Puligundla, 2017

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Journal of Functional Foods 34 (2017) 139–151
Contents lists available at ScienceDirect
Journal of Functional Foods
journal homepage: www.elsevier .com/ locate/ j f f
Nanotechnological approaches to enhance the bioavailability
and therapeutic efficacy of green tea polyphenols
http://dx.doi.org/10.1016/j.jff.2017.04.023
1756-4646/� 2017 Elsevier Ltd. All rights reserved.
⇑ Corresponding author.
E-mail addresses: puli@gachon.ac.kr, pradeepnaidu2009@gmail.com (P. Puligundla), mokck@gachon.ac.kr (C. Mok), sanghoonko@sejong.ac.kr (S. Ko), liangjin@a
cn (J. Liang), neeruphysio39@gmail.com (N. Recharla).
Pradeep Puligundla a,⇑, Chulkyoon Mok a, Sanghoon Ko b, Jin Liang c, Neeraja Recharla b
aDepartment of Food Science & Biotechnology, Gachon University, Seongnam-si, Gyeonggi-do 13120, Republic of Korea
bDepartment of Food Science and Technology, Sejong University, 209 Neungdong-ro, Gwangjin-gu, Seoul 05006, Republic of Korea
c State Key Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University, Hefei 230036, PR China
a r t i c l e i n f o
Article history:
Received 9 December 2016
Received in revised form 11 April 2017
Accepted 15 April 2017
Keywords:
Green tea
Polyphenols
Bioavailability
Nanoencapsulation
Solid lipid nanoparticle
Therapeutic efficacy
a b s t r a c t
Green tea contains numerous bioactive compounds that may provide multiple health benefits, including
antioxidative, anti-inflammatory, anti-carcinogenic, anti-proliferative, anti-hypertensive, antithrombo-
genic and lipid-lowering effects. Most of the chemopreventive and therapeutic effects of green tea
extracts have been attributed to the presence of different polyphenolic bioactives, especially catechins,
in their composition. Although these polyphenolic compounds have been shown promising therapeutic
effects under in vitro conditions, they met with limited efficacy in clinical settings due to various reasons
such as poor oral absorption and bioavailability. Different techniques have been proposed to improve the
bioavailability of green tea polyphenols. Among such strategies, nanoparticle-based delivery systems are
novel and promising tools. This review is intended to discuss the advances related to improvement of
in vitro and in vivo bioavailability of green tea polyphenols using nanotechnological approaches, which
in turn would aid in enhancing their therapeutic efficacy.
� 2017 Elsevier Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
1.1. Setbacks related to the use of green tea polyphenols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
1.1.1. Poor stability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
1.1.2. Low bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
1.1.3. Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
1.2. Strategies to overcome barriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
2. Nano-approaches for improved oral bioavailability and efficacy of green tea polyphenols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
2.1. Surfactant-based nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
2.1.1. Nanomicelles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
2.1.2. Nanoliposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
2.2. Lipid-based nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
2.2.1. Nanostructured lipid carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
2.2.2. Nanoemulsion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
2.2.3. Multiple emulsions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
2.3. Biopolymer-based nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
2.3.1. Polyelectrolyte complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
2.3.2. Hydrogel nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
2.3.3. Polymeric nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
3. Possible mechanisms of nanoparticle-based delivery systems in enhancing bioavailability of green tea polyphenols. . . . . . . . . . . . . . . . . . . . . 147
4. Limitations and challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
5. Safety aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
hau.edu.
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mailto:puli@gachon.ac.kr
mailto:pradeepnaidu2009@gmail.com
mailto:mokck@gachon.ac.kr
mailto:sanghoonko@sejong.ac.kr
mailto:liangjin@ahau.edu.cn
mailto:liangjin@ahau.edu.cn
mailto:neeruphysio39@gmail.com
http://dx.doi.org/10.1016/j.jff.2017.04.023
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140 P. Puligundla et al. / Journal of Functional Foods 34 (2017) 139–151
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
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1. Introduction
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http://refhub.elsevier.com/S1756-4646(17)30208-6/h0670
http://refhub.elsevier.com/S1756-4646(17)30208-6/h0670
	Nanotechnological approaches to enhance the bioavailability�and therapeutic efficacy of green tea polyphenols
	1 Introduction
	1.1 Setbacks related to the use of green tea polyphenols
	1.1.1 Poor stability
	1.1.2 Low bioavailability
	1.1.3 Toxicity
	1.2 Strategies to overcome barriers
	2 Nano-approaches for improved oral bioavailability and efficacy of green tea polyphenols
	2.1 Surfactant-based nanoparticles
	2.1.1 Nanomicelles
	2.1.2 Nanoliposomes
	2.2 Lipid-based nanoparticles
	2.2.1 Nanostructured lipid carriers
	2.2.2 Nanoemulsion
	2.2.3 Multiple emulsions
	2.3 Biopolymer-based nanoparticles
	2.3.1 Polyelectrolyte complexes
	2.3.2 Hydrogel nanoparticles
	2.3.3 Polymeric nanoparticles
	3 Possible mechanisms of nanoparticle-based delivery systems in enhancing bioavailability of green tea polyphenols
	4 Limitations and challenges
	5 Safety aspects
	6 Conclusion
	Conflict of interest
	Referencesthe world after water is
tea (Demeule et al., 2002; Kuriyama et al., 2006). Tea is generally
consumed in the form of green, black, oolong or white tea
(Rusak, Komes, Likić, Horžić, & Kovač, 2008). All these types of
tea are derived from the leaves of Camellia sinensis plant with dif-
ferent processing methods. Green tea refers to non-fermented tea,
contains a variety of bioactive compounds, such as tea polyphe-
nols, caffeine, tea polysaccharides, tea pigment, saponins, theanine
and others (Narotzki, Reznick, Aizenbud, & Levy, 2012). Several
reports show that these non-nutrient bioactive compounds have
antioxidant, anticancer, antiobesity and other pharmacological
functions, thus making it an excellent candidate for nutraceutical
applications (Basu et al., 2013; Johnson, Bryant, & Huntley, 2012;
able 1
olyphenolic components in green and black tea (% w/w of extract solids).
Polyphenolic
compounds
Green
tea
Black
tea
Reference
Catechins 30–42 3–10 Katiyar and Mukhtar
(1996)Flavonols 5–10 6–8
Other flavonoids 2–4 –
Theogallin 2–3 –
Gallic acid 0.5 –
Quinic acid 2.0 –
Theanine 4–6 –
Methylxanthines 7–9 8–11
Theaflavins – 3–6
Thearubigens – 12–18
OHO
OH
OH
OH
OH
OHO
OH
O
OH
C
O
EC ECG 
OHO
OH
O
O
EGCG
ig. 1. Chemical structure of major catechins in green tea. EC, (�)-epicatechin; ECG, (�
allate.
Liang, Puligundla, Ko, & Wan, 2014; Perumalla & Hettiarachchy,
2011; Rains, Agarwal, & Maki, 2011). The leaves of tea plant con-
tain many polyphenolic compounds, including flavonols (querce-
tin, kaempferol and rutin), caffeine, theanine, phenolic acids, and
leucoanthocyanins, which are accounting for up to 40% of the dry
weight of green tea leaves (Sajilata, Bajaj, & Singhal, 2008).
Polyphenols are powerful antioxidants and free radical scavengers.
About 60–80% of polyphenols in green tea are flavan-3-ols, com-
monly known as catechins. Major polyphenolic components in
green and black tea are given in Table 1.
The primary catechins in green tea include epicatechin (EC),
epicatechin-3-gallate (ECG), epigallocatechin (EGC), and
epigallocatechin-3-gallate (EGCG) (Ahmad & Mukhtar, 1999;
Rains et al., 2011). The chemical structures of these catechins are
shown in Fig. 1, and all these are the most abundant water-
soluble components of tea (Balentine, Wiseman, & Bouwens,
1997). An infusion (one cup or 200 ml) of green tea contains up
to 200 mg of catechins (Lakenbrink, Lapczynski, Maiwald, &
Engelhardt, 2000). Extracts of green tea have been reported to pos-
sess higher antioxidant potential than black tea, and this potential
correlates strongly with the total phenolic content of green tea
(Benzie & Szeto, 1999; Langley-Evans, 2000). EGCG is a water- sol-
uble polyphenol that occurs in highest concentrations in green tea,
and possesses numerous health benefits (Kumar, Thakur, & De,
2012). The green tea polyphenols exhibited anticancer activity
against several types of cancers in vitro and in vivo animal models
(Ahmad et al., 2014; Crespy & Williamson, 2004; Okabe et al.,
1997; Sajilata et al., 2008), and are believed to inhibit certain can-
cers, such as lung, skin, esophagus, liver, and stomach (Mandel,
Weinreb, Amit, & Youdim, 2004). Tea catechins have been reported
OH
OH
OH
OH
OHO
OH
OH
OH
OH
OH
 EGC
H
OH
C
O
OH
OH
OH
OH
 
)-epicatechin-3-gallate; EGC, (�)-epigallocatechin; EGCG, (�)-epigallocatechin-3-
P. Puligundla et al. / Journal of Functional Foods 34 (2017) 139–151 141
to exhibit neuroprotective activity, prevent atherosclerosis, inhibit
tumor angiogenesis and modulate cholesterol metabolism (Crespy
& Williamson, 2004; Tang et al., 2013; Zaveri, 2006). In addition,
the EGCG, EGC, ECG and EC polyphenolic components of green
tea possess anti-mutagenic, anti-diabetic, anti-inflammatory and
anti-bacterial properties (Ahmad et al., 2014; Sajilata et al.,
2008). Despite antibacterial effect, green tea extracts have been
shown to permit the in vitro survival of the selected probiotic bac-
teria (López de Lacey, Pérez-Santín, López-Caballero, & Montero,
2014).
Epidemiological studies, however, have suggested that large
volumes of green tea, ranging from 5 to 10 cups a day, have to
be consumed to obtain health benefits. Thus, tea drinking alone
may not provide a sufficient level of bioactives to achieve health
benefits (Vuong, Stathopoulos, Golding, Nguyen, & Roach, 2011).
This constraint impedes exploiting the therapeutic potential of
green tea, especially in the Western world where people are not
used to drinking green tea much. Therefore, extraction of the
bioactives, especially catechins, from green tea to provide concen-
trated preparations for use as food supplements or as additives for
functional foods has been considered as an alternative way to pro-
vide the health benefits of these green tea polyphenolic com-
pounds (Vuong et al., 2011). The commonly applied techniques
for isolation of tea polyphenols include supercritical carbon diox-
ide extraction, high-speed counter-current chromatography,
Sephadex-based chromatography, and other liquid chromato-
graphic techniques (Xu, Sandstro, Janson, & Tan, 2006). For the
purification of EGCG from crude green tea extracts, high perfor-
mance media (Sepharose HP) may be employed (Sajilata et al.,
2008). As tea catechins have a strong association with macronutri-
ents such as proteins, their extraction and analysis from complex
food matrices are somewhat complicated (Ferruzzi & Green, 2006).
1.1. Setbacks related to the use of green tea polyphenols
1.1.1. Poor stability
Although several isolated bioactive phytochemicals have been
shown promising therapeutic effects in preclinical settings, their
applicability to humans has met with limited success (Siddiqui,
Adhami, Ahmad, & Mukhtar, 2010). It has been shown that EGCG
was stable under acidic conditions, but rapidly degraded in body
fluids at pH 7.4 (Proniuk, Liederer, & Blanchard, 2002). Green tea
catechins are very unstable in neutral and alkaline solutions
(Shpigelman, Israeli, & Livney, 2010). It has also been shown that
catechins from green tea are very unstable after passing through
salivary, gastric and upper small intestinal phases of the digestion
process, the total catechins showed a poor digestive recovery
(5.3%) and EGC and EGCG significantly decreased with the diges-
tive recovery of 4.6% and 6.1%, respectively (Shim et al., 2012).
Under small intestinal conditions (elevated pH), the EGC and EGCG
were found to be unstable, while EC and ECG were relatively stable
(Chen, Zhu, Wong, Zhang, & Chung, 1998). This could be due to
residual dissolved oxygen may facilitate several reactions includ-
ing epimerization and auto-oxidation (Green, Murphy, Schulz,
Watkins, & Ferruzzi, 2007). The chemical instability of EGCG would
result in its poor bioavailability (Zou, Peng, Liu, Chen, & Liu, 2015).
In addition to the above, the tea polyphenols become unstable
when exposed to light, heat and oxidants (Shpigelman, Cohen, &
Livney, 2012; Zimeri & Tong, 1999), and is a major disadvantage
for their clinical applications. It is desirable to get a chemically
stable dosage form of tea polyphenols for the quality control of
drug products. Incorporation in solid lipid-based carriers such as
solid lipid nanoparticles has been recommended to overcome the
chemical instability (Sajilata et al., 2008). The majority of catechin
degradation is more likely to occur under small intestinal condi-
tions where elevated pH and presence of reactive oxygen species
provide favorable conditions for catechin auto-oxidative reac-
tions (Neilson et al., 2007; Tanaka & Kouno, 2003). The stability
of theaflavins in the oral cavity and gastrointestinal (GI) tract
may affect the bioavailability of these compounds.
1.1.2. Low bioavailability
The limitations to successful applicability majorly include inef-
ficient systemic delivery and bioavailability when administered
orally (Bharali et al., 2011; Huang, Yu, & Ru, 2010; Karn, Vanić,
Pepić, & Skalko-Basnet,2011). In ensuring bioefficacy of bioactive
food compounds, bioavailability is a key step. The bioavailability
of the tea polyphenols determines their efficacy (Alotaibi,
Bhatnagar, Najafzadeh, Gupta, & Anderson, 2013). Bioavailability
is a complex process involving several different stages: liberation,
absorption, distribution, metabolism and elimination (LADME)
phases (Rein et al., 2013). It has been reported that green tea
showed only limited efficacy in clinical settings in spite of signifi-
cant efficacy in preclinical settings due to limited bioavailability
(Khan et al., 2014; Siddiqui et al., 2009, 2010, 2014). Bioavailability
of catechins from tea is relatively poor. Several factors are believed
to limit the bioavailability of green tea polyphenols, such as bioac-
cessibility, delivery matrix effect, transporters, molecular struc-
tures and metabolizing enzymes. The harsh conditions of the GI
tract are the main obstacles that hinder the clinical availability of
naturally derived compounds, including catechins. Harsh GI envi-
ronments are due to physical barriers like the intestinal epithelium
and degradation by various enzymes and gastric juices (Ensign,
Cone, & Hanes, 2012; Record & Lane, 2001; Sun et al., 2012).
Another factor is poor intestinal transport (low absorption rate)
due to passive diffusion and active efflux (Vaidyanathan & Walle,
2001, 2003; Zhang, Zheng, Chow, & Zuo, 2004). There are no speci-
fic receptors on the surface of small intestinal epithelial cells to
carry tea polyphenols into cells. The ATP-binding cassette (ABC)
transporters exist on the apical surface of epithelial cells, including
P-glycoprotein (P-gp), multidrug resistance-associated proteins
(MRPs), and breast cancer resistance proteins (BCRPs), are respon-
sible for efflux of phenolic phytochemicals in epithelial cells. In
two different studies, much lower apparent permeability coeffi-
cient (Papp) of tea catechins was observed when sampling was done
from apical to basolateral side of Caco-2 monolayers rather than
from basolateral to apical side, indicating that efflux was involved
in the transport process (Zhang, Chow, & Zuo, 2006; Zhang et al.,
2004). Furthermore, rapid metabolism and clearance contribute
to limited bioavailability of catechins (Chow et al., 2005). In the
case of theaflavins, the low bioavailability is due to the high molec-
ular weight and large polar surface area of these compounds and
not due to pH or temperature-dependent degradation in the GI
tract (Sajilata et al., 2008).
1.1.3. Toxicity
Physiologically irrelevant concentrations of EGCG (in the range
of 10–200 lM) have been used in a majority of published cell cul-
ture studies (Kim, Hiraishi, Tsuchiya, & Sakamoto, 2010; Wang
et al., 2014). However, at lower or physiological relevant (achiev-
able by oral intake) concentrations, EGCG has little or very limited
effect. In addition, EGCG is a naturally occurring chemopreventive
agent, without major toxicity concerns. However, recent reports
showed that efficacious doses of EGCG used in health promotion
may not be far from its toxic dose level (Wang, Taylor, Wang,
Wan, & Zhang, 2012). High concentrations of green tea extract
can exert acute toxicity in rat liver cells, and EGCG seems to be a
key constituent responsible for this effect (Schmidt et al., 2005).
Therefore, techniques to attain reduced toxicity of green tea
extract or EGCG at high dosage levels have gained importance.
142 P. Puligundla et al. / Journal of Functional Foods 34 (2017) 139–151
1.2. Strategies to overcome barriers
Several strategies have been employed to improve the bioavail-
ability of tea polyphenols, especially catechins, such as formulation
with sucrose and ascorbic acid, which improved catechin bioavail-
ability by enhancing bioaccessibility and intestinal uptake from tea
(Peters, Green, Janle, & Ferruzzi, 2010); and formulations with vita-
min C and xylitol, which enhanced transport rate of nongallated
catechins by the inhibition of the efflux transport mechanism
(Chung et al., 2013). Among several such approaches, nanotechno-
logical methods are novel and promising. Nanotechnology is sug-
gested to be an appropriate approach to increase EGCG
bioavailability (Wang et al., 2014). Nanoencapsulation of bioactive
compounds represents a viable and efficient approach to increase
their physical stability under GI conditions, protecting them from
interacting with other components of digestion and premature
degradation in the body. It helps in increased bioactivity due to
the subcellular size. Bio-degradable nanoparticles of 100 nm size
showed 15- to 250-fold higher uptake efficiency as compared to
larger sized microparticles (>500 nm) (Desai, Labhasetwar,
Amidon, & Levy, 1996). Also, nanoparticles prolong phytochemicals
circulation time. Nanoencapsulation significantly increased EGCG
stability and improved its sustained release, which may partially
contribute to the increased cellular uptake of EGCG (Hu, Ting,
Zeng, & Huang, 2013). Nanoparticle-mediated delivery may
enhance bioavailability and limit any unwanted toxicity of chemo-
preventive agents, such as EGCG (Siddiqui et al., 2009). To increase
the concentration of the bioactive compounds in food matrices,
encapsulation can be used. In addition, encapsulation prevents
the interaction of bioactives with the food ingredients
(Kailasapathy, 2016).
2. Nano-approaches for improved oral bioavailability and
efficacy of green tea polyphenols
Nanotechnology has been utilized to create a variety of delivery
systems for the encapsulation, protection and controlled release of
bioactives and nutraceuticals. These delivery systems typically
consist of micronutrients or bioactives trapped within nanoparti-
cles (rNanoliposomes are spherical liquid structures smaller than
200 nm with an aqueous core surrounded by a single (unilamellar)
or several lipid bilayer(s) (multi-lamellar liposomes). The primary
advantage of liposomes is their ability to deliver both hydrophilic
and lipophilic bioactive compounds, even simultaneously; and
their similarity to natural cell membranes is an additional advan-
tage (Livney, 2015). Antiproliferative and proapoptotic effect of
EGCG encapsulated CS-coated nanoliposomes (CSLIPO-EGCG) were
tested using MCF7 breast cancer cells (de Pace et al., 2013). EGCG
stability and sustained release was significantly improved by
CSLIPO-EGCG. Also, in comparison with native EGCG and void
CSLIPO, increased intracellular EGCG content in MCF7 cells,
induced apoptosis of MCF7 cells, and inhibited MCF7 cell prolifer-
ation were noted for CSLIPO-EGCG. Even at 10 lM or lower con-
centrations, the CSLIPO-EGCG retained its antiproliferative and
proapoptotic effectiveness, whereas native EGCG did not exhibit
any beneficial effects. The results clearly indicate the potential of
CSLIPO-EGCG in the prevention or even treatment of breast cancer.
Rashidinejad, Birch, Sun-Waterhouse, and Everett (2014) exam-
ined the encapsulation of green tea catechin and EGCG in soy
lecithin liposomes at four concentrations (0%, 0.125%, 0.25% and
0.5% w/v), and inclusion in cheese at 0% and 0.25% w/v. High
encapsulation efficiency (>70%) and yield (�80%) were achieved
from the incorporation of catechin or EGCG inside the liposome
structure. The empty liposomes possessed a Z-average diameter
of 133 nm. Loading the liposomes with either catechin or EGCG
at all concentrations significantly increased the Z-average diameter
of the liposomes. The mean potential of empty liposomes was
�45.1 ± 0.7 mV suggesting good stability against aggregation. The
addition of catechin or EGCG did not change the zeta potential of
liposomes significantly. The liposomes are stable from oxidation
at room temperature up to at least 50 �C, suggesting that they
are good carriers for bioactive compounds. Within a low-fat hard
cheese, nanocapsules containing these antioxidants were effec-
tively retained. The study concluded that encapsulation of catechin
and EGCG in liposomes is a promising technique to protect and
deliver antioxidants to the gut.
EGCG nanoliposomes (EN) were successfully prepared by an
ethanol injection method combined with dynamic high-pressure
microfluidization (Zou, Peng, et al., 2014). The fabricated EN pos-
sessed better physicochemical characteristics: 92.1% entrapment
efficiency, small average particle size of 71.7 nm, low polydisper-
sity index of 0.286 and zeta potential of �10.81 mV. A relatively
good sustained release property was exhibited by the EN. By nano-
liposome encapsulation, the stability of EGCG in simulated intesti-
nal fluid (SIF) was significantly improved, and the degenerations of
in vitro antioxidant activities of EGCG were effectively slowed. To
overcome tea polyphenols’ instability in oxygen and alkaline envi-
ronments, the same research group later used the same technique
P. Puligundla et al. / Journal of Functional Foods 34 (2017) 139–151 143
(ethanol injection method with dynamic high-pressure microflu-
idization) for the fabrication of tea polyphenol nanoliposome
(TPN) (Zou, Liu, et al., 2014). The formed TPN possessed
good physicochemical characterizations (entrapment effi-
ciency = 78.5%, particle size = 66.8 nm, polydispersity
index = 0.213, and zeta potential = �6.16 mV). TPN exhibited
equivalent antioxidant activities when compared with tea
polyphenol solution. In addition, a relatively better sustained
release property was observed in TPN, with only 29.8% tea
polyphenols released from nanoliposome after 24 h of incubation.
Furthermore, the stability of tea polyphenol in alkaline solution
was improved by TPN. Zou et al. (2015) developed a novel delivery
system by coating dextran sulfate (DS) on the surface of amphiphi-
lic chitosan derivative nanoliposome (DCMC-NL). EGCG was encap-
sulated in DS-DCMC-NL as a hydrophilic model drug. At first,
DCMC-NL was prepared by dynamic high pressure microfluidiza-
tion combined with a film evaporation method. Then, DS-DCMC-
NL was prepared by coating DCMC-NL with DS. EGCG loaded DS-
DCMC-NL exhibited a relative good sustaining release property,
with a high encapsulation efficiency of 90.8%. It was further noted
that the degradation of EGCG in SIF was effectively slowed by the
encapsulation with DS-DCMC-NL.
2.2. Lipid-based nanoparticles
Lipids are the predominant building blocks of some generally
used nanoparticles in delivery systems for bioactive compounds.
Such delivery systems include nanostructured lipid carriers (NLCs)
and/or solid lipid nanoparticles (SLNs), nanoemulsions and multi-
ple emulsions.
2.2.1. Nanostructured lipid carriers
Nanostructured lipid carriers (NLCs) are modified solid lipid
nanoparticles (SLNs) in which the lipidic phase contains both solid
(fat) and liquid (oil) lipids at room temperature (Muller, Radtke, &
Wissing, 2002). These are nanovehicle particles with mean
size � 100 nm. The partially solid material creates interesting
nanostructures which enhance stability of entrapped bioactives,
enables high loading capacities, and offers sustained release pro-
files (Livney, 2015). NLCs can be made by various traditional dis-
persion methods, including solvent diffusion method,
homogenization technique, double emulsion, supercritical fluid
technology, etc. Large-scale production of NLCs is easily possible
(Selvamuthukumar & Velmurugan, 2012).
SLNs can increase drug or bioactive stability and possess high
drug loading capacity. SLNs loaded with green tea extract (GTE)
were synthesized by high shear homogenization method (Manea,
Andronescu, & Meghea, 2014). Cetyl palmitate and glyceryl stea-
rate were used as solid lipids in combination with two nonionic
surfactants, Tween 20 and Tween 80, and lecithin, an ionic surfac-
tant. The SLNs with small sizes, most of the NPs being smaller than
200 nm and having narrow diameter distribution, were success-
fully produced. The obtained SLNs exhibit a good physical stability,
with zeta potential values ranging from �34.1 mV to �52.3 mV.
The evaluation of in vitro antioxidant properties has shown that
all the obtained GTE-SLNs have high antioxidant activity, for both
types of surfactants. Furthermore, some of the tested samples were
highly efficient against Escherichia coli bacteria.
Using natural lipids, surfactant, CS and EGCG, Zhang, Nie, and
Wang (2013) have successfully synthesized EGCG encapsulated
nanostructured lipid carriers (NLCE) and CS-coated NLCE (CSNLCE).
EGCG stability was dramatically improved by nanoencapsulation.
Compared with nonencapsulated EGCG, CSNLCE significantly
increased EGCG content in human monocytic THP-1 cell line-
derived macrophages. Both NLCE and CSNLCE at 10 lM concentra-
tion significantly decreased macrophage cholesteryl ester content
compared to nonencapsulated EGCG at the same concentration.
Also, mRNA levels and protein secretion of monocyte chemoattrac-
tant protein-1 (MCP-1) levels in macrophages were significantly
decreased by NLCE and CSNLCE. The results suggest that, through
decreasing macrophage cholesterol content and MCP-1 expression,
nanoencapsulated EGCG may have a potential to inhibit
atherosclerotic lesion development.
Recently, Zhang, Nie, Martinez-Zaguilan, Sennoune, and Wang
(2016) successfully delivered EGCG to macrophages via CD36-
targeted NPs. EGCG-loaded NPs (Enano) were prepared using phos-
phatidylcholine, kolliphor HS15, alpha-tocopherol acetate and
EGCG. A CD36-targeted ligand found on oxLDL, 1-(Palmitoyl)-2-(
5-keto-6-octene-dioyl) phosphatidylcholine (KOdiA-PC), was
incorporated on the surface of Enano to make ligand-Enano (L-
Enano). The optimized NPs obtained in the study were spherical
with �108 nm in diameter, and showed �10% of EGCG loading
capacity and 96% of EGCG encapsulation efficiency. The CD36-
targeted L-Enanogreatly improved EGCG stability, delivered EGCG
to macrophage cytosol avoiding lysosomes and increased macro-
phage EGCG content. The macrophage mRNA levels and protein
secretion of monocyte chemoattractant protein 1 were signifi-
cantly decreased by L-Enano, but without a significant change in
macrophage cholesterol content. The results suggest that the
CD36-targeted NPs can facilitate targeted delivery of diagnostic,
preventive and therapeutic compounds to intimal macrophages
for the diagnosis, prevention and treatment of atherosclerosis with
enhanced efficacy and decreased side effects.
2.2.2. Nanoemulsion
Nanoemulsions are nano-scaled emulsions, in which the size of
the dispersed oil droplets is below a few 100 nm. They may be oil-
in-water (O/W) or water-in-oil (W/O) (or even bi-continuous), and
either liquid in liquid, or liquid in solid (Livney, 2015). Because of
their characteristic size, many nanoemulsions are thermodynami-
cally unstable systems, and may possess high kinetic stability. They
are generally made either by high shear-high energy homogeniza-
tion methods, or by low energy, spontaneous self-emulsification
methods (Komaiko & McClements, 2015). Nanoemulsions do not
cream (or sediment) because the Brownian motion is larger than
the small creaming rate induced by gravity (Huang et al., 2010),
and have greater surface area providing greater absorption. As a
drug delivery system they enhance physical stability and bioavail-
ability of drug, and therefore the therapeutic efficacy of drug can
be improved, minimizing adverse effect and toxic reactions
(Jaiswal, Dudhe, & Sharma, 2015).
Because of its highest free radical scavenging activity, EGCG is
considered the most significant tea catechin (Peng, Wargovich, &
Dixon, 2006). However, reports indicate that the bioavailability of
EGCG is very poor due to its large molecular size and number of
hydrogen bonds (Lante & Friso, 2013). The use of ultrasound to
extract catechins from green tea leaves with improved EGCG yield
has been demonstrated (Peng et al., 2006). Subsequently, W/O
green tea nanoemulsions were prepared with soy, peanut, sun-
flower, and corn oils. The green tea/peanut oil emulsion displayed
the highest oxidative stability. The specific surface area of the
nanoemulsions was very high and with an average value of about
40 m2/mL. The high surface area-to-mass ratio of the nanoemul-
sions indicates that they may be a promising vehicle for delivering
green tea bioactive compounds in nutraceutical applications.
In order to develop biocompatible carriers for the EGCG active
component of green tea, EGCG submicrometer O/W emulsions sta-
bilized by i-carrageenan and b-lactoglobulin were successfully
prepared by high-pressure homogenization (Ru, Yu, & Huang,
2010). In the process, emulsion (O/W) with a droplet size of about
400 nm was used to encapsulate EGCG. The results showed that
EGCG could be successfully encapsulated in O/W emulsion when
144 P. Puligundla et al. / Journal of Functional Foods 34 (2017) 139–151
EGCG concentration was up to 0.5% in the emulsion. Only negligi-
ble changes in emulsion droplet sizes were observed over a 14-day
storage. In addition, in comparison with the free EGCG, EGCG
encapsulated in an O/W submicrometer emulsion exhibited an
enhanced in vitro anticancer activity.
Kim et al. (2012) investigated the antioxidant and hypolipi-
demic effects of nanoemulsified green tea extract (NGTE) produced
using niosome technology and compared with regular GTE. The
average droplet size of nanoemulsion tested in the study was
approximately 300 nm in diameter. Total phenolic content was
104.7 and 87.5 mg/mL for GTE and NGTE, respectively. The total
flavonoid content was 38.48 and 42.98 mg/mL for GTE and NGTE,
respectively. Total catechin content was similar between NGTE
and GTE, i.e., about 15 mg/100 mg extract, indicating that the
nanoemulsion successfully captured the major active compounds
during the emulsification process. The antioxidative effect of GTE
was comparable with that of NGTE. In the mouse feeding experi-
ment, total and low-density lipoprotein (LDL) cholesterol concen-
trations were significantly reduced after NGTE treatment in
comparison with GTE treatment in high-fat-fed mice. The hypoc-
holesterolemic effects were greater in the NGTE group compared
with the GTE group.
Green tea catechins and Cranberry are well known to exhibit
antibacterial activity. Gupta et al. (2014) encapsulated polyphenon
60 (green tea catechins) and cranberry in a single nanoemulsion
system with an objective to have enhanced antibacterial effect
using single carrier. Developed nanoemulsion was able to inhibit
the growth at lower concentration as compared to the aqueous
formulation.
A stable formulation that delivers nanoemulsion consisting of
major catechins from the decaffeinated green tea was developed
by Gadkari and Balaraman (2015). Catechins were extracted using
hot water at various temperatures from supercritical CO2 decaf-
feinated green tea. The catechins extract were encapsulated at a
concentration of 0.1% (w/w) in lipid based nanoemulsion delivery
systems using sunflower oil and palm oil with the combination
of hydrophilic and lipophilic emulsifiers in a two-step process
involving high shear and high pressure homogenization. Encapsu-
lated extracts possess a significant amount of antioxidant activities
for maintaining the lag phase in oxidation of nanoemulsions. The
oxidation of nanoemulsions was arrested by the catechins in all
the formulations. In all the nanoemulsions, there was a good dis-
persion of oil in the continuous phase. The rheological properties
of nanoemulsion showed the Newtonian behavior of formulations.
The study concluded that nanoemulsions consisting of catechins
could be used in the field of nutraceuticals.
The effect of emulsion- based nanoencapsulation on the physic-
ochemical stability, in vitro bioaccessibility and epithelial perme-
ability of green tea catechins has been reported (Anu-Bhushani,
Karthik, & Anandharamakrishnan, 2016). The soy protein stabilized
nanoemulsion (O/W) formulation containing 10% oil and 0.5% cat-
echins was found to be stable, at refrigeration temperature, against
creaming, phase separation, sedimentation and changes in droplet
size, pH and catechin content. Compared to unencapsulated cate-
chins, a 2.78-fold increase in the bioaccessibility of major catechins
in the nanoemulsified form was observed. In addition, there was a
significant increase in intestinal permeability of catechins as
assessed by Caco-2 cell model. The results indicated that soy pro-
tein based nanoemulsions can improve the stability, bioaccessibil-
ity and permeability of green tea catechins.
2.2.3. Multiple emulsions
Multiple emulsions are complex polydispersed systems where
both oil-in-water and water-in-oil emulsion exists simultaneously
which are stabilized by lipophilic and hydrophilic surfactants
respectively (Khan, Talegaonkar, Iqbal, Ahmed, & Khar, 2006).
Cationic lipid nanoparticle (LN) dispersions loading EGCG were
successfully produced by multiple emulsion (W/O/W – water-in-
oil-in-water) technique (Fangueiro et al., 2014). EGCGwas incorpo-
rated in the aqueous core surrounded by a lipid layer composed of
physiological lipids. LNs with mean size below 300 nm showed pH,
osmolarity and viscosity compatible to the ocular administration.
The encapsulation of EGCG in the inner aqueous phase of double
emulsion also affected the crystal structure of LNs dispersions.
The study results evidence the possibility of lipid based systems
for EGCG ocular drug delivery. With this approach, drug stability
problems can be avoided and can provide a selective and pro-
longed drug concentration of EGCG in the eye. The results of a con-
tinuation study by the same research group indicated that the LNs
provide a prolonged release of EGCG, following the Boltzmann sig-
moidal release profile (Fangueiro et al., 2016). The ex vivo perme-
ation of EGCG was achieved in rabbit cornea and in the sclera.It
was concluded from the results that cationic LNs may provide
higher drug residence time, higher drug absorption and conse-
quently higher bioavailability of EGCG in the ocular mucosa. The
obtained results also proved the safety and non-irritant nature of
the developed LNs.
Mahmood, Akhtar, and Manickam (2014) developed stable mul-
tiple emulsions loaded with green tea and lotus extracts. Multiple
W/O/W emulsions have been generated using cetyl dimethicone
copolyol as lipophilic emulsifier and a blend of polyoxyethylene
(20) cetyl ether and cetomacrogol 1000� as hydrophilic emulsi-
fiers. It was found that the hydrophilic emulsifiers and hydrox-
ypropyl methylcellulose, a thickener, have considerably improved
the stability of multiple emulsions for the followed period of
12 months at different storage conditions. Conductivity analysis
revealed that entrapment efficiency of multiple emulsions was
excellent enough to offer sustained release of bio-functional
agents. The study concluded that the green tea and lotus extracts
loaded multiple emulsions are excellent carrier of these powerful
antioxidant substances ensuring long term stability of actives,
and could be explored for their cosmetic benefits.
Aditya et al. (2015a) investigated the formulation factors that
determine the stability of curcumin and catechin and their carrier
systems, and also fabricated emulsions (W/O/W) to prevent the
degradation of both the nutraceuticals in beverage systems. The
results showed that factors such as co-excipients, temperature,
and formulation stability can directly or indirectly affect the stabil-
ity of core materials, particularly catechin. The fabricated emulsion
exhibited a volume-weightedmean diameter (d43) of�4 m, with an
encapsulation efficiency of >90%. Encapsulating the catechin within
the inner aqueousphaseof thedouble emulsion increased the stabil-
ity of catechin by >20% at 23 ± 2 �C and by >40% at 4 �C after 15 days
of incubation, as compared to free catechin. In conclusion, encapsu-
lation of both curcumin and catechin, either individually or in com-
bination, has been shown to cause significant increase in their
stability in amodel beverage system. In a separate study, encapsula-
tion of green tea bioactives (catechins) in aW/O/Wdouble emulsion
has been reported by Aditya et al. (2015b). In that study, curcumin
and catechin co-loaded emulsion was fabricated using a two-step
emulsification method. Volume-weighted mean size (d43) of emul-
sion droplets �2.8–3.0 lm for curcumin and/or catechin-loaded
emulsions. High entrapment efficiencies of the bioactives in the
range 88–97% were observed, and noted a four-fold augmentation
in their bioaccessibility compared to that of freely suspended cur-
cuminand catechin solutions. And, no adverse effects on either com-
pound’s stability due to co-loading were noted.
2.3. Biopolymer-based nanoparticles
A range of colloidal delivery systems can be fabricated from
food grade biopolymers, such as proteins and polysaccharides
P. Puligundla et al. / Journal of Functional Foods 34 (2017) 139–151 145
(Joye et al., 2014). These include polyelectrolyte complexes, poly-
meric nanoparticles, hydrogel particles, and filled hydrogel parti-
cles (Matalanis, Jones, & McClements, 2011).
2.3.1. Polyelectrolyte complexes
Polyelectrolyte complexes are formed by the electrostatic inter-
action between two or more oppositely charged polyelectrolytes in
solution. A simple method for preparation of EGCG NPs by self-
assembly complexation between the positive charge of chitosan
(CS) and the negative charge of sodium carboxymethylcellulose
(SCMC) was developed by Okonogi, Saengsitthisak, and Duangrat
(2007). The nanoparticles obtained were spherical with the size
range around 200–300 nm. The ratio of 1:1:0.1 (CS:SCMC:EGCG)
was found to be the suitable systems to prepare NPs with the high-
est entrapment efficiency (EE) of 98.04%.
The efficacy of nanoparticulate technology to enhance the ther-
apeutic effectiveness of EGCGwas showed by Siddiqui et al. (2009).
They encapsulated green tea polyphenol EGCG in polylactic acid-
polyethylene glycol NPs. The effectiveness of nano-EGCG versus
nonencapsulated EGCG on proliferative ability in human prostate
cancer (PCa) PC3 cells was compared. The obtained results clearly
suggest that nano-EGCG retains its biological effectiveness
with >10-fold dose advantage over nonencapsulated EGCG for
exerting proapoptotic and angiogenesis inhibitory effects, which
are critically important determinants of chemopreventive effects
of EGCG in both in vitro and in vivo systems.
EGCG was encased into gelatin-based 200–300 nm nanoparti-
cles consisting of a soft gel-like interior and a surrounding shell
of polyelectrolytes (polystyrene sulfonate/polyallylamine
hydrochloride (PSS/PAH), polyglutamic acid/poly-L-lysine (PGA/
PLL), dextran sulfate/protamine sulfate (DexS/ProtS), car-
boxymethyl cellulose/gelatin, type A (CMC/GelA)) assembled using
the layer-by-layer technique (Shutava et al., 2009). Nanoparticle-
encapsulated EGCG retained its biological activity and blocked
hepatocyte growth factor (HGF)-induced intracellular signaling in
the breast cancer cell line MBA-MD-231 as potently as free EGCG.
Gelatin nanoparticles with PSS/PAH bilayer loaded with EGCG
demonstrated sustained release (the maximum concentration of
EGCG in solution was reached at 8 h) as compared with almost
immediate 15 min EGCG release from uncoated gelatin
nanoparticles.
Successful encapsulation of EGCG in novel nanocomplexes
(nanoparticles) assembled from food grade bioactive peptides,
caseinophosphopeptides (CPPs), and CS was achieved (Hu, Ting,
Zeng, & Huang, 2012) by an easy and robust self-assembly method.
The particle sizes and surface charges of the formed spherical NPs
were in the range of 150.0 ± 4.3 nm and 32.2 ± 3.3 mV respectively.
The intestinal permeability of EGCG using Caco-2 monolayer was
enhanced significantly as delivered by NPs, and the CS NPs exhib-
ited reduced cytotoxicity. Additional study showed that the EGCG-
loaded CS–CPP NPs remained intact in the range of pH 2.5–7.0 (Hu
et al., 2012). The CS–CPP NPs were biocompatible and able to
enhance the intestinal permeability and absorption of EGCG signif-
icantly. The study concluded that EGCG-loaded CS–CPP NPs are
believed to be effective for nanochemoprevention in cancer man-
agement and prevention. A further investigation, by the same
group (Hu et al., 2013), showed that the encapsulation efficiency
of EGCG in CS–CPP NPs was in the range of 70.5–81.7%. A con-
trolled release of EGCG from CS–CPP NPs was observed under
in vitro conditions. In the cellular antioxidant activity assay, the
EGCG-loaded CS–CPP NPs exerted stronger activity of scavenging
free radical than the free EGCG (p16.9 ± 5.8%, which was close to that of oral simvastatin
(15.6 ± 4.1%). For EGCG alone administered orally, the average ratio
of lipid deposit area was 42.1 ± 4.0%, whereas this value was
65.3 ± 10.8% for the blank NPs. The results indicated that the effec-
tiveness of EGCG against rabbit atherosclerosis was significantly
improved by incorporating EGCG into the nano-formulation.
Modification of CS through grafting with the phenolic acids, caf-
feic acid (CA, CA-g-CS) and ferulic acid (FA, FA-g-CS), was shown to
significantly improve its solubility under neutral and alkaline envi-
ronments (Hu et al., 2016). They investigated the EGCG encapsula-
tion in CA-g-CS-CPP and FA-g-CS-CPP nanocomplexes. Novel
polymer nanocomplexes composed of the phenolic acid grafted
CS and CPP were prepared initially in the process with particle
sizeefficacy of 97.33%, average particle
size of 84.55 nm, and zetapotential of 29.23 mV. Compared to only
TP loaded b-CS NPs, TP-Zn complex loaded b-CS NPs exhibited
higher antioxidant activity. The in vitro release study conducted
at pH 4.5 and 7.4 showed that the TP-Zn complex loaded b-CS
NPs sustained the release of the TP-Zn complex over 5.5 h. TP-Zn
complex was well incorporated into CS NPs and NPs exhibited
hardly any cytotoxicity. The results suggested that TP-Zn complex
loaded b-CS NPs can be used as an antioxidants delivery system for
food, dietary supplement, and other fields. In a continuation study
by the same research group, catechins (CAT) or CAT-Zn complex
loaded b-CS NPs were fabricated (Zhang, Jung, & Zhao, 2016). The
CAT-Zn complex loaded b-CS NPs exhibited particle size of 208–
591 nm, polydispersity index of 0.377–0.395, and positive zetapo-
tential of 39.17–45.62 mV. The antibacterial activity of CAT or CAT-
Zn complex loaded b-CS NPs against E. coli and Listeria innocua
were investigated based on bacterial growth curve, minimum inhi-
bitory concentration (MIC), and minimum bacterial concentration
(MBC). The MIC and MBC of CAT-Zn complex loaded b-CS NPs of
the smallest particle size against L. innocua and E. coli were 0.031
and 0.063 mg/mL, and 0.063 and 0.125 mg/mL, respectively. The
results indicated that encapsulation of CAT-Zn complex in b-CS
NPs improved the antibacterial activity of CAT and CAT-Zn com-
plex, and the encapsulators have great potential to be used as
antibacterial substances for food and other applications through
either direct addition or incorporation into packaging materials.
2.3.3. Polymeric nanoparticles
Polymeric nanoparticles (10–1000 nm) are prepared from bio-
compatible and biodegradable polymers where the drug/bioactive
is dissolved, entrapped, encapsulated or attached to a nanoparticle
matrix (Nagavarma, Hemant, Ayaz, Vasudha, & Shivakumar, 2012).
Narayanan et al. (2014) fabricated poly-L-lactide-co-glycolic acid
(PLGA)–casein NPs entrapping paclitaxel (Ptx) in the core and
EGCG in the shell by a simple emulsion–precipitation route. In vivo
pharmacokinetic studies in rats confirmed a sustained and sequen-
tial release of both the drugs from the NPs in plasma. In a contin-
uation study, by the same group, the chemotherapeutic effect of
the NPs against breast cancer cells (MDA-MB-231 cells and
patient-derived tumor cells) was determined (Narayanan et al.,
2015). The obtained results showed that the sequential release of
EGCG followed by Ptx from this core/shell nanocarrier sensitized
Ptx resistant MDA-MB-231 cells to Ptx, induced their apoptosis,
inhibited NF-jB activation and downregulated the key genes asso-
ciated with angiogenesis, tumor metastasis and survival.
Sanna et al. (2011) designed and developed novel targeted NPs
(EGCG-loaded PLGA-PEG NPs) in order to selectively deliver EGCG
to prostate cancer cells. The EGCG-loaded NPs exhibited a selective
in vitro efficacy against prostate-specific membrane antigen
(PSMA)-expressing PCa cells. The results also demonstrate that
the effectiveness of EGCG encapsulated NPs, in terms of antiprolif-
erative efficacy, can be significantly improved by incorporating
P. Puligundla et al. / Journal of Functional Foods 34 (2017) 139–151 147
specific ligands, such as small organic molecules, onto the NP sur-
face in order to bind PSMA antigen present on PCa cells.
3. Possible mechanisms of nanoparticle-based delivery systems
in enhancing bioavailability of green tea polyphenols
One of the primary reasons for the poor oral bioavailability of
many drugs/bioactives is due to their extensive first-pass metabo-
lism. Nanoparticle delivery systems may increase drug/bioactive
levels by avoiding presystemic hepatic metabolism (Suffredini &
Levy, 2013). Nanoparticle-based delivery systems may enhance
oral absorption of drug/bioactive by increasing the gastric resi-
dence time through mucosal adhesion (Takeuchi, Yamamoto,
Niwa, Hino, & Kawashima, 1996) or by increasing cell or tissue
entry (e.g., Peyer’s patches and M cell-mediated uptake)
(Florence, 2005; Torché et al., 2000). Nanoparticle formulations
may reduce tea polyphenols exposure to the adverse conditions
in the GI tract, thereby minimizing enzymatic and nonenzymatic
degradations, and this can result in increased plasma exposure of
the bioactive. The encapsulation of drug/bioactive molecules in
nanoparticles can significantly reduce their apparent clearance
from plasma, thereby enhancing the apparent drug/bioactive circu-
lation half-life and potential cumulative drug/bioactive delivery to
the target tissues (Kadam, Bourne, & Kompella, 2012). Enhanced
bioavailability can also result from the reduction of transporter-
mediated efflux by bioactive-loaded nanoparticles. The transport
ways that enhance the GI absorption of phenolic phytochemicals
encapsulated in nanoparticles are illustratively shown in Fig. 2.
Most of the investigated nanoparticle-based delivery systems
for green tea polyphenols used chitosan. Chitosan (CS), a linear
polymer composed of randomly distributed b-(1? 4)-linked D-
glucosamine and N-acetyl-D-glucosamine, is the only alkaline nat-
ural polysaccharide with degradable, biocompatible, and film-
forming properties. Chitosan possess some unique properties such
as controlled release, in situ gelling, mucoadhesion, hydrophilic
character, transfection enhancing, permeation enhancing, and
efflux pump inhibitory properties, which make it an ideal candi-
date for drug delivery applications. Chitosan possess positive
charge and therefore bind strongly to negatively charged surfaces,
Fig. 2. Cellular uptake of nanoparticles by epithelial cells (Li et
and this feature is responsible for many of observed biological
activities (Manivasagan, Senthilkumar, & Venkatesan, 2013).
Chitosan NPs have the ability to prevent oxidation/degradation
of tea polyphenols encapsulated within them in GI tract (Liang
et al., 2017). CS NPs have been reported to adhere to the GI tract
for a longer time. CS NPs can cross intestinal epithelial cell mem-
brane, and nano-sized particles are conducive to increased trans-
shipment across intestinal epithelial cells as chitosan structures
bigger than nano-sized chitosan mainly adhere on the cell surface
and difficult to enter into cell (Jia, Chen, Xu, Han, & Xu, 2009). CS
NPs carrier has been shown to inhibit intestinal P-gp (ABC trans-
porter) and enhance nutrient oral absorption (Mo et al., 2011).
The possible interactions between polymeric efflux pump inhibi-
tors (like chitosan) and efflux pumps as follows: (a) inhibition
mediated by ATP depletion, (b) inhibition mediated by interactions
with the membrane, (c) bypassing drug/bioactive efflux by a drug-
polymer conjugate, (d) inhibition mediated by interfering with
ATP-binding sites and (e) blocking of drug/bioactive binding sites
or other sites within the trans-membrane domains (Werle, 2008).
CS NPs as carrier can promote paracellular transport via reversibly
opening the tight junctions between epithelial cells (Hamman,
Stander, Junginger, & Kotze, 2000). It has been showed that
EGCG-loaded CS NPs could enter Caco-2 cells in dose and time
dependent manner, and the intestinal permeability and absorption
of EGCG was enhanced obviously as delivered by CS NPs (Hu et al.,
2012). In a study, the plasma exposure of EGCG was significantly
enhanced when delivered via CS NPs and this enhancement is
attributed to an increased exposure of EGCG to the jejunum due
to the stability-enhancing effect of the chitosan nanoparticles
(Dube, Ng, Nicolazzo, & Larson, 2011).
4. Limitations and challenges
Despite several advantages, nanodelivery systems suffer some
limitations such as the formation of nanoparticle aggregates. This
phenomenon makes physical handling of NPs difficult in liquid
and dry forms. A limited drug/bioactive loading and burst release
due to small particle size and large surface area are the additional
limitations (Mohanraj & Chen, 2006). A limited number of studies
al.,2015). Reproduced with permission from the publisher.
148 P. Puligundla et al. / Journal of Functional Foods 34 (2017) 139–151
have shown whether the NPs could protect EGCG from degradation
and oxidation (Granja, Pinheiro, & Reis, 2016). Since EGCG is very
susceptible to oxidation, especially in alkaline environments,
oxidative degradation studies would be particularly useful.
Nanoparticles after entering the GI tract are exposed to different
pH, excess amount of ions, and different kinds of digestive
enzymes, which may affect efficacy of nanoparticles for delivery
of phenolic phytochemicals (Li, Jiang, Xu, & Gu, 2015), including
green tea polyphenols.
In the case of nanoemulsions, emulsion stability is regarded as a
concern although these systems could remain stable for many
years. The instability of nanoemulsion is mainly due to intrinsic
factors including Oswald ripening, creaming, flocculation, and coa-
lescence, which could damage nanoemulsions. Nanoemulsion sta-
bility is also influenced by environmental parameters such as
temperature and pH (Chime, Kenechukwu, & Attama, 2014). For
stabilizing the nanodroplets, use of a large concentration of surfac-
tant and co-surfactant is necessary and there is a limited solubility
capacity for high melting substances. Additional challenges include
lack of understanding of the mechanism of submicron droplets
production and the role of surfactants and cosurfactant, and lack
of understanding of the interfacial chemistry that is involved in
production of nanoemulsions.
5. Safety aspects
The majority of the studies have focused on biopolymeric NPs
and liposomes, possibly due to their beneficial properties such as
biocompatibility (Granja et al., 2016). NPs made from biopolymers
are generally biodegradable and rarely pose any toxicity to normal
cells; therefore, such NPs are considered to be safe (Siddiqui,
Shukla, & Mukhtar, 2011). For safe application of nanotechnology
to the food industry, thorough characterization and assessment
in silico, in vitro, and in vivo have been recommended (He &
Hwang, 2016). Biocompatibility of biomaterial can be further
enhanced by modification of polymer with peptides, which elicit
a specific cellular response (Shoichet, 2010). Besides biocompati-
bility, cellular toxicity of NPs depends on several other factors
including surface charge.
Safety of EGCG-functionalized radioactive gold NPs has been
assessed. Intratumoral injection of gold NPs coated with EGCG
has shown high gold retention in tumor site and low gold leakage
into normal tissues, leading to pronounced tumor inhibition with-
out perceived host toxicity (Zhang, Wu, Wang, Wan, & Zhang,
2014). In some EGCG-anticancer activity studies, it was shown that
EGCGs were physically attached onto the surface of nanogold par-
ticles (pNG) (Hsieh et al., 2011). Although the prepared EGCG–pNG
were shown to be more effective than free EGCG in inhibiting blad-
der tumor in model mice, viabilities of both bladder cancer cells
(MBT-2) and Vero cells (acts as a normal cell) were significantly
decreased upon increasing the concentrations of EGCG and pNG
to 50 lM and 2 ppm, respectively, in EGCG-pNG complex. There-
fore, further studies on dose optimization and cytotoxicity to nor-
mal cells at higher concentrations are warranted to assess and
improve their in vivo safety.
It has been shown that theaflavins (TFs) and EGCG act as both
antioxidants and pro-oxidants, depending on the form in which
they are administered under the conditions of investigation
(Alotaibi et al., 2013). In that study, polymer (poly [lactic-co-
glycolic acid])-based NPs encapsulating EGCG were prepared. The
DNA damage effect of these NPs was tested in vitro against lym-
phocytes of healthy volunteers and colorectal cancer patients pre-
treated with oxaliplatin or satraplatin. The results showed that
encapsulated EGCG significantly intensified DNA damage levels
in a dose-dependent manner. In contrast, bulk form or non-
encapsulated EGCG promoted a reduction in DNA damage. TFs
and EGCG administered in NP form may switch their mode of
action in vitro, causing them to act as pro-oxidants at higher con-
centrations (Alotaibi et al., 2013). Therefore, further studies are
needed to determine whether NPs encapsulating EGCG at higher
concentrations exert pro-oxidant effects in normal cells under
in vivo conditions.
In addition, possible toxicity concerns related to chemical com-
ponents other than biocompatible materials used in the fabrication
of nanoparticle delivery systems need to be verified. For instance,
toxicity may arise from surfactants used in emulsions formulation
as most commercially available surfactants are generally of low
purity (contains surface-active impurities).
6. Conclusion
Nanotechnological methods may aid in the sustained release of
orally administered green tea polyphenol concentrates in the GI
tract, which in turn could improve their stability and enhance
bioavailability. The GI degradation of polyphenols can be mini-
mized or prevented through nanoencapsulation. In addition, the
potential antinutritional property of tea polyphenols could be
avoided through nanoencapsulation approaches as it has been
shown that tea polyphenol at a concentration of 0.05 mg/mL can
significantly inhibit the activities of four digestive enzymes,
including a-amylase, pepsin, trypsin, and lipase, under in vitro con-
ditions (He, Lv, & Yao, 2007).
At present, nanoencapsulation of green tea polyphenols using
biopolymers (e.g., CS), in the form of biopolymer-based nanoparti-
cles, is a most popular approach compared with other methods. For
instance, EGCG-loaded CS-CPP NPs can be synthesized by an easy
and robust self-assembly method (Hu et al., 2012). And, the CS–
CPP NPs were shown to be biocompatible and able to enhance
the intestinal permeability and absorption of EGCG significantly.
However, each fabrication technique has its own advantages and
disadvantages.
Conflict of interest
None.
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