Bioavailability of Neutraceuticals Nano

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Nanoencapsulation of nutraceuticals . . .

option is to encapsulate the functional ingredients using food-

grade 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 exam-

ple, 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 ingredientsare important applications in food and nutrition that can be at-

tained with nanotechnological approaches. Target delivery of nu-

trients to cells and cellular compartments was highlighted in the

Experimental Biology 2009 symposium entitled Nanotechnology

Research: Applications in Nutritional Sciences as an example of re-

search area in food and nutrition with nanotech enhancement po-

tential (Srinivas and others 2009). Although many different delivery

systems are now available to delivery bioactive components in nu-

traceuticals and functional foods (McClements and others 2009),

clearin vitroor in vivoevidences of their biological efficacies are

still limited. In this review article, we introduce some typical food-

grade delivery platforms with demonstrated biological efficacy that

can be used by food and beverage industry to deliver functionalingredients (that is, nutraceuticals). Formulation strategies and ex-

amples of the biological efficacy of encapsulated nutraceuticals are

also provided.

Nanoemulsions-Based Delivery Systems

Administration of active phytochemical components into thehuman body requires the use of an appropriate vehicle forbringing 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 phyto-

chemicals, 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 physico-

chemical 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, result-

ing in a poor oral bioavailability. Constructing an appropriate ve-

hicle and the desired efficient formulation possess a challenge to

dietary supplement researchers. To overcome instability, poor wa-

ter 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 translu-

cent with a bluish coloration. They contain continuous phase, dis-

persed 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 emul-

sions (Solans and others 2005). Since an emulsifier molecule size

is typically 2 nm long, a micelle, that is, a surfactant molecule ag-

gregate in water is typically 5 nm or more in diameter. When oil

phase moleculesenterthe micellar core, theaggregates getswollen,

sometimes to a large extent, to produce a spherical object whose

size canreach 100 nm or more. Compared with conventionalmeth-

ods, such as co-solvent addition, micronizing/milling, spray dry-

ing, and salt formation, the use of lipid based delivery systems,

such as micro/nanoemulsions and micelles, offers many advan-

tages: (i) high kinetic or thermodynamic stability, which provides

significantly better stability over unstable dispersions, such as con-

ventional emulsions and suspensions; (ii) either hydrophilic or

lipophilic phytochemicals can be incorporated into the same na-

noemulsions; and (iii) because of the small droplet sizes, phyto-

chemicals 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 microemul-

sions, which are thermodynamically stable, optically transparent,

and have droplet sizes smaller than 100 nm, are often also callednanoemulsions. Thermodynamically stable microemulsion sys-

tems were reviewed extensively in other articles (Lawrence and

Rees 2000; Narang and others 2007; Gupta and Moulik 2008). How-

ever, there are not many food-grade microemulsion systems avail-

able. 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 poten-

tial side effects (that is, obesity, cardiovascular diseases, and so on)

caused by the use of high amount of lipids.

Nanoemulsion preparationandcharacterizationNanoemulsion stability implies a high interfacial tension, and

thus a considerable surface energy (which is the surface tensiontimes the surface area). Although many nanoemulsions are ther-

modynamically 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 emul-

sions 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 na-

noemulsions. High-energy emulsification methods include highshear homogenization, high-pressure homogenization, microflu-

idization, 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 elec-

trified coaxial liquidjets 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 emulsifica-

tion methods, such as phase inversion temperature (PIT) method,

which uses the changes in solubility of polyoxyethylene-type

Water + oil + emulsifier

Stir

High-speed

homogenization

High-pressure

homogenization

Nanoemulsion

Water + oil + emulsifier

Stir

High-speed

homogenization

High-pressure

homogenization

Nanoemulsion

Figure 1 --- The generalhigh-energy process to preparekinetically stablenanoemulsions.

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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 accordingto

theoils 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 phyto-

chemicals, a common practice is to construct pseudoternary phase

diagrams with large one-phase regions. A phase diagram is usuallysuggested 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 am-

phiphilic, which have an affinity for both oil and water phases, and

partition to certain degrees into the interfacial layer of the emul-

sions. Compositional variables can also be studied as a function

of temperature, shear speed, and pressure, but majority of emul-

sions 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, wherea 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 labor-

intensive, and the phase boundary is especially different to deter-

mine. 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

andshapeof the emulsion droplets were routinelycharacterized by

static and dynamic light scattering techniques (McClements 2005).

Themajordrawback of light scattering techniques is that dilution of

emulsion samples is usually necessary to reduce multiple scatter-

ing and interdroplet interactions. The dilution process may mod-

ify 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 cryo-

transmission 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 an-

tioxidants 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 de-termined using electrochemical method for the reaction of the an-

tioxidant with an arenediazonium ion probe on the basis of the

well-established pseudophase model (Gunaseelanand others 2004;

Romsted andZhang 2004). Oil distributions between the oil andin-

terfacial regions can also be determined by diffusivities measured

by pulse field gradient spin echo NMR, PGSE-NMR (Nyden and So-

derman 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 () andthe diffusion

delays () constant. The echo intensity,I(GZ), decay as the value of

Gzincreasing is given by Eq. 1:

I(Gz) = I(0)exp[D2

2

G2

z( /3)] (1)

whereDis 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 simulta-

neous and rapid determination of the self diffusion coefficients of

many components existing in the nanoemulsions. Figure 2A shows

the 1H NMRspectra of a typical O/Wnanoemulsion (a), pure oil(b),

and pure water (c), while Figure 2B shows the processed 2D diffu-

sion spectra of the same O/W nanoemulsion as Figure 2A.

Bioavailability of nanoemulsion-encapsulatedphytochemicals

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 pharma-

cokinetic 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 1H NMR spectra ofa typical O/W nanoemulsion (a), pureoil (b), and pure water (c); (B). Theprocessed 2D diffusion spectra of thesame O/W nanoemulsion asFigure 2(A).

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consumers, and food manufacturers because they can be used to

lower blood pressure, reduce cancer risk factors, regulate diges-

tive tract system, strengthen immune systems, regulate growth, reg-

ulate sugar concentration in blood, lower cholesterol levels, and

serve as antioxidant agents (Hagerman 1992; Wildman 2001). Al-

though the use of polyphenols in capsules and tablets is abun-

dant, their biological effects are frequently diminished or even lost

due to incomplete absorption and first-pass metabolism. Manach

andothers (2005)reviewedthe oral bioavailability of 97 polyphenol

compounds and showed that proanthocyanidins, galloylated teacatechins, 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 (Mc-

Clements and Decker 2000), coenzyme Q10 (Xia and others 2007;

Xia and others 2009), and so on. The research on the in vivostud-

ies 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-3-

methoxyphenyl)-1,6- heptadiene-3,5-dione, is a polyphenol

Figure 3 --- (A). Chemical structure of curcumin; (B). Chem-ical structure of dibenzoyl methane (DBM).

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 cur-

cumin (Kuttan and others 1985; Hsu and Cheng 2007; Miller and

others 2008). It inhibits breast, bladder, prostate, or leukemia can-cer in cell culture. Curcumin affects arachidonic acid metabolism,

inhibits COX and LOX, and induces apoptosis by activating apop-

tosis 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 bioavail-

ability 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, buthad 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 formula-

tions have been developed and showed increased solubility and

promisingin vitroresults, but no in vivooral administration re-

sult is available yet (Bisht and others 2007; Tiyaboonchai and

others 2007). Liposome encapsulated curcumin has shown en-

hanced bioavailability and inhibition to pancreatic and colorec-

tal cancer in vitroand 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 re-

ported. Curcumin-phospholipid complex demonstrated about 2-

fold increase in plasma concentration in rat after oral intake (Liu

and others 2006). Yet, no therapeutic activity has been reported

with orally administrated curcumin. In addition, organic solvent

Figure 4 --- Photographic images ofcurcumin nanoemulsions (A),nanodispersion (B), and watersolution (C) (Yu and Huang 2010).



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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 acces-

sibility of different lipases and co-lipases and endogenous sur-

factants, such as bile salt, cholesterol, and phospholipids. They

may all facilitate the solubilization of lipophilic compound and in-

crease the absorption rate. The 2ndfactor 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 contributeto solubilization of lipophilic bioactives (Porter and others 2007).

Other Nutraceutical Delivery Systems

M icelles are formed by amphiphiles, which have both hy-drophilic and hydrophobic functional groups. When anamphiphile exceeds a certain concentration, the so-called critical

micelle concentration (CMC) in aqueous solution,a numberof am-

phiphiles spontaneously assemble to form structured complexes

called micelles. The hydrophilic region forms the shell of micelles,

while hydrophobic region forms the cores, where lipophilic bioac-

tives 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 com-

pound (either of low molecular weight or high molecular weight)

with concentration above CMC, and encapsulated bioactives. Al-

though the formulation is simpler, the loading process in micellar

encapsulation could be tricky and affect the encapsulation capac-

ity and efficiency. At least 4 methods are commonly used in the lit-

erature 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 evap-

oration; (iii) co-precipitation: amphiphiles and bioactives are dis-

solved 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 so-

lution, while bioactives are dissolved in water-immiscible volatile

organic solvent andthen brought into theaqueous 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 deliv-

ery of nutraceuticals or drugs because they prolong their blood cir-

culation time. Recently, a research in the authors group showed

hydrophobically modified starch (HMS) was able to form mi-

celles 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 mi-

cellar formulation could enhance the delivery of encapsulated

bioactives. Taking curcumin-encapsulation formulations as an ex-

ample, micelles formed by poly(ethylene oxide)-b-poly(epsilon-

caprolactone) 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 aqueoussolutions of a novel chitosan-based amphiphile, octanoyl-chitosan-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, octanoyl-

chitosan-polyethylene glycol monomethyl ether (acylChitoMPEG),

has been synthesized using both hydrophobic octanoyl and

hydrophilic polyethylene glycol monomethyl ether (MPEG) substi-

tutions. The synthesized acylChitoMPEG exhibited good solubil-

ity 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 con-

centration 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 hy-

drophilic PEG moieties, andcan be used to encapsulate wide range

of nutraceuticals or drugs. Figure 7 shows the photographic images

of-carotene of different concentrations in modified chitosan mi-celles (Huang and others 2009b). Although micelles have been a

good candidate to encapsulate nutraceuticals and exhibit some en-

hanced bioactivities, the bioactivities of micelle formulations are

usually tested in cell culture assay (as shown previously) or by in-

travenous (i.v.) injection into experimental animals (Jones and Ler-

oux 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 dupli-cated here.

Conclusions

Nanoemulsions-based delivery systems have been proved tobe one of the best platforms to enhance the oral bioavail-ability and biological efficacies (that is, antiinflammation, anti-

cancer, 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 pre-

pare compared with other lipid-based delivery systems, such as

multiple emulsions and solid lipid nanoparticles. In addition, hu-

man body has different lipases ready to digest these lipids, there-

fore, the potential toxicity of these phytochemical nanoemulsions

may be minimal. Similarly, polymer micelles also show promise to



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improve the water dispersibility of many crystalline phytochemi-

cals, such as -carotene and curcumin, and also show improved

in vitroanti-cancer activity. During the past decade, many efforts

have been devoted to the design and development of different nu-

traceutical 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 vivobiological ef-

ficacies of encapsulated phytochemicals remain largely unknown.

Many questions still remain unanswered. For example, why na-noencapsulated phytochemicals have better oral bioavailability?

How are the cellular signal transduction pathways different for

nanoencapsulated phytochemicals compared with the nonencap-

sulated 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 nanoen-

capsulated nutraceuticals to human body and environment to ad-

dress the public concerns.

AcknowledgmentThis study was supported by U.S. Dept. of Agriculture National Re-

search Initiative Program (#2009-35603-05071).

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