption and bioavailability in the gastrointestinal tract.
Fig. 1. The basic structure of phenolic phytochemicals. (A) Flavonoids; (B) Phenolic acid; (C) Hydroxycinammates; (D) Stilbenes.
Moreover, potential challenges for nanoparticles in the gastroin-
testinal tract are also discussed in the review.
2. Phenolic phytochemicals
Phenolic phytochemicals represent a variety of compounds that
are the largest category of phytochemicals and more than 8000
phenolic phytochemicals have been reported to exist in different
fruits and vegetables (Crozier, Jaganath, & Clifford, 2009). One of
the major phenolic phytochemicals is avonoids which are basi-
cally comprised of fteen carbons, with two aromatic rings conju-
gated by a three-carbon bridge (C6eC3eC6 structure) (Fig. 1). Main
avonoids include avonols (Castillo-Mun ~ oz, Go
 mez-Alonso,
Garca-Romero, & Hermosn-Gutie rrez, 2007; Drewnowski &
Gomez-Carneros, 2000; Suzuki, Honda, Funatsuki, & Nakatsuka,
2004), anthocyanidins (Barnes, Nguyen, Shen, & Schug, 2009; Li,
Pan, Cui, & Duan, 2010), avan-3-ols (Peleg, Gacon, Schlich, &
Noble, 1999; Souquet, Cheynier, Brossaud, & Moutounet, 1996;
Vidal et al., 2003; Xu, Zhang, Cao, & Lu, 2010), avanones (Majo
et al., 2005), and isoavones (Aoki, Akashi, & Ayabe, 2000; Wang
& Murphy, 1994). Other important phenolic phytochemicals also
include phenolic acid (C6eC1) (Ossipov, Salminen, Ossipova,
Haukioja, & Pihlaja, 2003), hydroxycinnamates and their de-
rivatives (C6eC3) (Li, Pan, Jin, Mu, & Duan, 2011), and stilbenes
(C6eC2eC6) (Jang et al., 1997; Romero-Pe rez, Ibern-Go mez,
Lamuela-Ravento  s, & de la Torre-Boronat, 1999).
2.1. Health benets
A number of in vitro and in vivo studies have been performed to
conrm that consumption of phenolic phytochemicals and
phenolic phytochemical-rich products showed anti-cancer prop-
erties and offered multiple benets for human health. For example,
Flavonols have been reported to show anti-cancer (Morris et al.,
2006; Yang et al., 2006), anti-inammation (Granado-Serrano,
Martn, Bravo, Goya, & Ramos, 2012; H amala
inen, Nieminen,
Vuorela, Heinonen, & Moilanen, 2007; Mondal, Rajalingam, &
Kumar Maity, 2013), and anti-diabetes functions (Vessal,
 Z. Li et al. / Food Hydrocolloids 43 (2015) 153e164
Hemmati, & Vasei, 2003; Youl et al., 2010). Anthocyanins had
antioxidant capacity to induce apoptosis of cancer cells and pre-
vented against cell proliferation (Devi, Kumar, & Das, 2011; Hsu,
Shih, Lin, Chiu, & Lin, 2012). What is more, anthocyanins pro-
tected against UV-induced oxidative damages (Afaq et al., 2006;
Murapa, Dai, Chung, Mumper, & D'Orazio, 2012; Tsoyi et al.,
2008), decreased the neurotoxicity to inhibit neurodysfunction
(Ke et al., 2011; Shih, Wu, Yeh, & Yen, 2011; Strathearn et al., 2014),
and inhibited diethylnitrosamine-induced hepatocellular carcino-
genesis (Bishayee et al., 2011, 2013; Longo et al., 2008). Isoavones
and derivatives have been widely studied correlated to the anti-
cancer properties. Soy isoavones inhibited the activity of tran-
scription factors and genes essential for tumor cell proliferation,
invasion, and neovascularization (Hillman & Singh-Gupta, 2011;
Sarkar & Li, 2003; Setchell, 1998). Flavan-3-ols have the potential
against a variety of human diseases. For example, epigallocatechin
gallate (EGCG), a major avan-3-ols, induced apoptosis and pro-
moted cell growth arrest by altering the expression of cell cycle
regulatory proteins, activating caspases, or suppressing oncogenic
transcription factors and pluripotency maintaining factors (Chen,
Yu, Owuor, & Tony Kong, 2000; Kim et al., 2006; Singh, Shankar,
& Srivastava, 2011). EGCG was also conrmed to block carcino-
genesis by affecting signal transduction pathways (Giunta et al.,
2006; Kim et al., 2004, 2006; Li, Li, & Tan, 2005). Resveratrol was
identied in red wine and has been conrmed to contribute to the
cardioprotection (Sun, Simonyi, & Sun, 2002; Vidavalur, Otani,
Singal, & Maulik, 2006; Wang et al., 2002; Wu et al., 2001), inhi-
bition of platelet aggregation (Bertelli et al., 1995; Schmatz et al.,
2013), and suppression of prostaglandin biosynthesis (Kuroyanagi
et al., 2014; Martinez & Moreno, 2000; Yu et al., 2012). Other
health-benecial properties of resveratrol were also reported,
including improvement of mitochondrial function, inhibitory
function of low-density-lipoprotein oxidation, apoptotic activity of
ment, Hirpara, Chawdhury,
tumor cells, anti-aging function, etc (Cle
& Pervaiz, 1998; Frankel, Waterhouse, & Kinsella, 1993; Kaeberlein
et al., 2005; Lagouge et al., 2006).
2.2. Low absorption rate of phenolic phytochemicals
Although the positive effects of phenolic phytochemicals on
human health have been conrmed by a variety of studies, low
absorption rate and limited bioavailability of phenolic phyto-
chemicals were also reported by many studies (Table 1). Naturally
low aqueous solubility, poor gastrointestinal stability, passive
diffusion, and active efux of phenolic phytochemicals in the
gastrointestinal tract result in such low absorption.
2.2.1. Low solubility and poor stability
Low solubility and poor stability of phenolic phytochemicals in
the gastrointestinal tract play important roles in their low ab-
sorption rate. Aqueous solubility of phenolic phytochemicals is
Table 1
Absorption rate of selected phenolic phytochemicals.
Phenolic phytochemicals Sources
Anthocyanins Berries
Flavan-3-ols or procyanidins Tea, chocolate, and grape seed extract
Isoavones Soy
Flavonols (Quercetin) Plant food
Flavanones (Hesperidin) Citrus
Stilbenes (Resveratrol) Grape and wine
Hydroxycinnamic acids Coffee, tomatoes, and cereals
155
determined by their afnity to water molecules and molecular
weight plays a primary role in aqueous solubility. It has been pro-
posed that higher molecular weight compounds were not dissolved
well in water (Gao & Hu, 2010). For example, proanthocyanidins are
synthesized by ()-catechin and ()-epicatechin units and their
polymers had much larger molecular weight compared to oligmers
and monomers. This higher molecular weight causes much lower
aqueous solubility for proanthocyanidin polymers and further leads
to extremely lower absorption (Ou, Percival, Zou, Khoo, & Gu, 2012;
Zhang, Zheng, Chow, & Zuo, 2004). Moreover, different pH condi-
tions in the gastrointestinal segments may also cause the degra-
dation of phenolic phytochemicals. For instance,
()-epigallocatechin gallate (EGCG) is unstable in acidic (below 1.5)
stomach and neutral pH environment in intestine and the degra-
dation process followed a rst-order reaction (Onoue, Ochi, &
Yamada, 2011; Zhu, Zhang, Tsang, Huang, & Chen, 1997). Antho-
cyanins has been reported to show a rapidly degradation process in
intestinal environment with neutral pH condition (McGhie &
Walton, 2007).
2.2.2. Low permeation due to passive diffusion and active efux
No specic receptors on the surface of small intestinal epithelial
cells have been found to carry phenolic phytochemicals into cells.
Thus, the mechanism for phenolic phytochemicals to transport
across epithelium was principally based on passive diffusion,
including paracellular and transcellular diffusions. After absorbed,
phenolic phytochemicals undergo active efux process by which
majority of phenolic phytochemicals are pumped back to lumen
(Fig. 2). For example, Kim et al. reported that hesperidin glycosides
permeated across the Caco-2 monolayers by the paracellular
pathway with the evidence that the transport was energy-
independent (Kim, Kometani, Okada, & Shimuzu, 1999). Perme-
ation of quercetin glucoside on Caco-2 monolayer needed cleavage
of glycoside moiety by lactase before transcellularly diffused across
the monolayers (Boyer, Brown, & Liu, 2004, 2005). A permeability
experiment of 36 avonoids on Caco-2 monolayers suggested that
avonoid aglycones permeated through monolayers via passive
diffusion, whereas avonoid glycosides were retarded on their
permeability due to the glycoside moiety (Tian, Yang, Yang, &
Wang, 2009). In vitro genistein, daidzein, and their glucoside con-
jugates permeability studies also suggested that aglycones were
more easily absorbed compared to their conjugates (Murota et al.,
2002). Proanthocyanidins permeation study revealed that proan-
thocyanidin dimers and trimers were absorbed across monolayer.
However, polymers with polymerization degree above 6 were
difcult to be transported through Caco-2 monolayer because of
their large molecular weight (Ou et al., 2012; Stephanie, Isabelle,
Jean-Francois, Daniel, & Augustin, 2001).
After phenolic phytochemicals are transcellularly diffused into
epithelial cells, active efux takes place to excrete them back to
lumen (Fig. 2). Efux process is associated with efux transporters
Absorption rate References
<1% (Felgines et al., 2003; Wu, Cao, & Prior, 2002)
<5% (Holt et al., 2002; Sano et al., 2003; Zhu, Chen, & Li, 2000)
<1% (Cassidy et al., 2006; Izumi et al., 2000; Setchell et al., 2001)
3e7% (Day et al., 2001; Mullen, Boitier, Stewart, & Crozier, 2004)
3e9% (Borges, Lean, Roberts, & Crozier, 2013; Takumi et al., 2012)
<1% (Rotches-Ribalta, Andres-Lacueva, Estruch, Escribano, &
Urpi-Sarda, 2012; Walle, 2011)
1e25% (Bourne & RiceeEvans, 1998; Kern, Bennett, Mellon,
Kroon, & Garcia-Conesa, 2003; Rechner, Spencer,
Kuhnle, Hahn, & Rice-Evans, 2001)
156 Z. Li et al. / Food Hydrocolloids 43 (2015) 153e164
Fig. 2. Passive diffusion, metabolism, and active efux of phenolic phytochemicals on epithelial cells.
that can recognize phenolic phytochemicals (Gao and Hu, 2010).
ATP-binding cassette transporters (ABC) exist on the apical surface
of epithelial cells and these transporters are responsible for efux
process of phenolic phytochemicals in epithelial cells. ABC efux
transporters include p-glycoprotein (P-gp), multidrug resistance-
associated proteins (MRPs), and breast cancer resistance proteins
(BCRPs). For example, tea catechins showed much lower apparent
permeability coefcient (Papp) when sampling from apical to
basolateral side of Caco-2 monolayers rather than that from baso-
lateral to apical side, indicating that efux was involved in the
transport process. However, the Papp values were signicantly
improved in the presence of MK571 (a multidrug resistance-
associated protein inhibitor) from apical to basolateral side of
Caco-2 monolayers, suggesting multidrug resistance-associated
proteins were the efux transporters of tea catechins (Zhang,
Chow, & Zuo, 2006; Zhang et al., 2004). ()-Epicatechin-3-gallate
(ECG) was reported to be a good substrate of P-glycoprotein in
Caco-2 cells and uxed after the transcellular diffusion
(Vaidyanathan & Walle, 2003).
Phenolic phytochemicals absorbed by epithelial cells are
metabolized by uridine 50 -diphospho-glucuronosyltransferases
(UGTs) and/or sulfotransferases (SULFs) to form phase II metabo-
lites (Fig. 2). These metabolites are also recognized by efux
transporters and then pumped back to lumen where they are
excreted or degraded. A small portion of conjugates can be trans-
ported across basolateral membrane of epithelial cells via multi-
drug resistance-associated protein 3, an efux transporter at
basolateral side of epithelial cells, to enter portal vein for blood
circulation (Yeh & Yen, 2006). For examples, glucuronide and sul-
fate metabolites of isoavonoids were observed in both apical and
basolateral sides of Caco-2 monolayers, indicating the metabolisms
happened in cells and efux transporters lowered the absorption of
the isoavonoids and phase II metabolites (Murota et al., 2002). It
should be noted that metabolites of phenolic phytochemicals in
human and rats were different. Sulfation metabolism largely
happened in human, whereas glucuronide metabolites were
mainly present in rats (Kuhnle et al., 2000; Vaidyanathan and
Walle, 2003; van der Woude, Boersma, Vervoort, & Rietjens,
2004; Zhang et al., 2004).
3. Nanoparticles
It is preferred that nanoparticles have an average size ranging
from 1 to 100 nm (Acosta, 2009). Particularly, in pharmaceutical
science, particles with size below 1000 nm can still be classied as
nanoparticles because of their unique physicochemical properties
compared to bulk materials (Li & Gu, 2011; Li, Percival, Bonard, &
Gu, 2011).
3.1. Nanoparticle fabrication
Nanoparticles are normally fabricated using two basic methods,
including top-down and bottom-up approaches (Shimomura &
Sawadaishi, 2001; Whitesides & Grzybowski, 2002). In top-down
process big materials can be shrunk down to nano-scale particles
by size-reduction mechanical process with energy input, whereas
small molecules can be aggregated to form nanoparticles in
bottom-up process depending on intermolecular afnity (Fig. 3).
A good example of nanoparticle fabrication via mechanical
process is nanoemulsion. In this process, high energy input is al-
ways required because this can generate intense forces to appro-
priately disrupt the oil and aqueous phases for formation of lipid
nanoparticles (Tadros, Izquierdo, Esquena, & Solans, 2004). For
example, Leong et al. created O/W nanoemulsion with average di-
ameters of 40 nm from sunower oil by inputting ultrasound or
high shear homogenization and the nanoemulsion could facilitate
lipid nanoparticles to encapsulate oil soluble bioactive compounds
into water based foods (Leong, Wooster, Kentish, & Ashokkumar,
2009).
A desolvation/antisolvent method is widespread used to fabri-
cate nanoparticles in bottom-up process. Three important compo-
nents are involved in this process, including a polymer, internal
 Z. Li et al. / Food Hydrocolloids 43 (2015) 153e164 157

aqueous solution and then being sheared into water to form zein
nanoparticles (Zhong & Jin, 2009). Self-assembly of nanoparticles is
another method that is widely used in chemical process, which
takes advantage of molecular interactions among fabrication
components in the system. The self-assembly to fabricate nano-
particles is affected by intermolecule mass ratios, fabrication pH
condition, temperature, etc (Chen et al., 2010; Grzelczak, Vermant,
Furst, & Liz-Marzan, 2010; Li & Gu, 2011, 2014; Yi, Cheng, & Xing,
2006).

3.2. Measurement technology

There are a number of instruments that have been applied to

Fig. 3. Nanoparticle fabrication method using (A) top-down and (B) bottom-up
process.
solvent, and external solvent. Polymer molecules rstly are dis-
solved in internal solvent. Subsequently, external solvent is grad-
ually added to the internal solvent. When external solvent is
sufcient in the whole system, polymer molecules cannot be dis-
solved and start to form aggregates (Coester, 2000). For example,
zein based nanoparticles was achieved by dissolving zein in ethanol
measure characteristics of nanoparticles. However, no best tech-
niques have been assured so far. Dynamic light scattering (DLS) and
electron microscopy (EM) are described in detail with the mecha-
nism in the following paragraphs of this review. Other technologies
are listed in Table 2 with the detailed features.
DLS is a common ensemble analytical technique to evaluate the
particle size and size distribution. The mechanism behind the DLS
measurement is based on the particle motility due to Brownian
motion. DLS measures the uctuation in intensity of scattered light
and applies algorithm to determine the size distribution, including
intensity-, number-, and volume-weighted distributions (Bootz,
Vogel, Schubert, & Kreuter, 2004; Filipe, Hawe, & Jiskoot, 2010;
Pusey, 1999).
EM is one of the single-particle techniques that measure size
and morphology of dry particles, including transmission electron
microscopy (TEM) and scanning electron microscopy (SEM) (Bootz
et al., 2004). The mechanism behind EM measurement is that a
beam of electrons is transmitted through a particle, interacting
with it and as a result
an image is formed from the interaction of the
electrons transmitted through the particle. The image is magnied
and focused onto an imaging device (Powers et al., 2006; Williams

Table 2
Common particle size measurements and relative sensitivity and reliability.

Technology Size range Sensitivity and reliability Suspension in vitro uids

Dynamic light scattering 1e1000 nm Accurate for monodisperse Yes

(Bootz et al., 2004; Filipe et al., 2010)
Inaccurate for polydisperse samples
Large inuence on size accuracy and distribution
Measurement fast (about 2e5 min per measurement)
No sample visualization
Approximate size distribution, intensity distribution

Scanning mobility analyzing 2.5e1000 nm High resolution data No

(Jillavenkatesa & Kelly, 2002) Fast measurements
Discreet particle measurement
Automatically ow control

Nanoparticle tracking analysis
(Filipe et al., 2010)
30e1000 nm Accurate for both mono- and poly-disperse samples Yes
Peak resolution high
Little inuence on size accuracy and size distribution
Measurement slow (5 mine1 h per measurement
Individual particle size, number distribution
Sample visualization
More reliable size distribution

Electron microscopy 0.3 nm e micron High resolution Maybe

(Williams & Carter, 2009) No calibration necessary Particles need to be dried
Particle sample shape (two-dimension)
Samples preparation before measurement
Poor statistics on size distribution

High vacuum needed

Atomic force microscopy 5 nm e micron A three-dimensional surface prole Maybe

(Binnig, Quate, & Gerber, 1986) No vacuum, work well in ambient air or a liquid in ambient or liquid
environment condition
Limitation on scanning speed
Only see surface of sample
158 Z. Li et al. / Food Hydrocolloids 43 (2015) 153e164
& Carter, 2009). Nanoparticles measured by EM must be dried from
suspension, which may cause particle aggregation. High voltage
during EM operation may also damage the integrity of particles
(Powers et al., 2006).
3.3. Nanoparticle system for delivery of phenolic phytochemicals
Nanoparticles can interact with phenolic phytochemicals by
hydrogen bonds and hydrophobic interactions to encapsulate
phenolic phytochemicals in nanoparticles, which can enhance
aqueous solubility of phenolic phytochemicals. Nanoparticles also
can prevent against oxidation/degradation of phenolic phyto-
chemicals encapsulated in the gastrointestinal tract. More impor-
tantly, nanoparticles can be taken directly up by epithelial cells in
small intestine, which signicantly increases absorption and
bioavailability of phenolic phytochemicals.
3.3.1. Nanoparticles enhance solubility of low-water-soluble
phenolic phytochemicals
Nanoparticles are established with hydrophobic groups inside
and polar groups on surface of particles (Li and Gu, 2014). There-
fore, nanoparticles can remain stable in dispersion system due to
their inter-particle repulsions and hydration. Phenolic phyto-
chemicals can interact with hydrophobic sites of nanoparticles via
hydrogen bonds and hydrophobic interactions. Sufcient surface
charges and suitable hydration property keep phenolic phyto-
chemical encapsulated nanoparticles stable in aqueous system,
which enhances the water solubility of phenolic phytochemicals.
For example, procyanidin were successfully encapsulated into zein
nanoparticles using a desolvation method and the resultant pro-
cyanidinezein nanoparticles increased procyanidin solubility in
aqueous system (Zou, Li, Percival, Bonard, & Gu, 2012). Poly (lactic-
co-glycolic acid) (PLGA) nanoparticles, chitosan nanoparticles, and
protein nanoparticles were all reported to encapsulate curcumin to
Fig. 4. Cellular uptake of nanoparticles by epithelial cells.
enhance its aqueous solubility (Anand et al., 2010; Das, Kasoju, &
Bora, 2010; Duan et al., 2010; Kim et al., 2011; Luz et al., 2012;
Mukerjee & Vishwanatha, 2009; Rejinold, Muthunarayanana,
Chennazhi, Nair, & Jayakumar, 2011; Teng, Luo, & Wang, 2012).
3.3.2. Nanoparticles prevent phenolic phytochemicals against
degradation in the gastrointestinal tract
Phenolic phytochemicals encapsulated by nanoparticles lower
the oxidation and/or degradation risks in the gastrointestinal tract.
For example, EGCG has been reported to be rapidly degraded in
both low acidic and neutral conditions (Kim & Hong, 2010; Sang,
Lee, Hou, Ho, & Yang, 2005; Zhu et al., 1997). After encapsulation
the stability of EGCG in simulated stomach uid (pH 1.2) was about
2 times higher than free EGCG (Onoue et al., 2011). EGCG showed
much higher stability in neutral and slightly alkaline pH conditions
with human serum albumin because interaction was established
between EGCG and human serum albumin via hydrogen bonds and
hydrophobic interactions. Sulfhydryl groups in human serum al-
bumin acted as antioxidant against EGCG degradation (Bae et al.,
2009; Ishii et al., 2011).
3.3.3. Nanoparticles enhance absorption of phenolic
phytochemicals in epithelial cells via endocytotic cellular uptake
Nanoparticles have been reported to be penetrated across small
intestinal epithelium by either paracellular or transcellular
pathway. These transport ways enhance absorption of phenolic
phytochemicals encapsulated in the gastrointestinal tract (Fig. 4).
Tight junctions are secreted by junctional protein among the
epithelial cells. They are responsible for the integrity of the
epithelium. Paracellular transport refers to a passive diffusion
through intercellular spaces among the epithelium (Nellans, 1991;
Sonaje et al., 2012). Either nanoparticles or junctional protein me-
diators can control disruption of tight junctions for enhancing
transport of bioactive compounds via paracellular way.
 Z. Li et al. / Food Hydrocolloids 43 (2015) 153e164
Nanoparticles with size below 20 nm may reversibly disrupt the
tight junctions among the epithelial cells and release bioactive
compounds to capillary blood. After delivery, tight junctions return
to normal state for function (Acosta, 2009; Jevprasesphant, Penny,
Attwood, McKeown, & D'Emanuele, 2003; Zha, Xu, Wang, & Gu,
2008). Tight junction mediators, such as chitosan, thiolated chito-
san, chitosan derivatives, and polyacrylate derivatives were re-
ported to fabricate nanoparticles or coating on nanoparticles to
enhance paracellular transport (Bravo-Osuna, Vauthier, Chacun, &
Ponchel, 2008; des Rieux et al., 2006; Kudsiova & Lawrence,
2008; Martien, Loretz, Sandbichler, & Schnrch, 2008; Sadeghi
et al., 2008; Vllasaliu et al., 2010). Chitosan was reported to
mediate transmembrane tight junction protein CLDN4 to reversely
disrupt tight junctions (Yeh et al., 2011). Polyacrylate derivatives
were reported to interact with Ca2 from intestinal epithelial cells
to form poly(acrylic acid)-Ca2 complexes, which loosened the
cellular barrier and induced opening of tight junctions (Borchard
et al., 1996; Junginger & Verhoef, 1998).
Cellular uptake of nanoparticles by cells in transcellular path-
ways is associated with energy input. Leroux et al. reported that an
energy-requiring process was associated with the uptake of pol-
y(D,L-lactic acid) nanoparticles labeled by a uorescent dye because
more uptakes of the nanoparticles were observed when the incu-
bation temperature was elevated from 4 to 37  C (Leroux et al.,
1994). The energy-dependent uptakes of nanoparticles were also
reported in PLGA nanoparticles, protein based nanoparticles, and
other types of nanoparticles (Benfer & Kissel, 2012; Chang et al.,
2009; Kim et al., 2007; Ofokansi, Winter, Fricker, & Coester, 2010;
Panyam & Labhasetwar, 2003; Smith et al., 2012; Tseng et al., 2007).
Cellular uptake process of nanoparticles is conducted by mac-
ropinocytosis or endocytosis containing clathrin-mediated endo-
cytosis, caveolae-mediated endocytosis, and clathrin- and
caveolae-independent endocytosis (Acosta, 2009; Roger, Lagarce,
Garcion, & Benoit, 2010; Wang, Byrne, Napier, & DeSimone,
2011). Macropinocytosis is an actin-driven process that can inter-
nalize the nanoparticles without receptor mediation. Particles with
an average size below 2 mm are enclosed by macropinosomes
formed on the surface of enterocytes and internalized to cells. The
internalized nanoparticles are further translocated to endolyso-
some (Mercer & Helenius, 2009; Sahay, Alakhova, & Kabanov,
2010). O'Neill et al. reported that the cyclodextrin nanoparticles
with the lipid tail were taken up by Caco-2 cells via macro-
pinocytosis and conrmed by inhibiting clathrin- and caveolae-
mediated endocytosis (O'Neill, Guo, Byrne, Darcy, & O'Driscoll,
2011).
Clathrin-mediated endocytosis requires clathrin-coated pits
formed by assembly of clathrin. Coated pits develop to form vesicles
of 120 nm, a process mediated by GTPase. These vesicles engulf
nanoparticles into cells via low-density lipoprotein receptor or
iron-loaded transferring receptors that interact with clathrin
adaptor proteins (Ogunkoya, Nickel, Gay, & Murray, 2009). Nano-
particles internalized by clathrin-mediated endocytosis are trans-
located into lysosome for degradation (Roger et al., 2010; Wang
et al., 2011). For example, Ogunkoya et al. demonstrated in quan-
tum dot clathrin association study that one clathrin adaptor AP-2
was located easily to coated pits and vesicles and clathrin and
AP-2 cooperated to generate coated pits. Specically, AP-2 bound to
the regions of the plasma membrane, recruited clathrin, and pro-
moted polymerization of clathrin into lattice that developed to
invaginate the membrane until the coated pit separated from the
rest of the membrane to form the coated vesicle (Ogunkoya et al.,
2009). Other clathrin adaptors have been reported to perform the
similar behavior on the clathrin-mediated endocytosis (Rappoport,
Kemal, Benmerah, & Simon, 2006; Traub, 2003). Nanoparticles with
average sizes below 200 nm had the ability to stabilize the clathrin-
159
coated pits, and the internalization of nanoparticles was primarily
clathrin-mediated endocytosis (Ehrlich et al., 2004). For example,
layered double hydroxide nanoparticles were taken up via clathrin-
mediated endocytosis and these particles escaped endosomal
accumulation probably by the deacidication (Xu et al., 2008).
Harush-Frenkel et al. reported that positive charged poly(lactic
acid) nanoparticles via the clathrin-mediated endocytosis were
internalized into HeLa cells and the uptake efciency was signi-
cantly higher than negative charged nanoparticles due to the
repulsion with negative charged HeLa cell surfaces (Harush-
Frenkel, Debotton, Benita, & Altschuler, 2007).
In caveolae-mediated endocytosis, caveolae is formed by
assembling caveolin protein, choloestrol, and sphingolipids on cell
membrane (Kiss, 2012; Reilly, Larsen, & Sullivan, 2012; Roger et al.,
2010). Caveolae-mediated transport was inhibited in the presence
of lipin by binding with sterol whereas clathrin-mediated trans-
port remained effective (Schnitzer, Oh, Pinney, & Allard, 1994).
Nanoparticles with an average size below 60 nm tend to be inter-
nalized by caveolae-mediated endocytosis and the smaller size
enhances the caveolae-mediated endocytosis. Hao et al. reported
that gold nanoparticles with the average size around 5 nm were
internalized by living HeLa cells via caveolae-mediated endocy-
tosis, and the endocytosis pathway was not inhibited in the pres-
ence of sucrose which can disrupt the formation of clathrin-
mediated endocytosis (Hao et al., 2012). However, Rejiman et al.
also claimed that nanoparticles with 500 nm were taken up by
caveolae-mediated pathway with escape of lysosomal accumula-
tion (Rejman, Oberle, Zuhorn, & Hoekstra, 2004). Nanoparticles by
caveolae-mediated endocytosis can escape degradation of endoly-
sosome, and further be delivered to the endoplasmic reticulum and
the nucleus of cells.
Clathrin- and caveolae-independent endocytosis may be asso-
ciated with cholesterol-rich microdomains on cell membrane. Lai
et al. reported that the small polymeric particles with the size
below 25 nm were internalized to live cells via a novel mechanism
that led to trafcking outside the endo/lysosomal pathway and this
endocytosis did not rely on cholesterol, clathrin, or caveolae
mediation (Lai et al., 2007).
After being internalized in epithelial cells, nanoparticles may be
translocated to endo/lysosome and further degraded in lysosome to
release bioactive compounds. These bioactive compounds may
continue to undergo the metabolism process in epithelial cells (Jin
et al., 2011; Li et al., 2008; Ma et al., 2011). Nanoparticles may
potentially remain intact in endolysosome and enter blood circu-
lation by exocytosis. Additionally, nanoparticles may escape the
accumulation in endo/lysosome and can be translocated to the
endoplasmic reticulum and Golgi complex. These nanoparticles
may further experience the exocytosis across the membrane (Qian,
Cai, Verhey, & Tsai, 2009).
3.4. Potential challenges of nanoparticle application
3.4.1. Effects of pH, ions, and enzymes in the gastrointestinal tract
on stability of nanoparticles
Nanoparticles after entering the gastrointestinal tract are
exposed to different pH, excess amount of ions, and different kinds
of digestive enzymes, which may affect efcacy of nanoparticles for
delivery of phenolic phytochemicals. pH plays an important role in
affecting stability of nanoparticles in the gastrointestinal tract. For
example, gelatin nanoparticles were aggregated at pH 6e7 because
isoelectric point of gelatin signicantly reduced the inter-particle
repulsion (Li & Gu, 2011; Yi et al., 2006). Chitosan/PLGA nano-
particles had the particle size below 500 nm at pH below 6 and
above 8 but showed micron level at pH 6e8 (Murugeshu, Astete,
Leonardi, Morgan, & Sabliov, 2011). Also, Samstein et al. reported
160 Z. Li et al. / Food Hydrocolloids 43 (2015) 153e164
that PLGA particles were degraded via acid-catalyzed ester hydro-
lysis at the low pH of the stomach, limiting the functions of this
type of nanoparticles (Samstein, Perica, Balderrama, Look, & Fahmy,
2008).
Large quantities of ions are present in the gastrointestinal tract
to balance the pH condition (such as hydrochloride acid, sodium
bicarbonates, etc), to provide the signals (such as sodium and po-
tassium) to transport of nutrient compounds, and to activate the
enzyme to proceed the digestion process (Stone, Johnston, & Clift,
2007). The interaction between nanoparticles and ion due to
ionic attraction may increase the nanoparticles sizes. Excess of the
ions in the gastrointestinal tract may cause the nanoparticles to
aggregation or precipitation because excess ions can bind with
water via dipole attraction, lowering the hydration of nanoparticles
in water (Bootz et al., 2004; Zou et al., 2012).
Nanoparticles can be digested by digestive enzymes in the
gastrointestinal tract (Acosta, 2009; Chen, Remondetto, & Subirade,
2006; Roger et al., 2010). Luo et al. reported a burst release of
toropherol from zein nanoparticles in simulated gastric uid with
pepsin and in simulated intestinal uids with pancreatin
(Luo, Zhang, Whent, Yu, & Wang, 2011). Li et al. studied the stability
of vitamin D3 loaded alginate derivates nanoparticles in simulated
gastrointestinal uids containing enzymes and scanning electron
microscopy visualized that nanoparticles increased the size from
200 nm to 500 nm in simulated gastric uid after 0.5 h, and were
further collapsed in simulated intestinal uids after 6 h (Li, Liu,
Huang, & Xue, 2011).
3.4.2. Effect of mucus layer on stability of nanoparticles dispersion
Mucus layer is considered a physical barrier to protect and
lubricate the epithelial surfaces (Ensign, Cone, & Hanes, 2012;
Fagerholm & Lennern as, 1995; Frey et al., 1996). It prevents the
residence between nanoparticles and epithelial cells (Cone, 2009;
Ensign et al., 2012; Tang et al., 2009). Mucus possesses negative
charges and it is easier to interact with positive charged nano-
particles by electrostatic interactions. Nanoparticles may rapidly
penetrate the mucus by electrostatic interactions and load on small
intestinal epithelial cells for cellular uptake (Hariharan et al., 2006;
Norris, Puri, & Sinko, 1998; Roger et al., 2010). Hariharan et al. re-
ported that positively charged PLGA nanoparticles had an increased
cellular uptake compared to negatively and neutrally charged
nanoparticles (Hariharan et al., 2006). On the other hand, electro-
static interactions between mucus and nanoparticles may result in
the cease of nanoparticles in the mucus layers, which lowers the
cellular uptakes of nanoparticles by epithelial cells. Behrens et al.
reported that hydrophobic polystyrene nanoparticles got anchored
in the mucus, leading to the lower association with epithelial cells
(Behrens, Pena, Alonso, & Kissel, 2002). Nanoparticles with nega-
tive surface charges can be repulsed by mucus layer, decreasing
residence to epithelial cells (Hariharan et al., 2006).
4. Conclusion
The extremely low absorption and bioavailability of phenolic
phytochemicals is generally attributed to their low solubility, poor
stability, low permeability and active efux process, and metabo-
lisms in the gastrointestinal tract. Nanoparticles may improve the
aqueous solubility by encapsulating phenolic phytochemicals.
Nanoparticles can also prevent phenolic phytochemicals against
the oxidation/degradation in the gastrointestinal tract by nano-
encapsulation. Most importantly, nanoparticles have the poten-
tials to enhance the absorption of phenolic phytochemicals by
disrupting tight junctions and/or directly uptake by epithelial cells
via endocytosis. However, the stability of nanoparticles in the
gastrointestinal tract should be taken into account since a variety of
factors in the gastrointestinal tract, such as pH, ions, digestive en-
zymes, and mucus layer, impact the properties of nanoparticle
delivery system. Future work would be focused on phenolic
phytochemical encapsulated nanoparticles designed for oral
administration, better gastrointestinal stability, mucus penetrating
function, and intestinal epithelial cell targeting properties.
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