R: Concise Reviews

in Food Science

JFS R: Concise Reviews and Hypotheses in Food Science

Bioavailability and Delivery of Nutraceuticals

Using Nanotechnology
QINGRONG HUANG, HAILONG YU, AND QIAOMEI RU
Editors note: We are pleased to present in this issue 3 of 6 papers presented in symposia at the IFT09 annual meeting in Anaheim,
Calif. that were organized by Jochen Weiss, Univ. of Hohenheim, and Kumar Mallikarjunan, Virginia Polytechnic & State Univ., with
coordination by Professor M.A. Rao, Scientific Editor of the Nanoscale Food Science, Engineering, and Technology section of the Journal
of Food Science. The Concise Reviews and Hypotheses section of JFS continues to serve as a mechanism to publish several peer-reviewed
papers as a group. We look forward to receiving other opportunities to bundle papers together to serve the scientific community.
Daryl Lund, Editor in Chief

ABSTRACT: Nanotechnology is an enable technology that has the potential to revolutionize agriculture and food
systems. Driven by increasing consumer demand for healthy food products, researchers have been applying tools
and knowledge in nanotechnology to address the issues relevant to food and nutrition. This concise review is mainly
focused on nanoemulsions and polymer micelles-based delivery systems which have shown enhanced oral bioavailability and biological efficacies (that is, antiinflammation, anti-cancer, and so on) of different phytochemicals.
Nanoemulsions are a class of extremely small droplets that appear to be transparent or translucent with a bluish
coloration. They are usually in the range 50 to 200 nm but much smaller than the range (from 1 to 100 m) for conventional emulsions. Nanoemulsion preparation, characterization, and bioavailability have been discussed. Curcumin nanoemulsions show 85% inhibition of TPA-induced mouse ear inflammation as well as the inhibition of
cyclin D1 expression, while dibenzoylmethane (DBM) nanoemulsion shows about 3-fold increase in oral bioavailability compared to the conventional DBM emulsion. Biopolymer micelles show significantly improved water
solubility/dispersibility and in vitro anti-cancer activity of phytochemicals. More research efforts are still needed
for the understanding of the potential impacts of nanoencapsulated phytochemicals on the human body and environment to address the public concerns.
Keywords: biopolymer micelles, curcumin, nanoemulsions, nanoencapsulation, nutraceuticals

Introduction

sive review of the applications of nanotechnology in food science

and agricultural sector is also available (Moraru and others 2009).
One important application of nanotechnology in food and nutrition is to design and development of novel functional food ingredients with improved water solubility, thermal stability, oral
bioavailability, sensory attributes, and physiological performance.
According to the Intl. Food Information Council (IFIC), functional food is defined as foods that provide health benefits beyond basic nutrition (Shibamoto and others 2008; Vaclavik and
Christian 2008). Driven by increasing consumer demand for novel
food products, as well as increased fortification with healthy
food ingredients, the functional food market is expected to increase at an annual growth rate of 5.7% between 2007 and 2012
(http://www.foodsciencecentral.com). For example, phytochemicals, which are food supplements with health benefits, are commonly used as part of the daily diet. Because of their low solubility,
many phytochemicals are poorly absorbed by human body, thus
one of the most important and interesting applications for encapsulation of phytochemicals is to enhance the bioavailability of
phytochemicals by changing the pharmacokinetics (PK) and
biodistribution (BD). In recent years, extensive research has been
carried out to study the health promotion properties of differMS 20091048 Submitted 10/22/2009, Accepted 10/28/2009. Authors are ent phytochemicals and to devise novel encapsulation materials
with Dept. of Food Science, Rutgers Univ., 65 Dudley Road, New and methods, trying to incorporate functional ingredients into
Brunswick, NJ 08901, USA. Direct inquiries to author Huang (E-mail: foods (Pegg and Shahidi 2007; Huang and others 2009a). To enqhuang@aesop.rutgers.edu).
hance nutritional quality and stability of the functional foods, one

anotechnology is an enabling technology that has the potential to revolutionize agriculture and food systems. The unusual properties of materials that are on the nanometer (109 m)
length scale, and the development of technology to manipulate or
self-assemble such materials molecule by molecule, provide potentially world-changing scientific, technological, and commercial opportunities. Nanoscale control over food molecules may lead to the
modification of many macroscale characteristics, such as texture,
taste, other sensory attributes, processability, and stability during
shelf life. The applications of nanotechnology in food and agricultural systems are growing very fast. Since the 1st feature article in Food Nanotechnology was published in 2003 (Moraru and
others 2003), there is a growing interest in this exciting research
area. Several more feature articles have recently been published
to address the potential of food nanotechnology in the areas of
food safety/security (Baeumner 2004), functional foods for health
promotion applications (Chen and others 2006; Weiss and others
2006), nanoscale properties of food materials (Lee and others 2007),
and structural design principles for delivery of bioactive components (McClements and others 2009). A more recent comprehen-

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R
2009 Institute of Food Technologists
doi: 10.1111/j.1750-3841.2009.01457.x


C

Further reproduction without permission is prohibited

option is to encapsulate the functional ingredients using foodgrade or generally recognized as safe (GRAS) materials that
can exhibit controlled-release behavior. Materials that can fulfill
these requirements include polysaccharides of plant (for example,
pectin, starch, gum Arabic, carrageenan, and so on) or microbial
(that is, Xanthan gum, dextran) origin, food proteins (for example, soy proteins, casein, gelatin, oat proteins, whey proteins, and
so on), emulsifiers, such as lecithin, Tweens, Spans, sugar esters,
monoglycerides, and so on.
Encapsulation and controlled-release of active food ingredients
are important applications in food and nutrition that can be attained with nanotechnological approaches. Target delivery of nutrients to cells and cellular compartments was highlighted in the
Experimental Biology 2009 symposium entitled Nanotechnology
Research: Applications in Nutritional Sciences as an example of research area in food and nutrition with nanotech enhancement potential (Srinivas and others 2009). Although many different delivery
systems are now available to delivery bioactive components in nutraceuticals and functional foods (McClements and others 2009),
clear in vitro or in vivo evidences of their biological efficacies are
still limited. In this review article, we introduce some typical foodgrade delivery platforms with demonstrated biological efficacy that
can be used by food and beverage industry to deliver functional
ingredients (that is, nutraceuticals). Formulation strategies and examples of the biological efficacy of encapsulated nutraceuticals are
also provided.

Nanoemulsions-Based Delivery Systems

dministration of active phytochemical components into the

human body requires the use of an appropriate vehicle for
bringing an effective amount of the active component intact to
the desired site in the body. The desired site varies and it may be
the blood stream, organs, and cells, and so on. Majority of phytochemicals, such as polyphenols and carotenoids, are either poorly
soluble or lipophilic compounds. It is known that the delivery of
these phytochemicals is significantly influenced by their physicochemical properties, such as water solubility, partition coefficient,
lipophilicity, and crystallinity, and so on. Active components that
poorly dissolve in oil or water pose a problem as to the route for
their administration, transport, and reaching their targets, resulting in a poor oral bioavailability. Constructing an appropriate vehicle and the desired efficient formulation possess a challenge to
dietary supplement researchers. To overcome instability, poor water solubility, and to enhance the bioavailability of nutraceuticals,
one option to entrap the compound of interest into a food matrix
is to use nanoemulsion. Nanoemulsions are a class of extremely
small droplet emulsions that appear to be transparent or translucent with a bluish coloration. They contain continuous phase, dispersed phase and emulsion stabilizer, the emulsifier or called the
surfactant. They are usually in the range 50 to 200 nm but much
smaller than the range (from 1 to 100 m) for conventional emulsions (Solans and others 2005). Since an emulsifier molecule size
is typically 2 nm long, a micelle, that is, a surfactant molecule aggregate in water is typically 5 nm or more in diameter. When oil
phase molecules enter the micellar core, the aggregates get swollen,
sometimes to a large extent, to produce a spherical object whose
size can reach 100 nm or more. Compared with conventional methods, such as co-solvent addition, micronizing/milling, spray drying, and salt formation, the use of lipid based delivery systems,
such as micro/nanoemulsions and micelles, offers many advantages: (i) high kinetic or thermodynamic stability, which provides
significantly better stability over unstable dispersions, such as conventional emulsions and suspensions; (ii) either hydrophilic or

lipophilic phytochemicals can be incorporated into the same nanoemulsions; and (iii) because of the small droplet sizes, phytochemicals can be transported through the cell membranes much
more easily, resulting in an increased phytochemical concentration
in plasma and bioavailability.
It should be pointed out that nanoemulsions are nano-scaled
emulsions, in which the size of the dispersed oil droplets is below a
few 100 nanometers. On the other hand, conventional microemulsions, which are thermodynamically stable, optically transparent,
and have droplet sizes smaller than 100 nm, are often also called
nanoemulsions. Thermodynamically stable microemulsion systems were reviewed extensively in other articles (Lawrence and
Rees 2000; Narang and others 2007; Gupta and Moulik 2008). However, there are not many food-grade microemulsion systems available. In addition, they often require high oil or emulsifier contents,
or the use of organic cosolvents like ethanol. Therefore, one has to
balance the benefits brought by the use of bioactives and potential side effects (that is, obesity, cardiovascular diseases, and so on)
caused by the use of high amount of lipids.

Nanoemulsion preparation and characterization

Nanoemulsion stability implies a high interfacial tension, and
thus a considerable surface energy (which is the surface tension
times the surface area). Although many nanoemulsions are thermodynamically unstable systems, because of their characteristic
size, they may possess high kinetic stability. Nanoemulsions do not
cream (or sediment) because the Brownian motion is larger than
the small creaming rate induced by gravity. The internal phases of
nanoemulsions supply an excellent reservoir for phytochemicals
that need protection and transportation. The nanosizes of emulsions enhance not only stability of the emulsions, but also the
bioavailability of the encapsulated phytochemicals.
Generally speaking, nanoemulsions can be prepared through
either high or low energy emulsifications. Figure 1 shows the
general high-energy process to prepare kinetically stable nanoemulsions. High-energy emulsification methods include high
shear homogenization, high-pressure homogenization, microfluidization, ultrasonic homogenization (Solans and others 2005), and
electrified coaxial liquid jets (Loscertales and others 2002). It should
be pointed out that, although ultrasonic homogenization and electrified coaxial liquid jets could also be used to form nanoemulsions,
they are currently limited in laboratory use and have not been
used in large batch production (Solans and others 2005; Mason
and others 2007). High-energy methods are effective in reducing
droplet sizes, but may not be suitable for some unstable molecules,
such as proteins or peptides. Alternatively, low-energy emulsification methods, such as phase inversion temperature (PIT) method,
which uses the changes in solubility of polyoxyethylene-type

Water + oil + emulsifier

Stir

Figure 1 --- The general

high-energy process to prepare
kinetically stable
nanoemulsions.

High-speed
homogenization
High-pressure
homogenization
Nanoemulsion

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nonionic surfactants with temperature (Shinoda and Saito 1968;
Rang and Miller 1999), colloidosomes (Dinsmore and others 2002),
cubosomes (Spicer 2004), and microfluidic channels (Xu and others
2005), can also be used to prepare nanoemulsions.
The formulation of nanoemulsions may be different according to
the oils and emulsifiers used. At the same time, bioactives dissolved
in the dispersed oil phase may also influence the formulation. To
determine the right emulsion formulation for the specific phytochemicals, a common practice is to construct pseudoternary phase
diagrams with large one-phase regions. A phase diagram is usually
suggested to determine the formulation by interplaying water, oils,
emulsifiers, and/or cosolvents as well as coemulsifiers of various
HLB values at different mass ratios. The coemulsifiers are also amphiphilic, which have an affinity for both oil and water phases, and
partition to certain degrees into the interfacial layer of the emulsions. Compositional variables can also be studied as a function
of temperature, shear speed, and pressure, but majority of emulsions were studied under ambient conditions with vortexing or
magnetic stirring. Optimization methods, such as response surface
methodology, are used to obtain smaller and more uniform (lower
polydispersity) emulsion systems (Yuan and others 2008). For food
applications, it is common that 4 or more components are involved
to form isotropic regions in the pseudo-ternary diagrams, where
a corner typically represents a mixture of 2 or more components
such as emulsifier/coemulsifier, water/cosolvent/phytochemicals,
or oil/cosolvent/phytochemicals (Garti 2003). The construction of
precise phase diagrams can be very time consuming and laborintensive, and the phase boundary is especially different to determine. A general strategy is to prepare a series of pseudo binary
mixtures, and then titrate with the 3rd component. The mixtures
are evaluated 24 h after each addition. It should be noted that
many food-grade emulsifiers can only produce limited regions of
nanoemulsions.
The structure and physical properties of nanoemulsions can
be characterized by the combination of a wide variety of
techniques. For example, the macroscopic properties, such as
viscosity/viscoelasticity, conductivity, and interfacial tension can
be characterized by rheometer, conductivity meter, and pendant
drop tensiometer, respectively (Boonme and others 2006). The size
and shape of the emulsion droplets were routinely characterized by
static and dynamic light scattering techniques (McClements 2005).
The major drawback of light scattering techniques is that dilution of
emulsion samples is usually necessary to reduce multiple scattering and interdroplet interactions. The dilution process may modify the structure and composition of the pseudoternary phases of
the nanoemulsions. The structure of the different pseudoternary
phases can be investigated by small-angle X-ray scattering (SAXS),

small-angle neutron scattering (SANS), and microscopy like cryotransmission electron microscopy (TEM) (Spicer and others 2001;
Borne and others 2002; Boonme and others 2006).
Antioxidant efficiencies of phytochemicals in nanoemulsions
are often determined by the distributions of antioxidants in the
oil, water, or oil/water interfacial regions. The distributions of antioxidants are described by 2 partition constants, one between the
oil/interfacial regions and the other between aqueous/interfacial
regions. The 2 partition constants are obtained by fitting 2 sets of
observed rate constants versus emulsifier concentration data determined using electrochemical method for the reaction of the antioxidant with an arenediazonium ion probe on the basis of the
well-established pseudophase model (Gunaseelan and others 2004;
Romsted and Zhang 2004). Oil distributions between the oil and interfacial regions can also be determined by diffusivities measured
by pulse field gradient spin echo NMR, PGSE-NMR (Nyden and Soderman 1995; Soderman and Nyden 1999), where the experiments
are usually performed by varying the gradient strength along Z-axis
(Gz ) while keeping the gradient pulse duration () and the diffusion
delays () constant. The echo intensity, I(GZ ), decay as the value of
Gz increasing is given by Eq. 1:
I (G z ) = I (0) exp[D 2 2 G 2z ( /3)]

(1)

where D is the self-diffusion coefficient (diffusivity) of the species

responsible of the spin-echo decay, I(0) is the echo intensity in the
absence of any pulse gradient and is the gyromagnetic constant
of the observed nucleus. The applied field gradient strength (G) is
calibrated before each experiment. PGSE-NMR allows the simultaneous and rapid determination of the self diffusion coefficients of
many components existing in the nanoemulsions. Figure 2A shows
the 1 H NMR spectra of a typical O/W nanoemulsion (a), pure oil (b),
and pure water (c), while Figure 2B shows the processed 2D diffusion spectra of the same O/W nanoemulsion as Figure 2A.

Bioavailability of nanoemulsion-encapsulated
phytochemicals
Bioavailability is defined as a measurement of the extent of
a therapeutically active component that reaches the systemic
circulation and is available at the site of action (http://en.
wikipedia.org/wiki/Bioavailability). It is one of the key pharmacokinetic properties of a phytochemical or drug. Phytochemicals
with health benefits, such as plant polyphenols (that is, curcumin,
resveratrol, epigallocatechin gallate, and so on) and carotenoids
(that is, lycopene, -carotene, lutein, zeaxanthin, and so on),
have received much attention from the scientific community,
Figure 2 --- (A). The 1 H NMR spectra of
a typical O/W nanoemulsion (a), pure
oil (b), and pure water (c); (B). The
processed 2D diffusion spectra of the
same O/W nanoemulsion as
Figure 2(A).

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consumers, and food manufacturers because they can be used to

lower blood pressure, reduce cancer risk factors, regulate digestive tract system, strengthen immune systems, regulate growth, regulate sugar concentration in blood, lower cholesterol levels, and
serve as antioxidant agents (Hagerman 1992; Wildman 2001). Although the use of polyphenols in capsules and tablets is abundant, their biological effects are frequently diminished or even lost
due to incomplete absorption and first-pass metabolism. Manach
and others (2005) reviewed the oral bioavailability of 97 polyphenol
compounds and showed that proanthocyanidins, galloylated tea
catechins, curcumin, and the anthocyanins are the least absorbed
pholyphenols. Until now, most of the researches are focused on the
improved solubilities of oil-soluble lycopene (Spernath and others
2002), phytosterols (Garti and others 2005), -3 fatty acids (McClements and Decker 2000), coenzyme Q10 (Xia and others 2007;
Xia and others 2009), and so on. The research on the in vivo studies of nanoencapsulated polyphenols is still limited. Following is a
summary of recent advances in the biological efficacies of one of
the most challenged polyphenols-curcumin.
Curcumin,
chemically
named
1,7-bis(4-hydroxy-3methoxyphenyl)-1,6- heptadiene-3,5-dione, is a polyphenol

extracted from the rhizomes of turmeric (Curcuma longa). The

chemical structure of curcumin is shown in Figure 3A (Khanna
1999). Curcumin has very strong yellow color and can be used as
a natural food color. Curcumin has exhibited antioxidant (Sharma
1976), antiinflammatory (Srimal and Dhawan 1973), antimicrobial
(Kim and others 2003), and anticarcinogenic (Miller and others
2008) activities. Various cell/animal models and human studies
have demonstrated the preventive or therapeutic functions of curcumin (Kuttan and others 1985; Hsu and Cheng 2007; Miller and
others 2008). It inhibits breast, bladder, prostate, or leukemia cancer in cell culture. Curcumin affects arachidonic acid metabolism,
inhibits COX and LOX, and induces apoptosis by activating apoptosis signaling (Hong and others 2004). It also blocks many cell
proliferation signaling pathways, such as MAP kinase pathway,
AKT pathway, and mTOR pathways (Joe and others 2004; Duvoix
and others 2005; Howitz and Sinclair 2008). However, low bioavailability is a general problem for oral administration of curcumin.
Oral intake of curcumin inhibited chemically induced esophagus,
fore-stomach, and colon cancer, but had negligible effect on lung
or breast cancer in mice due to the low circulation concentration in
blood (Huang and others 1998). Hsu and Cheng (2007) showed in
phase I clinical trial that curcumin only had efficacy on the tissues
(colorectum, oral mucosa and skin) exposed to drug directly, but
had no clear effect on other chronic inflammation or cancer.
Several delivery systems have been studied to increase the
bioavailability of curcumin, including nanoparticles, liposomes,
and micelles (Anand and others 2007). Nanoparticle formulations have been developed and showed increased solubility and
promising in vitro results, but no in vivo oral administration result is available yet (Bisht and others 2007; Tiyaboonchai and
others 2007). Liposome encapsulated curcumin has shown enhanced bioavailability and inhibition to pancreatic and colorectal cancer in vitro and in vivo (intravenous) (Li and others 2005;
Li and others 2007). Small molecular-weight surfactants, such as
cetyltrimethylammonium bromide (CTAB) (Iwunze 2004; Wang
and others 2006; Leung and others 2008), as well as synthetic
amphiphilic polymers, such as PEO-b-PCL [poly(ethylene glycol)block-poly(caprolactone)] (Ma and others 2008) and methoxy
poly(ethylene glycol)-palmitate (Sahu and others 2008a), were also
reported to form polymer micelles to encapsulate curcumin. The
improved solubilization capacity and loading efficiency were reported. Curcumin-phospholipid complex demonstrated about 2fold increase in plasma concentration in rat after oral intake (Liu
and others 2006). Yet, no therapeutic activity has been reported
Figure 3 --- (A). Chemical structure of curcumin; (B). Chem- with orally administrated curcumin. In addition, organic solvent
ical structure of dibenzoyl methane (DBM).
Figure 4 --- Photographic images of
curcumin nanoemulsions (A),
nanodispersion (B), and water
solution (C) (Yu and Huang 2010).

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and other nonfood grade ingredients are often involved in these
studies.
Recently, Wang and others (2008) used high pressure homogenization method to successfully generate nanoemulsions with a
formulation using medium chain triglyceride (MCT), Tween 20
and water at the ratio of 10 : 10 : 80. It was found that multiple
cycles of high pressure homogenization generated smaller sized
nanoemulsions with less polydispersity. The finest oil droplets
obtained were about 79.5 nm in diameter. Furthermore, this
nanoemulsion was able to encapsulate 1% curcumin. Tested in
a 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear
inflammation model, it was found that curcumin nanoemulsions
had much better bioactivity than curcumin solution, and the curcumin nanoemulsion of 79.5 nm inhibited 85% mouse ear inflammation compared with 43% inhibition for 618.6 nm curcumin
nanoemulsion. This study suggests: (i) lipids like MCT in the formulation have a positive impact on the antiinflammation properties
of curcumin (Wang and others 2008); and (ii) smaller curcumin
emulsion droplets have better biological efficacy than larger curcumin emulsions (Wang and others 2008). Very recently, Jiang
improved the nanoemulsion formulation prepared from the mix-

Figure 5 --- Oral administration of curcumin nanoemulsion

could repress cyclin D1 induced by TPA in CD-1 mouse
ear. Total of 100 g/well protein samples were subjected
to immunoblotting for cyclin D1. The primary antibody
was diluted in the Odyssey blocking buffer (1 : 1000)
(Jiang 2009).

tures of water, Tween 40/Span 20, and MCT. Oral administration of these new curcumin nanoemulsions could inhibit 12O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation
on mouse ears by 100%. ELISA and immune-blotting results
also showed dose-responsive and significant inhibition of proinflammatory factors interleukin-1 (IL-1), interleukin (IL-6),
Matrix Metalloproteinases-9 (MMP-9), and cyclin D1 (Jiang 2009).
Figure 5 shows clearly that oral administration of 2 doses (1% and
1.5%) of nano-emulsified curcumin could inhibit the expression
of cyclin D1, and the higher dose (that is, 1.5%) of curcumin suppressed the expression to a larger degree than the lower dose (that
is, 1.0%) (Jiang 2009). It should be pointed out that, curcumin
plasma concentration was unable to determine because curcumin
may metabolize within half an hour.
The improved oral bioavailability through nanoemulsion route
has been confirmed by dibenzoylmethane (DBM) nanoemulsion
(Lin and others 2009). DBM, which is found as a minor constituent in the root of licorice, is a natural phytochemical with anticancer activities. It is a beta-diketone analog of curcumin. Thus, its
structure is similar to curcumin, as shown in Figure 3B. The typical scheme of bioavailability determination has been described
in Figure 6. In brief, phytochemical nanoemulsions were orally
administrated to rats by gavage. Blood samples were collected
every few minutes following the phytochemical administration.
Separate group of rats are also given phytochemical through jugular vein cannulae (i.v. injection). Blood samples should be separated immediately by centrifugation and stored at 80 C until
analysis. Plasma samples are analyzed by high-performance liquid
chromatograph-mass spectrometer (HPLC-MS) detection method.
In pharmacokinetic analysis, the area under the plasma concentration versus time curve (AUC) from time zero to the time of last
measured concentration can be calculated using the log-linear
trapezoidal rule. The absolute bioavailability (F) is determined by
the ratio of the dose-normalized AUC0 following oral and intravenous administration. In the pharmacokinetic studies of DBM
nanoemulsions, it is found that the mean plasma concentration of
DBM with nanoemulsion reached its peaks at 1.6 h (t max ), as compared to a t max of 3.3 h for the conventional emulsion, suggesting
that DBM administrated in the nanoemulsion route was absorbed
much faster than the conventional emulsion (Lin and others 2009).
The bioavailability of DBM in nanoemulsion was 22.8% compared
with 7.7% in DBM conventional emulsion, about 3 times increase
in oral bioavailability (Lin and others 2009).
From the limited examples available in the literature, we speculate that 2 parameters are important for nanoemulsion-based
delivery systems to increase the bioavailability of encapsulated bioactives. The 1st parameter is the sizes of emulsion

Figure 6 --- The scheme of

pharmacokinetics analysis of
phytochemical nanoemulsions.

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Nanoencapsulation of nutraceuticals . . .
droplets. Compared with conventional micron-sized emulsions,
nanoemulsions have much smaller droplet sizes, thus have much
larger surface areas. Such large surface area increases the accessibility of different lipases and co-lipases and endogenous surfactants, such as bile salt, cholesterol, and phospholipids. They
may all facilitate the solubilization of lipophilic compound and increase the absorption rate. The 2nd factor is the lipid component in
the formulation. Digested by various lipases in the gastrointestinal
tract, triglyceride is degraded into diglyceride, monoglyceride, and
free fatty acids, all of which are amphiphilic and could contribute
to solubilization of lipophilic bioactives (Porter and others 2007).

Other Nutraceutical Delivery Systems

icelles are formed by amphiphiles, which have both hydrophilic and hydrophobic functional groups. When an
amphiphile exceeds a certain concentration, the so-called critical
micelle concentration (CMC) in aqueous solution, a number of amphiphiles spontaneously assemble to form structured complexes
called micelles. The hydrophilic region forms the shell of micelles,
while hydrophobic region forms the cores, where lipophilic bioactives are trapped. Different from most of the emulsion systems,
micelles are thermodynamically stable, with no exogenous energy
input required.
Micellar encapsulation system is relative simple compared to
nanoemulsion: it comprises aqueous solution, amphiphilc compound (either of low molecular weight or high molecular weight)
with concentration above CMC, and encapsulated bioactives. Although the formulation is simpler, the loading process in micellar
encapsulation could be tricky and affect the encapsulation capacity and efficiency. At least 4 methods are commonly used in the literature to encapsulate bioactives: (i) solvent dialysis: amphiphiles
and bioactives are dissolved in a common watermiscible solvent
and then dialyzed against water or aqueous solution to remove the
solvent; (ii) solvent evaporation: amphiphiles and bioactives are
dissolved in a common volatile solvent and then brought into an
aqueous solution. Subsequently, the solvent is removed by evaporation; (iii) co-precipitation: amphiphiles and bioactives are dissolved in a common solvent and then solvent is evaporated to
form an AB mixture, to which the aqueous solution is added;
and (iv) emulsification: amphiphiles are dissolved in aqueous solution, while bioactives are dissolved in water-immiscible volatile
organic solvent and then brought into the aqueous solution to form
emulsion. Subsequently, the organic solvent is evaporated. Among
these 4 approaches, (i) and (iv) were compared, and it was found
that emulsification method generated higher encapsulation yields
(Kwon and others 1997).
Biopolymer micelles are now a fast growing area in the delivery of nutraceuticals or drugs because they prolong their blood circulation time. Recently, a research in the authors group showed
hydrophobically modified starch (HMS) was able to form micelles in aqueous solution (Yu and Huang 2010). Additionally,
the solubility of curcumin in HMS micelles was increased almost
1700-fold compared with that in pure water. Furthermore, the
bioactivity of encapsulated curcumin was tested on an in vitro
anti-cancer model and it was found that encapsulated curcumin
demonstrated a significantly higher anti-cancer activity than free
curcumin (Yu and Huang 2010). It is noteworthy that not all micellar formulation could enhance the delivery of encapsulated
bioactives. Taking curcumin-encapsulation formulations as an example, micelles formed by poly(ethylene oxide)-b-poly(epsiloncaprolactone) and methoxy poly(ethylene glycol)-palmitate did not
increase the delivery of curcumin to tested cancer cells (Ma and
others 2008; Sahu and others 2008a). On the contrary, curcumin

Figure 7 --- Nanodispersions of -carotene in the aqueous

solutions of a novel chitosan-based amphiphile, octanoylchitosan-polyethylene glycol monomethyl ether.

encapsulated in HMS micelles and in casein micelles displays

enhanced bioactivity, which gives rise to a hypothesis that natural
components may facilitate the cellular uptake of micelles (Sahu and
others 2008b; Yu and Huang 2010).
Very recently, a novel chitosan-based amphiphile, octanoylchitosan-polyethylene glycol monomethyl ether (acylChitoMPEG),
has been synthesized using both hydrophobic octanoyl and
hydrophilic polyethylene glycol monomethyl ether (MPEG) substitutions. The synthesized acylChitoMPEG exhibited good solubility in either aqueous solution or common organic solvents such
as ethanol, acetone, and CHCl3 . Cytotoxicity results showed that
acylChitoMPEG exhibited negligible cytotoxicity even at the concentration as high as 1 mg/mL. The most attractive feature of this
group of chitosan-based amphiphiles is the ability to tune the HLB
values by controlling the amount of hydrophobic octanoyl or hydrophilic PEG moieties, and can be used to encapsulate wide range
of nutraceuticals or drugs. Figure 7 shows the photographic images
of -carotene of different concentrations in modified chitosan micelles (Huang and others 2009b). Although micelles have been a
good candidate to encapsulate nutraceuticals and exhibit some enhanced bioactivities, the bioactivities of micelle formulations are
usually tested in cell culture assay (as shown previously) or by intravenous (i.v.) injection into experimental animals (Jones and Leroux 1999). Experiments with oral administration of phytochemical
micelles are still very rare, and more research needs to be done.
There are many other delivery platforms that can also be used
to delivery phytochemicals and micronutrients, such as solid
lipid nanoparticles, multiple emulsions, protein/polysaccharide
complexes-based multilayer emulsions, soluble complexes, and
complex coacervates. Their structural design principles have been
reviewed by McClements and others (2009) and will not be duplicated here.

Conclusions

anoemulsions-based delivery systems have been proved to

be one of the best platforms to enhance the oral bioavailability and biological efficacies (that is, antiinflammation, anticancer, and so on) of different phytochemicals. They are especially
appealing to food industry because there are many food-grade
lipids and emulsifiers available. They are simpler and easier to prepare compared with other lipid-based delivery systems, such as
multiple emulsions and solid lipid nanoparticles. In addition, human body has different lipases ready to digest these lipids, therefore, the potential toxicity of these phytochemical nanoemulsions
may be minimal. Similarly, polymer micelles also show promise to
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Nanoencapsulation of nutraceuticals . . .
improve the water dispersibility of many crystalline phytochemicals, such as -carotene and curcumin, and also show improved
in vitro anti-cancer activity. During the past decade, many efforts
have been devoted to the design and development of different nutraceutical delivery systems, and significant progresses have been
made. A wide variety of delivery systems with different structures
are now available, and their design principles are quite clear now.
For the majority of the delivery systems, the in vivo biological efficacies of encapsulated phytochemicals remain largely unknown.
Many questions still remain unanswered. For example, why nanoencapsulated phytochemicals have better oral bioavailability?
How are the cellular signal transduction pathways different for
nanoencapsulated phytochemicals compared with the nonencapsulated forms? Are the nanoencapsulated phytochemicals toxic?
Therefore, more efforts should be devoted to the development of
novel value-added food-grade or GRAS materials from biomass, as
well as the understanding of the potential impacts of these nanoencapsulated nutraceuticals to human body and environment to address the public concerns.

Acknowledgment
This study was supported by U.S. Dept. of Agriculture National Research Initiative Program (#2009-35603-05071).

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