Progress in Lipid Research: David Julian Mcclements

JPLR 823 No.
of Pages 15, Model 5G

17 May 2013
Progress in Lipid Research xxx (2013) xxx–xxx

1
Contents lists available at SciVerse ScienceDirect
Progress in Lipid Research

journal homepage: www.elsevier.com/locate/plipres
2 Review
3 Edible lipid nanoparticles: Digestion, absorption, and potential toxicity

4 Q1 David Julian McClements ⇑
5 Q2 Department of Food Science, University of Massachusetts, Amherst, MA 01003, United States
6
a r t i c l e i n f o a b s t r a c t
8
2 2
9 Article history: Food-grade nanoemulsions are being increasingly used in the food and beverage industry to encapsulate, 23
10 Received 13 September 2012 protect, and deliver hydrophobic functional components, such as oil-soluble flavors, colors, preservatives, 24
11 Accepted 29 April 2013 vitamins, and nutraceuticals. These nanoemulsions contain lipid nanoparticles (radius <100 nm) whose 25
12 Available online xxxx
physicochemical characteristics (e.g., composition, dimensions, structure, charge, and physical state) 26
can be controlled by selection of appropriate ingredients and fabrication techniques. Nanoemulsions have 27
13 Keywords: a number of potential advantages over conventional emulsions for applications within the food industry: 28
14 Nanoemulsions
higher stability to particle aggregation and gravitational separation; higher optical transparency; and, 29
15 Nanoparticles
16 Bioavailability
increased bioavailability of encapsulated components. On the other hand, there are also some risks asso- 30
17 Bioactivity ciated with consumption of lipid nanoparticles that should be considered before they are widely utilized, 31
18 Nutraceuticals such as their ability to alter the fate of bioactive components within the gastrointestinal tract and the 32
19 Absorption potential toxicity of some of the components used in their fabrication (e.g., surfactants and organic sol- 33
20 Toxicity vents). This article provides an overview of the current status of the biological fate and potential toxicity 34
21
of food-grade lipid nanoparticles suitable for utilization within the food and beverage industry. 35
Ó 2013 Published by Elsevier Ltd. 36
37
38
39 Contents
40 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
41 2. Lipid nanoparticle fabrication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
42 3. Lipid nanoparticle characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
43 3.1. Particle composition and structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
44 3.2. Particle dimensions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
45 3.3. Interfacial properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
46 3.3.1. Thickness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
47 3.3.2. Polarity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
48 3.3.3. Environmental responsiveness and digestibility. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
49 3.4. Particle physical state . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
50 4. Biological fate of lipid nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
51 4.1. Potential changes in lipid nanoparticle characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
52 4.1.1. Particle composition and structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
53 4.1.2. Particle dimensions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
54 4.1.3. Interfacial properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
55 4.1.4. Physical state . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
56 4.2.1. Mouth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
57 4.2.2. Stomach. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
58 4.2.3. Small intestine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
59 4.2.4. Colon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
60 4.3. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
61 4.3.1. Particle absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
62 4.3.1.1. Paracellular . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
63 4.3.1.2. Transcellular. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
64 4.3.1.3. Persorption. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
⇑ Tel.: +1 413 545 1019.

E-mail address: mcclements@foodsci.umass.edu
0163-7827/$ - see front matter Ó 2013 Published by Elsevier Ltd.

http://dx.doi.org/10.1016/j.plipres.2013.04.008
Please cite this article in press as: McClements DJ. Edible lipid nanoparticles: Digestion, absorption, and potential toxicity. Prog Lipid Res (2013), http://
dx.doi.org/10.1016/j.plipres.2013.04.008
JPLR 823 No. of Pages 15, Model 5G
17 May 2013
2 D.J. McClements / Progress in Lipid Research xxx (2013) xxx–xxx
65 4.3.2. Bioactive absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

66 4.3.2.1. Bioaccessibility. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
67 4.3.2.2. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
68 4.3.2.3. Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
69 4.5. Potential toxicity of lipid nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
70 4.5.1. Increased bioavailability of bioactive components that are toxic at high levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
71 4.5.2. Direct absorption of lipid nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
72 4.5.3. Interference with normal GI function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
73 4.5.4. Compositional effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
74 5. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
75 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
76 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
77
78
79 1. Introduction because there utilization is already well-established from the pro- 127
duction of conventional emulsions, they are capable of large scale 128
80 Oil-in-water (O/W) nanoemulsions are a type of colloidal dis- production, and they can be used to prepare nanoemulsions from a 129
81 persion that consists of lipid nanoparticles dispersed within an variety of different starting materials. Low energy methods rely on 130
82 aqueous medium [1–3]. This type of system is finding increasing the spontaneous formation of lipid nanoparticles within surfac- 131
83 utilization within the food and beverage industry for encapsula- tant-oil–water (SOW) systems when solution or environmental 132
84 tion, protection, and delivery of hydrophobic functional compo- conditions are altered, e.g., phase inversion temperature, phase 133
85 nents, such as oil-soluble flavors, colors, preservatives, vitamins, inversion composition, emulsion inversion point, and spontaneous 134
86 and nutraceuticals [4–6]. emulsification methods [7,24–28]. The principles behind different 135
87 Indeed, incorporation of lipid nanoparticles into foods and bev- nanoemulsion fabrication methods have been discussed in some 136
88 erages is currently one of the most widely used applications of detail in a number of recent review articles [1,6]. 137
89 nanotechnology in the food industry [6]. The main reason for the
90 interest in nanoemulsions is that they have a number of potential 3. Lipid nanoparticle characteristics 138
91 advantages over conventional emulsions for certain applications
92 within the food and beverage industry [2]. Nanoemulsions usually Nanoparticle characteristics influence the bulk physicochemical 139
93 have better stability to particle aggregation and gravitational sep- properties and functional performance of nanoemulsions, e.g., opti- 140
94 aration due to the relatively small size of the particles they contain cal properties, rheology, stability, biological fate, and release pro- 141
95 [2,7,8]. The small particles in nanoemulsions only scatter light file. In this section, we therefore briefly review the most 142
96 waves weakly, and so they are suitable for incorporation into prod- important characteristics of lipid nanoparticles that may influence 143
97 ucts that need to be optically transparent, such as fortified soft their biological fate. 144
98 drinks and waters [3,9,10]. The bioavailability of certain types of
99 hydrophobic substances has been reported to increase as the size 3.1. Particle composition and structure 145
100 of the particles encapsulating them decreases into the nanoemul-
101 sion range [11–14]. Despite the potential benefits of encapsulating The nanoparticles in edible nanoemulsions may be fabricated 146
102 functional components within lipid nanoparticles for food and from a variety of food-grade ingredients [29]. The simplest and 147
103 beverage applications, there are also some concerns about potential most common form of nanoparticle has a core–shell structure 148
104 risks associated with the ingestion of edible nanoparticles [15–17]. (Fig. 1). The core may be formed from various non-polar compo- 149
105 This article therefore focuses on the potential biological fate of lipid nents, including triacylglycerols, diacylglycerols, monoacylglyce- 150
106 nanoparticles within the human gastrointestinal tract (GIT), and rols, flavor oils, mineral oils, fat substitutes, waxes, weighting 151
107 considers how this may influence their potential toxicity. More de- agents, oil-soluble vitamins, and nutraceuticals [29]. The shell is 152
108 tailed information on the fabrication, characterization, properties, typically formed from one or more surface-active components, 153
109 and utilization of edible nanoemulsions within foods and beverages including small molecule surfactants, phospholipids, proteins, 154
110 can be found in recent review articles [1,2,4,6,18,19]. polysaccharides, and inorganic particles [29]. The materials that 155
comprise the core and shell may be more or less digestible within 156
111 2. Lipid nanoparticle fabrication different regions of the human GI tract, which plays an important 157
role in determining their biological fate. For example, triacylglyc- 158
112 Initially, some key aspects of the fabrication and properties of erol oils are usually fully digested and absorbed within the stom- 159
113 lipid nanoparticles are briefly reviewed so as to provide some con- ach and small intestine, whereas mineral oils may pass through 160
114 text to the later discussion of their potential biological fate. Lipid the entire GI tract without being digested [30,31]. Similarly, many 161
115 nanoparticles with different physicochemical characteristics (e.g., proteins and starches are digested within the mouth, stomach or 162
116 composition, structure, dimensions, interfacial characteristics, small intestine, whereas dietary fibers tend to pass through these 163
117 and physical state) can be fabricated by controlling the ingredients regions undigested and therefore reach the colon [32]. 164
118 and preparation conditions used. In general, lipid nanoparticles In addition to the simple core–shell structure, a variety of other 165
119 can be prepared using two different approaches: high-energy or structures can be assembled using lipid nanoparticles as building 166
120 low-energy methods [7,11,20–22]. High-energy methods utilize blocks [33,34], such as nanolaminated-nanoparticles, nanoparti- 167
121 mechanical devices (‘‘homogenizers’’) that generate intense cle-clusters, nanoparticle-colloidosomes, and nanoparticle-filled 168
122 disruptive forces to disrupt and intermingle the oil and aqueous hydrogels and droplets (Fig. 1). Some of these more elaborate 169
123 phases, thereby leading to the formation of fine lipid particles, structures may be useful for specific applications where novel or 170
124 e.g., high pressure valve homogenizers, microfluidizers, and sonica- improved functional performances are required, e.g., protection of 171
125 tors [9,10,20,23]. High-energy methods are commonly used to an encapsulated component during storage, novel rheological 172
126 prepare nanoemulsions in industrial food and beverage operations properties, or controlled release within the GI tract. However it 173
17 May 2013
D.J. McClements / Progress in Lipid Research xxx (2013) xxx–xxx 3
Nanoparticle Filled Nanoparticle Filled

Droplets Hydrogels
Core-Shell
Nanoparticles
Nanolaminated
Nanoparticle
Nanoparticles
Clusters
Nanoparticle Solid Lipid

Colloidomes Nanoparticles
Fig. 1. A variety of structures can be assembled using lipid nanoparticles as building blocks, including nanoparticle filled droplets and hydrogels, nanoparticle clusters,
nanoparticle colloidosomes, solid lipid nanoparticles, and nanolaminated nanoparticles.
174 should be noted that any changes in the structural organization of ical size thresholds, e.g., translocation routes across the gastroin- 215
175 the lipid nanoparticles within a delivery system may alter its bio- testinal tract [16,38]. 216
176 logical fate, and therefore its potential toxicity. It is often convenient to report the particle dimensions of a 217
polydisperse colloidal dispersion, such as a nanoemulsion or emul- 218
sion, as a mean value rather than as the full PSD. Nevertheless, it is 219
177 3.2. Particle dimensions important to recognized that the mean value can also be specified 220
in a number of different ways, such as the volume-weighted (rV), 221
178 Controlling lipid nanoparticle dimensions is important because surface-weighted (rS), number-weighted (rN) or intensity- 222
179 it influences the physicochemical properties, functional perfor- weighted (rI) mean radius [29]. Each of these mean values has a 223
180 mance and potential biological fate of edible nanoemulsions, e.g., different numerical value for a polydisperse system, which is 224
181 reducing particle size can lead to increases in clarity, viscosity, sta- determined by the way that they are calculated. For example, the 225
182 bility, and bioavailability [1,2]. Food-grade nanoemulsions can be volume-weighted and number-weighted mean radii calculated 226
183 fabricated with mean particle radii in the range 10–100 nm from the PSD of the colloidal dispersion shown in Fig. 2 are 227
184 depending on the fabrication method and ingredients used to pre- rV = 149 nm and rN = 86 nm. Thus, the system would be referred 228
185 pare them [1]. In high-energy methods, the particle size mainly de- to as an emulsion if the volume-weighted mean radius was used 229
186 pends on the mechanical device used, the intensity and duration of to define its dimensions, but it would be referred to as a nanoemul- 230
187 the energy input, the type and concentration of emulsifier used, the sion if the number-weighted mean radius was used. It is therefore 231
188 oil–water interfacial tension, and the relative viscosities of the dis- important to establish which method of expressing the particle 232
189 perse and continuous phases [2,29,35]. In low-energy methods, the size distribution and mean particle size is most appropriate for 233
190 particle size mainly depends on system composition (surfactant-
191 oil–water ratio, surfactant type, ionic strength), preparation
192 method (such as order of addition, initial location of ingredients, 20
193 stirring speed), and environmental conditions (such as tempera- 18 Number
194 ture history) [21,26]. Volume
195 It is often important to measure and report the particle size of a 16
196 nanoemulsion for scientific, technological, and regulation reasons.
14
197 A variety of analytical techniques are available that are capable of
Fraction in Class
198 providing information about the size of the particles in nanoemul- 12

199 sions, including static light scattering, dynamic light scattering,
200 and electron microscopy [18,36]. Commercial nanoemulsions are 10
201 polydisperse colloidal dispersions that contain a range of differ- 8
202 ently-sized particles, which has important implications for devel-
203 oping definitions of nanoemulsions that might be used to 6
204 regulate the use of nanoparticles in foods. The dimensions of the
4
205 particles within a polydisperse system are usually described as a rN = 84 nm
rV = 149 nm
206 particle size distribution (PSD), which represents the fraction of 2
207 particles that fall within different size classes [29,37]. It is impor-
208 tant to recognize that the fraction of particles within a particular 0
10 100 1000
209 size class can be represented in different ways (e.g., as a number
210 or volume fraction), which leads to different particle size distribu- Particle Radius (nm)
211 tions for exactly the same system (Fig. 2). Knowledge of the PSD of
Fig. 2. The dimensions of the particles in a polydisperse emulsion can be described
212 a colloidal dispersion can be used to specify the percentage of par- by the particle size distribution and mean particle radius. However, these properties
213 ticles that fall below some critical size (e.g., r < 100 nm), which may can be represented in different ways, depending on the method used to specify
214 be important if there are specific biological barriers that have crit- particle concentration, such as number or volume.
17 May 2013
234 the particular situation being addressed. The author believes that and may vary appreciably with changes in pH or ionic strength 298
235 for most applications the particle concentration should be ex- [51]. The electrical characteristics of lipid nanoparticles can be con- 299
236 pressed in terms of the volume (rather than number) when plot- trolled by using different types of emulsifiers: non-ionic surfac- 300
237 ting PSD and calculating mean sizes. tants (neutral to slightly negative); anionic surfactants (highly 301
238 Nevertheless, other means of expressing the particle concentra- negative); cationic surfactants (highly positive); proteins (posi- 302
239 tion may be important to certain applications, e.g., the surface- tive-to-negative as pH increases from below-to-above the isoelec- 303
240 weighted mean is more useful when considering adsorption pro- tric point); polysaccharides (usually negative). Lipid nanoparticles 304
241 cesses or chemical reactions that occur at oil–water interfaces. with tailored electrical characteristics can be prepared by mixing 305
242 The above discussion also highlights the fact that an emulsion with ionic and non-ionic surfactants in different ratios [52]. The electri- 306
243 a mean radius >100 nm may actually contain a substantial fraction cal characteristics of emulsifier-coated lipid-nanoparticles can also 307
244 of particles within the nanoemulsion range. In summary, it is usu- be altered by adsorption of other charged substances onto their 308
245 ally always important to have knowledge of the full PSD, rather surfaces after they have been prepared, such as proteins, polysac- 309
246 than just the mean particle size. charides, phospholipids, inorganic particles, or multivalent ions 310
[29,42–45]. 311
247 3.3. Interfacial properties
3.3.1. Thickness 312
248 The composition, structure, and properties of lipid nanoparticle The thickness of the interfacial coating surrounding each of the 313
249 surfaces will have a major impact on their functional performance lipid particles can also have a major impact on their functional per- 314
250 in foods and beverages, as well as their potential biological fate formance. Typically, the stability of an emulsion or nanoemulsion 315
251 after ingestion. The nanoparticle surface typically consists of a dy- to particle aggregation improves as the thickness of the interfacial 316
252 namic mixture of molecules and ions with different structures, ori- coating increases because of the increase in the range of the steric 317
253 entations, properties, and interactions. The nature of the molecules repulsion [29,53]. This effect is particularly important for lipid 318
254 present at the nanoparticle surface determines interfacial proper- nanoparticles because the dimensions of the interfacial coating 319
255 ties such as thickness, charge, permeability, rheology, environmen- may be on the same order as the dimensions of the internal lipid 320
256 tal responsiveness, and digestibility. Controlling the interfacial core [2]. 321
257 characteristics of lipid nanoparticles is therefore one of the most
258 powerful means of designing nanoemulsions with specific func- 3.3.2. Polarity 322
259 tional performances and biological activities [3,29]. The interfacial The polarity of the interfacial coating depends on the nature of 323
260 characteristics of lipid nanoparticles can be controlled by selecting the various molecules present at the lipid nanoparticle surface. 324
261 emulsifiers with different properties, e.g., surfactants, phospholip- Typically, lipid nanoparticles have a relatively polar surface be- 325
262 ids, proteins, or polysaccharides [39,40]. They can also be modified cause the hydrophilic regions of the adsorbed emulsifier molecules 326
263 after a nanoemulsion has been formed using various approaches. protrude into the surrounding aqueous phase. Nevertheless, they 327
264 The existing emulsifier molecules can be replaced by other sur- may have some non-polar character if the lipid core is not com- 328
265 face-active molecules using a competitive adsorption approach, pletely covered by emulsifier molecules so there are some hydro- 329
266 i.e., by adding another emulsifier to the system after it is formed phobic patches present, or if the emulsifier has some non-polar 330
267 [1,41]. Depositing successive layers of charged biopolymers or col- regions that protrude into the aqueous phase (e.g., some globular 331
268 loidal particles onto oppositely charged lipid nanoparticles can be proteins, particularly after heating). The polarity of the lipid nano- 332
269 used to modify their interfacial properties by forming nanolami- particle surface determines how it interacts with other molecules, 333
270 nated coatings or colloidosomes, such as those shown in Fig. 2 particles, and biological surfaces within the GI tract. 334
271 [42–45]. Hydrophilic polymers can be covalently attached to nano-
272 particle surfaces to modify their interfacial properties [46]. Parti- 3.3.3. Environmental responsiveness and digestibility 335
273 cles with highly hydrophilic surfaces tend to be less prone to The interfacial coating surrounding a lipid nanoparticle deter- 336
274 removal by the bodies’ natural defenses (after absorption), which mines the way that the particle responses to changes in environ- 337
275 increases the residence time of the particles within the systemic mental conditions, such as temperature, pH, ionic composition, 338
276 circulation. Specific ligands may also be attached to nanoparticle and enzyme activity. For example, some emulsifiers are able to 339
277 surfaces to increase their chances of binding to specific biological produce lipid nanoparticles that are relatively stable to changes 340
278 entities or organs within the human body [47,48]. Surface-modi- in pH, ionic strength, and temperature, such as some non-ionic sur- 341
279 fied nanoparticles may be used for targeted or sustained release factants [54] and amphiphilic polysaccharides [55,56]. On the 342
280 applications. This is an area that has not been extensively explored other hand, other emulsifiers produce lipid nanoparticles that are 343
281 in the food industry, but is being actively researched in the phar- highly sensitive to environmental conditions, e.g., globular pro- 344
282 maceutical area.One of the most important interfacial characteris- tein-stabilized emulsions tend to flocculate at pH values near their 345
283 tics of nanoparticles is their electrical charge [49]. Lipid isoelectric point, at high ionic strengths, and above their thermal 346
284 nanoparticles often have an appreciable charge due to adsorption denaturation temperature [51,57]. There are also important differ- 347
285 of ionized or ionizable species onto their surfaces, such as surfac- ences in the susceptibility of interfacial coatings to displacement 348
286 tants, phospholipids, proteins, polysaccharides, or mineral ions and degradation within the GI tract. As mentioned earlier, some 349
287 [29]. The sign and magnitude of the electrical charge on the lipid interfacial components are digestible (such as proteins, modified 350
288 nanoparticles plays a crucial role in their overall functional perfor- starches, and some surfactants), whereas other interfacial compo- 351
289 mance: physical and chemical stability; interaction with other food nents are indigestible (such as dietary fibers, inorganic nanoparti- 352
290 components; interactions with molecules and structures within cles, and some surfactants). The digestibility of an interfacial 353
291 the GIT. The electrical properties of lipid nanoparticles are usually coating will play an important role in determining its potential 354
292 characterized by their f-potential versus pH profile under standard- biological fate within the GI tract. 355
293 ized solution conditions (e.g., ionic strength). The f-potential of a
294 particle depends on the type and number of ionized groups at 3.4. Particle physical state 356
295 the particle surface, as well as the type and concentration of the
296 counter-ions within the surrounding aqueous phase [50]. The Lipid nanoparticles are usually prepared from oil phases that 357
297 charge on lipid nanoparticles may be positive, neutral, or negative, are liquid, but it is also possible to prepare them from oil phases 358
17 May 2013
359 that are either fully or partially solid at the final application tem- potential advantage of SLN and NLC systems are that the rate of 399
360 perature [58,59]. There are a number of nanoemulsion fabrication molecular diffusion through the lipid phase can be reduced, which 400
361 methods available to achieve this goal. In the hot homogenization can slow down chemical degradation reactions and improve the 401
362 approach, the oil phase is maintained in a liquid state throughout stability of encapsulated lipophilic components [62]. The physical 402
363 the process by holding it above its melting point, but is then state of the lipid phase within a nanoparticle may also have some 403
364 crystallized when the system is cooled. The type and amount of influence on its biological fate, e.g., the rate and extent of digestion 404
365 crystals present within the final lipid nanoparticles can be modu- within the small intestine [66]. 405
366 lated by controlling their composition and/or preparation condi-
367 tions [29,37,60,61]. For example, the lipid nanoparticles in
4. Biological fate of lipid nanoparticles 406
368 triacylglycerol nanoemulsions can be crystallized by reducing the
369 temperature sufficiently below the melting point of the oil phase.
There has been some concern from the public, industry, and 407
370 The melting point of the oil phase can also be controlled by using
regulators about the increasing use of nanoparticles within food 408
371 triacylglycerol blends with different compositions – the melting
and beverage products because of potential toxic effects associated 409
372 point usually increases with increasing molecular weight and
with their small dimensions [15,67–69]. Altering the size of parti- 410
373 decreasing degree of unsaturation [29]. In the solvent removal ap-
cles to within the nanometer range may cause them to behave dif- 411
374 proach, a crystalline lipid is dissolved in an organic solvent and
ferently within the human body by influencing their absorption, 412
375 then emulsified with an aqueous emulsifier solution to form an
distribution, metabolism and excretion (ADME), thereby altering 413
376 oil-in-water emulsion or nanoemulsion. The solvent is then re-
their potential toxicity [15,67,70]. In general, the biological fate 414
377 moved (e.g., by evaporation) leading to the formation of crystalline
of a nanoparticle depends on its initial physicochemical character- 415
378 lipid nanoparticles dispersed within an aqueous medium.The
istics (such as composition, structure, dimensions, interfacial prop- 416
379 above approaches have been used to form solid lipid nanoparticles
erties, and physical state), as well as any changes in these 417
380 (SLN) and nanostructured lipid carriers (NLC), which are nanoemul-
properties as it passes through the different regions of the GIT. 418
381 sions where the oil phase is either fully or partly solidified [58,62].
An understanding of the biological fate of lipid nanoparticles after 419
382 An SLN contains lipid nanoparticles that are fully crystallized and
ingestion is therefore required to understand and predict their 420
383 have a highly ordered crystalline structure, whereas an NLC con-
potential toxicity. 421
384 tains lipid nanoparticles that have a less ordered crystalline or
385 amorphous structure, which can aid in the encapsulation and
386 retention of hydrophobic components. The crystallization temper- 4.1. Potential changes in lipid nanoparticle characteristics 422
387 ature of a lipid within a nanoparticle may be appreciably less than
388 that of the same lipid in a bulk phase because of supercooling ef- Before considering the influence of the different environments 423
389 fects [63,64]. In addition, the nature of the crystals formed in a within the GI tract on the properties of lipid nanoparticles, a gen- 424
390 nanoemulsion may be different from those formed by a bulk fat be- eral overview of some of the potential changes that might occur is 425
391 cause of curvature affects, the limited volume present for nucle- given (Fig. 3). 426
392 ation and crystal growth in fine droplets, and the lack of
393 secondary nucleation sites [60,61]. The concentration, nature and 4.1.1. Particle composition and structure 427
394 location of the fat crystals within the lipid nanoparticles in a nano- The composition and structure of ingested lipid nanoparticles 428
395 emulsion can be controlled by careful selection of oil type (e.g., so- may change appreciably as they pass through the GIT. As men- 429
396 lid fat content versus temperature profile, polymorphic forms), tioned earlier, lipid nanoparticles may initially be present within 430
397 thermal history (e.g., temperature–time profile), emulsifier type a food in a variety of different structural organizations, such as 431
398 (e.g., tail group characteristics) and droplet size [37,60,65]. A major core–shell nanoparticles, nanolaminated-nanoparticles, nanoparti- 432
Flocculation
Ostwald
Coalescence Ripening
Particle Size
Changes Association
Merging Molecular
Diffusion
Interfacial Stable
Changes Enzyme
Nanoparticles
Hydrolysis
Protein emulsifier Bile, lipase, phospholipids, fatty acids… Digestion
Original In Intestine
Fig. 3. The properties of nanoparticles may occur in a number of different ways as they pass through the GI tract. Some potential changes in particle dimensions and
interfacial properties are illustrated below.
17 May 2013
433 cle-clusters, nanoparticle-colloidosomes, and nanoparticle-filled of the lipid particles within different regions of the GI tract de- 484
434 hydrogels or droplets (Fig. 1). These initial structures may be dis- pended strongly on initial emulsifier type, e.g., the lipid particles 485
435 rupted as the particles pass through the various regions of the coated by casein were highly susceptible to aggregation within the 486
436 GIT due to alterations in environmental conditions such as dilution, stomach, whereas those coated by Tween 20 were relatively stable. 487
437 pH, ionic strength, temperature, and enzyme activities. The initial
438 composition of the particles may also change, e.g., due to exchange
439 of molecules with the surrounding media, or due to chemical or 4.1.3. Interfacial properties 488
440 enzymatic degradation reactions. It is therefore important to be The interfacial composition and properties of a lipid nanoparti- 489
441 aware of how the composition and structure of an ingested nano- cle may also be altered appreciably as it passes through the GI tract 490
442 particle changes within the different regions of the GIT. due a variety of physicochemical and biological processes (Fig. 3): 491
(i) competitive adsorption – surface active components within the 492
intestinal fluids may adsorb to the nanoparticle surfaces and dis- 493
443 4.1.2. Particle dimensions place some of the original emulsifier molecules; (ii) co-adsorption 494
444 The size of the particles in an emulsion or nanoemulsion may – surface active components within the intestinal fluids may 495
445 change appreciably as they pass through the GIT for a number of adsorb to the nanoparticle surfaces and penetrate between the 496
446 reasons (Fig. 3): (i) flocculation – a number of particles may associ- emulsifier molecules in the original interfacial coating; (iii) multi- 497
447 ate with each other (but keep their individual integrities); (ii) layer formation – components within the intestinal fluids may ad- 498
448 coalescence – a number of liquid particles may merge together to sorb on top of the original interfacial coating; (iv) digestion or 499
449 form a larger particle; (iii) partial coalescence – a number of par- degradation – some of the original emulsifier molecules at the 500
450 tially crystalline particles may fuse together to form a clump; (iv) oil–water interface may be fully or partially digested due to the 501
451 Ostwald ripening – large particles may grow and small ones shrink highly acidic environment in the stomach or due to the presence 502
452 due to molecular diffusion of oil molecules through the aqueous of specific enzymes [79]. Consequently, the surface characteristics 503
453 phase; (v) digestion – a particle may shrink due to enzymatic deg- of a lipid nanoparticle may be very different to those of the origi- 504
454 radation and release of digestion products; (vi) solubilization – a nally ingested nanoparticle when it reaches the site of absorption. 505
455 particle may shrink due to transfer of some of the lipid molecules Various studies have shown that the interfacial properties of lipid 506
456 into the surrounding aqueous phase. nanoparticles and microparticles change appreciably as they pass 507
457 It is therefore important to monitor changes in the size and through different regions of the GIT [73,78,80–84]. 508
458 structure of any ingested lipid nanoparticles throughout the gas-
459 trointestinal tract. An ingested food may initially contain nanopar-
460 ticles, but they may be converted into microparticles or larger
Initial
461 sized objects within the GI tract. Conversely, an ingested food
Mouth
462 may initially contain microparticles or larger sized objects that
Stomach
Mean Particle Radius (nm)
463 are converted into nanoparticles within the GI tract. Numerous re- 10000
Intestine
464 cent studies have reported appreciable changes in the dimensions
465 of ingested nanoparticles using in vivo and in vitro models [71–76].
466 An example, the changes in the microstructure of a protein-sta-
467 bilized oil-in-water emulsion as it passes through the various
468 stages of a simulated GI tract are shown in Fig. 4. Initially, this sys- 1000
469 tem contained relatively small lipid particles (rV 150 nm), but
470 these particles underwent appreciable flocculation and coales-
471 cence in the stomach and small intestine. Consequently, the
472 dimensions of the particles at the site where they are potentially
473 adsorbed (the small intestine) is much larger than the original 100
474 dimensions. This phenomenon obviously has important
475 consequences for understanding the influence of particle dimen-
476 sions on the digestion and adsorption of lipid nanoparticles, and
477 is highly dependent on initial system composition and structure.
10
478 In particular, the nature of the emulsifier that initially coats the li-
Casein BLG Tween 20 SMP
479 pid particles has been shown to have an appreciable effect on their
Emulsifier Type
480 stability within different regions of the GI tract [77,78]. This effect is
481 demonstrated in Fig. 5a, which shows the change in mean particle Fig. 5a. Changes in the mean particle radius of colloidal dispersions initially
482 diameter of oil-in-water emulsions initially stabilized by different containing lipid nanoparticles as they pass through different stages of the GI tract:
483 emulsifiers as they pass through a simulated GI tract. The stability b-lactoglobulin (BLG); casein; Tween 20; sodium monopalmitate (SMP).
Initial Mouth Stomach Small

Intestine
Fig. 4. Changes in the microstructure of a colloidal dispersion initially containing protein-coated lipid nanoparticles as it passes through different stages of the GI tract. The
microstructures are confocal fluorescence microscopy images with the green regions being lipids (provided by Alison Matalanis).
17 May 2013
509 Evidence for alterations in the interfacial properties of lipid par-

510 ticles as they pass through a simulated GI tract is given in Fig. 5b,
511 which shows the change in particle charge (f-potential) of oil-in- Mouth
512 water emulsions initially stabilized by different emulsifiers. The • pH 5-7
• Enzymes
513 charge of the lipid particles within different regions of the GI tract • Salts
514 clearly depended on the initial emulsifier type. • Biopolymers Small Intestine
• 5 – 60 s • pH 6-7.5
• Enzymes
• Salts, Bile
515 4.1.4. Physical state • Biopolymers
516 The physical state (i.e., solid versus liquid form) of a component • Agitation
• 1 – 2 hours
517 used to fabricate a lipid nanoparticle may also change when it
518 encounters the gastrointestinal tract. A lipid phase within a frozen Stomach
519 or chilled food product may be solid at freezer or refrigerator tem- • pH 1-3
• Enzymes Colon
520 peratures, but it may melt when it is exposed to body temperature. • Salts • pH 5-7
521 Conversely, a lipid component within a hot food product may be • Biopolymers • Enzymes
• Agitation • Bacteria
522 liquid at elevated temperatures, but it may crystallize when it is • Agitation
• 30 min – 4 hours
523 exposed to body temperature. Crystalline bioactive components • 12-24 hours
524 that are fully dissolved within a food product, may precipitate
525 when the oil phase is digested and the bioactive component is re-
526 leased into the gastrointestinal juices [64]. Conversely, a bioactive Fig. 6. Schematic diagram of the physicochemical and physiological conditions in
different regions of the human gastrointestinal tract. The diagram of the human
527 component that is initially crystalline within a food product may
body was taken from <http://en.wikipedia.org/wiki/Digestive_tract> (Copyright
528 be dissolved when it is exposed to gastrointestinal juices. All of free).
529 these changes in physical state of an ingested component may alter
530 their biological fate, and therefore potential health benefits and
531 toxicity. A number of studies have highlighted the importance of matrices (as in some deserts and yogurts); they may be trapped 547
532 the physical state of the lipid phase on the behavior of lipid nano- within solid matrices (as in some dried spices, flavors, and colors). 548
533 particles and microparticles under simulated GIT conditions The initial environment of the lipid nanoparticles within a food 549
534 [66,80,85,86], but more research is clearly needed in this important matrix may have a strong influence on their subsequent biological 550
535 area. fate. For example, the surrounding food matrix may have to be dis- 551
rupted or dissolved before the nanoparticles are released, which 552
may alter the location and time that they initially come into direct 553
536 4.2. Pre-absorption
contact with gastrointestinal fluids. Indeed, encapsulation of lipid 554
nanoparticles within specific matrices (such as hydrogel beads) 555
537 A brief overview of the complex conditions and processes
has been proposed as a method for controlling their biological fate 556
538 occurring within different regions of the gastrointestinal tract is
[32,34,88]. 557
539 given (Fig. 6), and their potential influence on the properties of
540 lipid nanoparticles prior to absorption is discussed [32,87]. In this
541 section, we assume that the lipid nanoparticles are originally pres-
4.2.1. Mouth 558
542 ent within a food or beverage product, rather than being formed
The first environment a food or beverage containing lipid nano- 559
543 within the human GIT after ingestion. Lipid nanoparticles may be
particles experiences after ingestion is the oral cavity (Fig. 6) 560
544 present in a number of different forms within an initial product:
[32,33,75,76,87]. The ingested material will undergo a number of 561
545 they may be freely suspended within an aqueous medium (as in
compositional and structural changes as a result: it will be mixed 562
546 beverages and soft drinks); they may be trapped within hydrogel
with saliva; it may become dissolved, dispersed and/or diluted; it 563
may change its pH, ionic strength and temperature; it may be acted 564
upon by digestive enzymes; it may interact with the surfaces of the 565
10
oral cavity; and, it may experience a complex flow/force pattern. As 566
0 a result there may be appreciable changes in the characteristics of 567
the lipid nanoparticles that were present within the initial product 568
-10
(Section 4.1). 569
-20
ζ-Potential (mV)
-30 4.2.2. Stomach 570

After a food is swallowed and passes through the esophagus it 571
-40
enters the gastric cavity (Fig. 6) [32,33,75,76,87]. Within the stom- 572
-50 ach the ingested material is exposed to a variety of physicochem- 573

ical conditions that may greatly alter its properties: strong acid 574
-60 (pH 1–3); high ionic strength (e.g., calcium and sodium salts); high 575
Initial
enzyme activity (e.g., proteases and lipases); presence of surface 576
-70 Mouth
Stomach
active substances (e.g., phospholipids and proteins); complex 577
-80 Intestine flow/force patterns. Strong acids may cause chemical degradation 578
of some components, e.g., hydrolysis of surfactants or proteins. A 579
-90
change in pH and ionic strength may alter the electrical charge 580
Casein BLG Tween 20 SMP
on ionic groups, which will alter any electrostatic interactions in 581
Emulsifier Type the system. Surface active substances in the gastric juices may 582
Fig. 5b. Changes in the particle charge (z-potential) of colloidal dispersions initially
adsorb to the lipid nanoparticle surfaces through competitive 583
containing lipid nanoparticles as they pass through different stages of the GI tract: adsorption and/or co-adsorption processes thereby altering their 584
b-lactoglobulin (BLG); casein; Tween 20; sodium monopalmitate (SMP). surface composition and properties. Gastric lipases will initiate li- 585
17 May 2013
586 pid digestion, while gastric proteases will initiate protein

587 digestion.
588 A number of studies have examined the behavior of lipid nano-
Large particles are unable to Intestinal
589 particles within simulated gastrointestinal conditions, which have
enter mucus layer Lumen
590 been reviewed in recent publications [75,85,87,89]. There may be
591 appreciable changes in the composition, structure, dimensions,
592 charge and physical state of lipid nanoparticles as a result of their
593 presence within the gastric environment. The degree and nature of Small particles may penetrate
mucus layer thereby increasing Mucus layer
594 these changes depends on the precise nature of the initial lipid
retention time and ability to
595 nanoparticles used. For example, globular protein-coated lipid reach epithelium cells
596 nanoparticles have been shown to be highly prone to droplet floc-
597 culation within the stomach, whereas some surfactant-stabilized Epithelium
598 lipid nanoparticles have been shown to be more stable (Fig. 5a). Cells
599 The tendency for particle aggregation and gravitational separation
600 to occur within the stomach may have an important influence on
601 the biological response to ingested foods, e.g., satiety and satiation Para-cellular Trans-cellular
602 [90,91]. It has been postulated that acid-stable emulsions that re- Uptake Uptake
603 main evenly distributed throughout the stomach lead to slower
Fig. 7. Lipid nanoparticles may penetrate into the mucus layer and become trapped
604 gastric emptying and a higher feeling of satiety, than acid-unstable
(mucoadhesion) or transported across it. Nanoparticles that are not digested and
605 emulsions [92–94]. that travel through the mucus layer may be directly adsorbed by the epithelium
cells.
606 4.2.3. Small intestine
607 The material leaving the stomach (the ‘‘chyme’’) is squirted and utilizing various components that reach it [98]. Thus, dietary 650
608 through a small muscular valve (‘‘pylorus sphincter’’) capable of fibers are usually broken down by microbial enzymes leading to 651
609 opening and closing so as to control the amount of food entering the formation of small chain fatty acids and other products that 652
610 the small intestine (Fig. 6) [95]. Upon entering the small intestine may be beneficial to human health [99,100]. This phenomenon 653
611 the chyme is mixed with alkaline small intestinal fluids, which may be used to design delivery systems capable of releasing bioac- 654
612 contain bile salts, phospholipids, pancreatic lipase, co-lipase, bicar- tive components into the colon [101]. On the other hand, there 655
613 bonate, and various other salts, leading to an increase in the pH of may be some adverse effects associated with altering the amount 656
614 the mixture to around neutral. This cocktail of biological juices is and type of undigested food materials that reach the colon. 657
615 designed to further digest any macronutrients within the food so In summary, the lipid nanoparticles in an ingested food or bev- 658
616 that they can be subsequently absorbed by the epithelium cells erage product change considerably as they pass through the GI tract 659
617 [95]. Thus, proteins are converted to peptides and amino acids by as a result of exposure to this complex physiological environment 660
618 proteases, triacylglycerols are converted to free fatty acids (FFA) [32,85,87,102,103]. There may be changes in the composition, 661
619 and monoacylglycerols (MAG) by lipases, and starches are con- structure, dimensions, interfacial properties, and physical state of 662
620 verted to oligosaccharides and glucose by amylases. In addition, the lipid particles, all of which may alter their biological fate and 663
621 the processes that occur in the small intestine lead to the forma- potential toxicity. Recently, there has been considerable progress 664
622 tion of colloidal structures that can enhance the absorption of in understanding the impact of specific physiological conditions 665
623 micronutrients and digested macronutrients [76]. For example, on the fate of lipid nanoparticles within the GI tract using in vitro 666
624 mixed micelles and vesicles are formed that are capable of solubi- and in vivo experiments, but further work is certainly required [89]. 667
625 lizing FFAs, MAGs, and oil-soluble vitamins, and nutraceuticals

626 [96]. The mixed micelles then transport the encapsulated compo- 4.3. Absorption 668
627 nents through the mucous layer to the surfaces of the enterocytes
628 where they are absorbed (Fig. 7). It is interesting to note that the Absorption is the process where a substance is transferred from 669
629 mixed micelles and some of other colloidal structures naturally the lumen of the GI tract into and/or through the epithelium cells 670
630 formed during lipid digestion can be considered to be lipid nano- that line it [95]. After absorption a substance may be further trans- 671
631 particles since they have dimensions <100 nm. ported to the systemic circulation and onto various tissues. In the 672
case of colloidal delivery systems initially consisting of bioactive 673
632 4.2.4. Colon components entrapped within carrier particles there are two as- 674
633 The majority of an ingested food material would normally be pects of absorption that need to be considered: (i) absorption of 675
634 broken down and absorbed within the stomach and small intes- the bioactive components; and, (ii) absorption of the carrier parti- 676
635 tine, but an appreciable fraction may reach the colon depending cles. It should be noted that carrier particles may influence the 677
636 on its initial composition and structure (Fig. 6). If all the compo- absorption of encapsulated bioactive compounds, without actually 678
637 nents used to fabricate a lipid nanoparticle were fully digestible, being absorbed themselves (e.g., by altering the rate and extent of 679
638 then one would expect it to be largely digested and absorbed with- lipid digestion and mixed micelle formation). Toxicologically, it is 680
639 in the stomach and small intestine. For example, one would expect important to establish whether nanoparticle characteristics signif- 681
640 this to happen for lipid nanoparticles with a triacylglycerol core icantly influence these absorption mechanisms, and whether any 682
641 and a protein shell, e.g., b-lactoglobulin stabilized corn oil-in-water resulting changes have potentially adverse effects on human health. 683
642 nanoemulsions [97]. On the other hand, if one or more of the com- When considering the absorption of bioactive components and/ 684
643 ponents used to fabricate a lipid nanoparticle were indigestible, or nanoparticles it is important to determine the region where 685
644 then it may be able to reach the colon without being absorbed. absorption occurs within the GIT (usually the small intestine), as 686
645 For example, this might be expected to happen if a lipid nanopar- well as the physical form of the bioactives and nanoparticles when 687
646 ticle consisted of a mineral oil core and a cross-linked dietary fiber they reach the absorption site. If the original lipid nanoparticle was 688
647 shell, or if the lipid nanoparticles were embedded within a dietary fully digested before reaching the absorption site, then one only 689
648 fiber hydrogel particle [34]. It should be noted that the colon con- needs to consider absorption of the bioactive component. On the 690
649 tains a rich diversity of microbes that are capable of breaking down other hand, if the original lipid nanoparticle had an indigestible 691
17 May 2013
692 core and/or shell then it may remain intact at the absorption site, static, hydrophobic, van der Waals, and hydrogen bonding. 756
693 and so one has to consider absorption of both the nanoparticle The nature of the interactions between a particle and the 757
694 and the bioactive (which may or may not still be encapsulated). mucous layer influence its biological fate. If a particle is strongly 758
695 For example, if the nanoparticle core is fabricated from digestible attracted to the mucous layer, then it may become embedded 759
696 components (such as triacylglycerols) and the surrounding matrix within it, without actually being transported across. This 760
697 (shell) is made from digestible components (such as proteins), then mucoadhesion process increases the residence time of the par- 761
698 one would expect the nanoparticles to be fully digested before ticle within the GIT, which may lead to a greater degree of 762
699 reaching the absorption site. In this case, one would expect lipid digestion and absorption. If a particle is not strongly attracted 763
700 nanoparticles to behave in a similar manner to conventional lipid to the mucous layer, and it is small enough, then it may 764
701 microparticles. In other words, the TAGs would be digested by li- penetrate through the mucous layer and reach the underlying 765
702 pase and converted into MAGs and FFAs that are incorporated into epithelium cells. 766
703 mixed micelles that diffuse through the mucous layer and are ab- 767
704 sorbed by epithelium cells. If the lipid nanoparticles contained any Once a particle has penetrated through the mucous layer then it 768
705 encapsulated bioactive components then they may be fully or par- may be absorbed by the epithelium cells depending on its size, 769
706 tially incorporated within the mixed micelles too, and also be trans- shape, and surface characteristics [38,105]. There are two main 770
707 ported to the epithelium cells. On the other hand, if the lipid types of epithelium cells in the GIT where particle absorption 771
708 nanoparticle core was fabricated from indigestible core components may occur: enterocyte cells and M-cells [38,48]. Enterocyte cells 772
709 (such as essential oils, flavor oils, minerals oils or fat replacers) or is are the most numerous type of cell lining the GIT, but they are 773
710 coated with indigestible shell components (such as mineral parti- not particularly efficient at absorbing particles. On the other hand, 774
711 cles or dietary fibers), then it may remain as nanoparticles or micro- M-cells are much less numerous (<1% of epithelium surface), but 775
712 particles within the small intestine. These particles may be they are much more efficient at absorbing particles. The M-cells 776
713 absorbed directly into the human body by some of the mechanisms are mainly found in specialized regions called ‘‘Peyers patches’’, 777
714 mentioned below, depending on their size, structure, and surface which are responsible for absorbing and sampling ingested anti- 778
715 characteristics. Hydrophobic bioactive components that were orig- gens, including, macromolecules, microorganisms, and certain 779
716 inally located within an indigestible lipid nanoparticle may experi- types of particles, which are then delivered to the underlying lym- 780
717 ence a number of different biological fates: (i) they may remain phoid system to induce immune responses [17,48]. Nanoparticles 781
718 inside the particles and not be absorbed; (ii) they may remain inside may be absorbed by these epithelium cells through a number of 782
719 the particles and be absorbed with the entire particle; (iii) they may different translocation mechanisms [16,17]: 783
720 diffuse out of the particles and be incorporated into mixed micelles;
721 (iv) they may diffuse out of the particles and precipitate in the aque- 4.3.1.1. Paracellular. Nanoparticles may be small enough to pass 784
722 ous phase. Experiments are required with different bioactive com- between the narrow gaps (‘‘tight junctions’’) separating neighbor- 785
723 ponents and delivery systems to establish which of these ing epithelial cells (Fig. 7). This mechanism has been suggested 786
724 mechanisms is most important for specific systems [80,104]. for the transport of solid lipid nanoparticles across epithelium cells 787
[106]. The critical cut off point for this process has been estimated 788
725 4.3.1. Particle absorption to be relatively small (a few nm) under normal circumstances, but 789
726 Once a particle has reached the small intestine there are two certain substances may increase the gap dimensions such as some 790
727 principle barriers to its direct absorption: (i) it must penetrate surfactants, polymers, and chelating agents. 791
728 through the mucous layer that normally coats the epithelium cells;
729 (ii) it must be translocated through the epithelium cell layer [38]. 4.3.1.2. Transcellular. Nanoparticles may be small enough to be ab- 792
730 The mucous layer is a highly complex and dynamic viscoelastic sorbed directly through epithelial cell membranes by either pas- 793
731 gel-like substance that coats the epithelium cells [11,38,105]. The sive or active transport mechanisms (Fig. 7). Typically, absorption 794
732 thickness, structure, and composition of mucous layers depend occurs by an ‘‘endocytosis’’ mechanism that involves the nanopar- 795
733 on their location within the gastrointestinal tract, as well as an ticle encountering the cell membrane, the membrane wrapping it- 796
734 individual’s diet, health, and genetics. The mucous layer consists self around the nanoparticle, and then part of the membrane 797
735 of physically and chemically cross-linked biopolymers, lipids and budding-off to form a vesicle with a nanoparticle trapped inside. 798
736 minerals, and serves a number of important biological functions: This process may occur in enterocyte cells, but is usually much 799
737 it traps and removes pathogens and foreign particles present in more prevalent in M-cells. The critical cut-off point for this process 800
738 the GIT; it lubricates the flow of foods through the GIT; it protects has been estimated to be from less than 50 to around 100 nm for 801
739 the epithelium cells from damage. The mucous layer acts as a phys- enterocyte cells, and to be from 20 to 500 nm for M-cells. 802
740 icochemical barrier that restricts the movement of particles from
741 the lumen to the surface of the epithelium cells. There are two ma- 4.3.1.3. Persorption. Nanoparticles may be able to be absorbed 803
742 jor mechanisms that may restrict particle movement through the through holes formed in the layer of epithelium cells lining the 804
743 mucous layer [38,105]: GIT due to gaps formed when some of the cells are shed and replaced 805
[16]. 806
744 Mesh size – The size of the pores between the cross-linked and The pathway taken, and the rate and extent of nanoparticle up- 807
745 entangled biopolymer molecules within the mucous layer take, depends on the properties of the nanoparticles, e.g., size, 808
746 restricts particle penetration. In practice there are a range of shape, charge and interfacial chemistry [48,70]. At present there 809
747 mesh sizes within the mucous layer, but the critical cut-off is a relatively poor quantitative general understanding of the 810
748 point for particle penetration has been reported to be around relative importance of these different mechanisms. Nevertheless, 811
749 400 nm [105]. Particles appreciably smaller than the mesh size some studies have shown that certain kinds of nanoparticles can 812
750 will penetrate through the mucous layer relatively easily, be directly absorbed by an amount that depends on their physico- 813
751 whereas the movement of particles with similar or larger chemical characteristics. It has been reported that: cationic 814
752 dimensions to the mesh size will be hindered or prevented. nanoparticles are absorbed more readily than anionic nanoparticles 815
753 Molecular interactions – The mucous layer is chemically complex [15,67]: nanoparticles are usually absorbed more readily than 816
754 and is capable of interacting with particles through a variety of microparticles (but there may be an optimum intermediate particle 817
755 non-specific and specific molecular interactions, e.g., electro- size for maximum absorption) [70]; hydrophobic particles are ab- 818
17 May 2013
819 sorbed more readily than hydrophilic ones [38,48]. In practice, the a triacylglycerol) then all of the bioactive compound may be re- 883
820 role of nanoparticle characteristics is likely to depend on the precise leased after digestion, but if the carrier oil is indigestible (such as 884
821 nature of the particles and translocation mechanisms involved. a mineral oil) then the bioactive compound may remain within 885
822 The physicochemical characteristics of nanoparticles will also the lipid particles. The rate and extent of lipid digestion and bioac- 886
823 determine their fate once they have entered the epithelium cells: tive solubilization also depends on the molecular characteristics of 887
824 (i) they may be digested by cellular enzymes into their constituent digestible triacylglycerols oils. Medium chain triglycerides (MCT) 888
825 parts, which are then absorbed; (ii) they may be transported di- tend to be digested more rapidly than long chain triglycerides 889
826 rectly out of the cell and into the blood or lymph systems; or (iii) (LCT) [96], on the other hand the mixed micelles formed by the 890
827 they may accumulate within specific locations in the cell [70]. digestion products of LCT tend to have a higher solubilizing capac- 891
828 Some types of nanoparticles have been shown to promote cellular ity than those formed by MCT. This effect is highlighted in Fig. 8, 892
829 damage if they accumulate within biological cells [70,107]. The which shows that the bioaccessibility of a lipophilic compound 893
830 nanoparticles that are transported out of the epithelial cells via (b-carotene) is strongly influenced by the nature of the carrier 894
831 the portal vein or lymphatic system may circulate through the hu- oil: LCT; MCT; orange oil. The bioavailability is relatively high for 895
832 man body, where they may then be metabolized, excreted, or accu- the long chain triglyceride which is attributed to the large solubi- 896
833 mulate within certain tissues [15]. As mentioned, these processes lization capacity of the mixed micelles. On the other hand, the bio- 897
834 depend on the precise physicochemical characteristics of the nano- availability was relatively low for the bioactive compound initially 898
835 particles involved. For example, smaller (inorganic) particles have dissolved in MCT (even though the MCT was fully digested), which 899
836 been found to accumulate within a wider range of tissues than lar- was attributed to the fact that the mixed micelles formed were not 900
837 ger particles [108]. large enough to accommodate the long hydrophobic b-carotene 901
838 One would expect that the direct absorption and accumulation molecules. The bioavailability was lowest for the orange oil, which 902
839 of the lipid nanoparticles in most commonly used edible nano- is a non-digestible oil that does not form mixed micelles. 903
840 emulsions would be unlikely because they would be expected to The bioaccessibility of a hydrophobic bioactive compound may 904
841 be rapidly digested within the stomach, small intestine, or epithe- also be influenced by the size of the carrier particles. Lipid diges- 905
842 lium cells. However, if the lipid nanoparticles were formed from tion occurs at the surface of lipid particles, and so its rate tends 906
843 indigestible oils (such as hydrocarbons, mineral oils, flavor oils or to increase as the particle size decreases, because this results in 907
844 fat substitutes) or if they were coated with indigestible shells (such an increase in the surface area of lipids exposed to the digestive en- 908
845 as dietary fibers or inorganic particles) then direct absorption zymes [91,111]. Thus, the rate of lipid digestion should increase as 909
846 could in principle occur. Direct particle absorption might also oc- the particle size decreases, which may lead to the faster generation 910
847 cur if the lipid nanoparticles were able to diffuse through the mu- of lipid digestion products capable of solubilizing bioactive compo- 911
848 cous layer so rapidly that only limited digestion had time to occur. nents (see below) as well as to the faster release of any encapsu- 912
849 There is currently little empirical data on the direct absorption of lated components [112]. Nevertheless, the rate of lipid digestion 913
850 lipid nanoparticles by epithelium cells, and further work is needed may not always be faster for smaller lipid particles. Recent exper- 914
851 in this area. As mentioned earlier, the physicochemical characteris- iments in our laboratory found that globular protein-stabilized 915
852 tics of the droplets in a nanoemulsion may be altered considerably nanoemulsions prepared using the homogenization/solvent evapo- 916
853 as they pass through the GI tract (e.g., their size, aggregation state, ration method were digested at a slower rate than conventional 917
854 charge, and composition), and these changes must be considered emulsions, which was attributed to the fact that the nanoemulsion 918
855 when assessing the relative importance of different particle particles had a thicker protein coating than the conventional 919
856 absorption mechanisms. emulsion particles [51]. The same phenomenon was observed in 920
another recent study, which showed that the rate of lipid digestion 921
857 4.3.2. Bioactive absorption (normalized to droplet surface area) had a complex dependence on 922
858 Lipid nanoparticles are often used to encapsulate, protect, and droplet size (Fig. 9), which was attributed to changes in interfacial 923
859 deliver hydrophobic bioactive components, such as colors, flavors, structure during the nanoemulsion fabrication procedure [82]. 924
860 vitamins and nutraceuticals [10,11,109]. It is therefore important The bioavailability of an encapsulated component may also de- 925
861 to understand how the small size of lipid nanoparticles influences pend on the properties of the interfacial coating. The lipid phase 926
862 the absorption of bioactive components.
863 Bioavailability is usually defined as the fraction of an ingested 70
864 component that eventually reaches the systemic circulation
865 [110]. The overall bioavailability (F) of hydrophobic components 60
866 that have poor water-solubility depends on a number of physico-
Bioaccessibility (%)
867 chemical and physiological factors: F = FB FA FM. Here, FB is 50

868 the fraction of hydrophobic component released from the delivery
869 system into the lumen of the GIT to become bioaccessible, FA is the 40
870 fraction of the released hydrophobic component that is absorbed
871 across the layer of intestinal epithelial cells, and FM is the fraction 30
872 of the absorbed hydrophobic component that reaches the systemic
873 circulation without being metabolized. Nanoparticle characteristics 20
874 may alter the bioavailability of encapsulated hydrophobic compo-
10
875 nents by influencing one or more of these mechanisms [11].
0
876 4.3.2.1. Bioaccessibility. The fraction of the hydrophobic compound Corn oil MCT Orange oil
877 released from the lipid nanoparticles may depend on their physico-
878 chemical characteristics in a number of ways. The bioaccessibility Oil Type
879 of a hydrophobic bioactive compound may be influenced by the
Fig. 8. The bioaccessibility of a lipophilic compound is often influenced by the
880 composition of the carrier oil surrounding it. The carrier oil must nature of the carrier oil. In this study, we examined the bioaccessibility of b-
881 usually be digested before the bioactive compound can be released carotene encapsulated within nanoemulsions made from long chain triglycerides
882 into the intestinal fluids. If the carrier oil is fully digestible (such as (corn oil), medium chain triglycerides (MCT), or an indigestible oil (orange oil).
17 May 2013
927 within a lipid nanoparticle is coated by a layer of surface-active within the mucous layer (which mainly consists of anionic bio- 968
928 materials, which may influence the ability of digestive components polymers), increasing their intestinal transit time. An increase in 969
929 (such as bile salts, lipase, and co-lipase) to absorb to particle sur- transit time should enable more lipids to be digested, and a greater 970
930 faces and interact with lipids. For example, if a coating can prevent fraction of the bioactive component to be solubilized within mi- 971
931 lipase molecules from adsorbing to the lipid surfaces, then it will celles and therefore absorbed by enterocytes [11]. 972
932 retard the rate and extent of lipid digestion [113,114]. This may
933 happen if the coating consists of indigestible materials (such as 4.3.2.3. Metabolism. Bioactive components may be metabolized by 973
934 dietary fibers or inorganic particles) or if it consists of highly sur- various types of enzymes during their passage from the GIT tract, 974
935 face active molecules that are not displaced from the droplet sur- to the epithelium cells, and then into the systemic circulation 975
936 face [83,89,115]. [117–119]. The extent and nature of the changes in the chemical 976
structure of a bioactive component will depend on the route that 977
937 4.3.2.2. Absorption. For digestible lipid carrier particles, the hydro- it is adsorbed, e.g., through the lymphatic or blood systems. At 978
938 phobic bioactive compounds are usually released within the gas- present, there has been little research on the role of lipid nanopar- 979
939 trointestinal tract, solubilized within mixed micelles, transported ticle structure on the metabolism of encapsulated components. 980
940 across the mucus layer, and then transferred into the epithelium A number of studies have reported that encapsulation of bioac- 981
941 cells. The characteristics of lipid nanoparticles may influence this tive components within lipid nanoparticles was able to appreciably 982
942 process by altering the solubilization of carrier lipids and lipophilic increase their bioavailability [5,13,120–122], whereas others have 983
943 components within mixed micelles [96,116]. First, the presence of reported little influence of particle size on bioavailability [123]. 984
944 the lipid carrier itself stimulates the release of bile salts and phos- There are a number of potential reasons that can account for the 985
945 pholipids from the bile duct, which increases the number of mixed difference between different bioavailability studies. First, the bio- 986
946 micelles present to solubilize the lipophilic component. Second, availability of a bioactive compound encapsulated within a nano- 987
947 the surface-active digestion products from the lipid carrier mate- particle is usually compared to that encapsulated in a control 988
948 rial, such as FFAs, MAGs and DAGs, are incorporated into mixed mi- system, which may be carrier oil particles of larger dimensions, a 989
949 celles thereby increasing their solubilization capacity. The precise bulk carrier oil, or a non-encapsulated compound. One often finds 990
950 nature of the digestion products produced may also be important, that the bioavailability of a hydrophobic compound encapsulated 991
951 e.g., long chain FFAs are able to solubilize more hydrophobic com- within a lipid nanoparticle is considerably greater than that of 992
952 pounds than medium chain FFAs, presumably because they form the non-encapsulated compound [13,121], but that it is only 993
953 bigger mixed micelles with a high solubilization capacity (Fig. 8). slightly greater or similar for a compound encapsulated within a li- 994
954 In the case of a non-digestible nanoparticle, the bioactive compo- pid microparticle [123]. To establish the potential toxicity of lipid 995
955 nent may not be released by the normal mechanism, and its nanoparticles it is therefore important to compare them to a suit- 996
956 absorption may then be governed by the rate of absorption of able control. For toxicological purposes, it may be advisable to use 997
957 the particle itself (see previous section). a control that closely represents the current form that the bioactive 998
958 The time that a lipid particle spends within the GI tract may also component is normally delivered within a food or beverage, e.g., li- 999
959 affect the rate and extent of the enzymatic hydrolysis of digestible pid microparticles or dissolved within an oil phase. Second, the 1000
960 lipids (such as triacylglycerols), as well as the extent of absorption in vitro and in vivo methods of analysis used to measure the bio- 1001
961 of any encapsulated lipophilic substances. The particles in availability of hydrophobic compounds often vary widely between 1002
962 nanoemulsions may increase the transit time in the GI tract com- studies, which may lead to different conclusions. There is certainly 1003
963 pared to those in conventional emulsions through a number of a need to develop standardized methods that can be used by differ- 1004
964 mechanisms [15]: (i) the small size of lipid nanoparticles means ent laboratories to compare materials under similar conditions. 1005
965 they may be able to penetrate into the mucous layer coating the Third, different types of lipid nanoparticle may behave differently 1006
966 epithelium cells, whereas larger lipid particles cannot (Fig. 7); (ii) within simulated or real GI tracts due to differences in their com- 1007
967 positively charged lipid nanoparticles may also become trapped positions or structures. 1008
4.4. Post-absorption 1009

25
If a lipid nanoparticle is directly absorbed by the human body 1010
Normalized Digestion Rate ( mol s-1 m-2)
(rather than being digested first), then its distribution, accumula- 1011
20 tion, metabolism and excretion may be different from that of nor- 1012
mally digested components [15,67]. Studies on indigestible 1013
metallic and inorganic nanoparticles have shown that they may 1014
15 accumulate in various organs, with the degree of retention depend- 1015
ing upon their dimensions [16,108]. For example, it was reported 1016
that smaller-sized gold nanoparticles accumulated within a greater 1017
10
number of organs than larger-sized ones. Further work is needed to 1018
establish whether edible lipid nanoparticles can be directly ab- 1019
5 sorbed by the human body, and if they can, what their biological 1020
fate is. 1021
0 4.5. Potential toxicity of lipid nanoparticles 1022

45 50 55 60 65 70 75 80 85 90
Particle Radius (nm) Currently, few systematic studies have been carried out that 1023
specifically address the potential toxicity of the lipid nanoparticles 1024
Fig. 9. The normalized lipid digestion rate should be independent of droplet size, that might be present in foods and beverages. Nevertheless, some 1025
but this may not always be the case. This figure shows the normalized digestion
rate for oil-in-water nanoemulsions stabilized by a globular protein (b-lactoglob-
insights into the potential toxicity of these nanoparticles can be 1026
ulin). Droplets with different sizes were produced using a solvent evaporation gained by considering the influence of particle characteristics on 1027
method. their biological fate, and by examining the research carried out 1028
17 May 2013
1029 on non-food lipid nanoparticles, such as those used in the pharma- (iv) Once they have reached the epithelium cells, smaller parti- 1068
1030 ceutical industry. cles may be more easily translocated across them than larger par- 1069
ticles [17]. A number of different particle uptake mechanisms have 1070
1031 4.5.1. Increased bioavailability of bioactive components that are toxic been identified into epithelium cells, and the route taken by a par- 1071
1032 at high levels ticle will depend on its size and other characteristics (such as 1072
1033 Recent reviews of the literature on the influence of particle size shape, charge and polarity). The subsequent biological fate of the 1073
1034 on the biological fate of hydrophobic bioactive compounds indicate lipid nanoparticle and any encapsulated bioactive component will 1074
1035 that their bioavailability increases when the size of the particles depend on the cellular absorption pathway taken. For example, a 1075
1036 encapsulating them falls below some critical level, typically within particle may be broken down within the cell or it may be trans- 1076
1037 the 100–1000 nm range [11,14,124,125]. Various mechanisms ported across the cell to the blood stream or lymphatic pathway. 1077
1038 have been proposed to account for an increase in oral bioavailabil-
For many bioactive components, an increase in oral bioavail- 1078
1039 ity with decreasing particle dimensions (Fig. 10):
ability is desirable since it means that either their effective bioac- 1079
tivity can be increased or that a lower amount is needed to get the 1080
1040 (i) The water-solubility of hydrophobic bioactives encapsulated
same biological effect [11,19,32]. In other bioactive components, 1081
1041 within particles increases as the particle size decreases due to an
an increase in oral bioavailability may have no adverse effects on 1082
1042 interfacial free energy effect. Thus, there may be a higher concen-
human health and therefore cause no concern for potential toxic- 1083
1043 tration of soluble hydrophobic bioactive within the aqueous envi-
ity. On the other hand, there are health concerns associated with 1084
1044 ronment of the gastrointestinal fluids, which facilitates adsorption;
increasing the oral bioavailability of bioactive components that ex- 1085
1045
hibit toxic effects when consumed at too high levels. If one of these 1086
1046 (ii) Digestible triacylglycerols are often used as carrier oils for bioactive components normally has a very low bioavailability but 1087
1047 hydrophobic bioactive compounds, and it is often important that
its absorption by the human body is increased substantially by 1088
1048 these oils are digested before the bioactive compound is released. encapsulating it within lipid nanoparticles, then it could exhibit 1089
1049 The rate of triacylglycerol digestion tends to increase as the dimen-
toxic effects that could not be predicted from data obtained on 1090
1050 sions of the particles decreases because this leads to an increase in the same material in microscopic or macroscopic form. This is par- 1091
1051 the area of the oil phase exposed to digestive enzymes (lipase). In ticularly true if the bioactive component is incorporated into a 1092
1052 addition, the digestion products formed during this process product that is consumed regularly in large volumes, such as a soft 1093
1053 (monoacylglycerols and free fatty acids) assemble into mixed drink or beverage. 1094
1054 micelles that are capable of solubilizing and transporting any
1055 hydrophobic bioactives released. Thus, the faster that triacylglyce-
1056 rols are digested, the faster mixed micelles will be formed and 4.5.2. Direct absorption of lipid nanoparticles 1095
1057 available for solubilization and transport. Non-digestible nanoparticles, such as metals (silver and gold) 1096
1058 (iii) The rate at which particles can penetrate into and diffuse and inorganic materials (titanium dioxide and silicon oxide), can 1097
1059 through the mucous layer coating the epithelium cells tends to cross the layer of epithelial cells by a number of different routes, 1098
1060 increase as the particle size decreases (provided that they do not e.g., paracellular, transcellular, or persorption [16,108]. Once ab- 1099
1061 have surface characteristics that allow them to bind strongly to sorbed into an epithelium cell a nanoparticle may accumulate, be 1100
1062 components within the mucous layer) [38,105]. Thus, smaller par- digested, or be transported into the systemic circulation via the 1101
1063 ticles will tend to have longer retention times within the small blood or lymph systems [17,70]. The nanoparticles that are trans- 1102
1064 intestine than larger ones, thereby enhancing their tendency to ported out of the epithelial cells may circulate through the human 1103
1065 be fully digested. In addition, sufficiently small particles may be body, where they may then be metabolized, excreted, or accumu- 1104
1066 able to penetrate completely through the mucous layer and reach late within certain tissues [15]. These processes depend on the pre- 1105
1067 the epithelium cells where absorption occurs; cise physicochemical characteristics of the nanoparticles involved, 1106
Differences in Solubility Differences in Surface Area
Larger particles Smaller particles
Differences in Translocation
Q3 Fig. 10. A number of mechanisms have been proposed to account for the observed higher bioavailability of hydrophobic compounds in lipid nanoparticles: (i) increased
water-solubility in smaller particles: (ii) faster digestion of smaller particles due to higher surface area; (iii) increased mucoadhesion and translocation of smaller particles.
17 May 2013
The fabrication of lipid nanoparticles using some homogeniza- 1169

1107 e.g., composition, size, shape, charge and interfacial chemistry. At
tion methods (e.g., solvent displacement or evaporation methods) 1170
1108 present, there is no evidence that lipid nanoparticles fabricated
involves the use of organic solvents, such as acetone, hexane, or 1171
1109 from components that are normally digested within the GI tract
ethyl acetate [132]. These organic solvents are usually removed 1172
1110 are absorbed directly into the human body. Nevertheless, if these
by evaporation during the preparation of the lipid nanoparticles, 1173
1111 nanoparticles were prepared using indigestible oils (such as flavor
but some residual organic solvent may remain in the final product. 1174
1112 oils, mineral oils, or fat replacers) or if they were coated with an
It is therefore important to be aware of the potential toxic effects 1175
1113 indigestible shell (such as dietary fibers or solid particles) then di-
associated with any residual organic solvents if nanoemulsions 1176
1114 rect absorption could occur. However, it should also be recognized
are fabricated using these approaches. 1177
1115 that even indigestible lipid nanoparticles may undergo consider-
1116 able growth in size due to aggregation (flocculation or coalescence)
1117 as they pass through the mouth, stomach, and small intestine. In- 5. Conclusions 1178
1118 deed, preliminary studies in our laboratory with flavor oil emul-
1119 sions have shown that they may be susceptible to droplet Conventional oil-in-water emulsions containing relatively large 1179
1120 coalescence within the GI tract. Further work is clearly needed to lipid particles (r > 100 nm) have been widely used in the food and 1180
1121 determine whether direct adsorption of indigestible or digestible beverage industry to encapsulate, protect, and deliver lipophilic 1181
1122 edible lipid nanoparticles is important in humans. food components, such as triacylglycerol oils, flavors, colors, pre- 1182
servatives, vitamins, and nutraceuticals. Recently, there has been 1183
great interest in the utilization of nanoemulsions that contain rel- 1184
1123 4.5.3. Interference with normal GI function atively small lipid nanoparticles (r < 100 nm) for the same purpose, 1185
1124 The presence of lipid nanoparticles within the mouth, stomach, since they have some potential advantages over conventional 1186
1125 and small intestine may alter the normal functioning of certain ele- emulsions: higher optical clarity; better stability; and enhanced 1187
1126 ments of the GI tract, which could lead to potential toxicity [69]. bioavailability. Nevertheless, the use of very small particle sizes 1188
1127 First, very small lipid nanoparticles could absorb directly through may alter the biological fate of ingested lipids and encapsulated 1189
1128 the epithelium cells in the mouth, esophagus, or stomach before bioactive components, which could potentially have some adverse 1190
1129 reaching the small intestine, and therefore behave in a different effects on human health. Recently, considerable progress has been 1191
1130 way to lipid particles that are normally digested in the small intes- made in understanding the potential response of lipid nanoparti- 1192
1131 tine prior to adsorption. Second, the specific surface area and cur- cles to gastrointestinal conditions, but further work is clearly 1193
1132 vature of particles increases as their dimensions decreases, which needed. The knowledge gained from this type of research could 1194
1133 may affect the absorption and activity of lipase, co-lipase, bile salts, be utilized by the food industry to design foods with improved 1195
1134 and other digestive components at the oil droplet surfaces. For quality and health benefits, without introducing any adverse 1196
1135 example, the adsorption of globular proteins (such as digestive en- health effects. In addition, it could be used by regulators to develop 1197
1136 zymes) to hydrophobic particle surfaces can lead to conformational science-based regulations to better govern the safe application of 1198
1137 changes (surface denaturation) that alter protein function, such as nanotechnology in foods. 1199
1138 enzyme activity [126–128]. Third, as mentioned earlier, very small
1139 particles may be able to penetrate through the mucous layer and Acknowledgements 1200
1140 interact directly with epithelium cells, whereas larger ones cannot.
1141 In summary, the small size, high surface area, and high surface en- This material is based upon work supported by the Cooperative 1201
1142 ergy of nano-sized lipid particles may lead to effects in the GI tract State Research, Extension, Education Service, United State Depart- 1202
1143 that are not predictable from knowledge of the behavior of micro- ment of Agriculture, Massachusetts Agricultural Experiment 1203
1144 or macro-sized lipids [129]. Station and an United States Department of Agriculture, CREES, 1204
NRI Grant. 1205
1145 4.5.4. Compositional effects

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Progress in Lipid Research: David Julian Mcclements

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JPLR 823 No.

of Pages 15, Model 5G

Progress in Lipid Research xxx (2013) xxx–xxx

Contents lists available at SciVerse ScienceDirect

Progress in Lipid Research

3 Edible lipid nanoparticles: Digestion, absorption, and potential toxicity

⇑ Tel.: +1 413 545 1019.

0163-7827/$ - see front matter Ó 2013 Published by Elsevier Ltd.

2 D.J. McClements / Progress in Lipid Research xxx (2013) xxx–xxx

65 4.3.2. Bioactive absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

D.J. McClements / Progress in Lipid Research xxx (2013) xxx–xxx 3

Nanoparticle Filled Nanoparticle Filled

Nanoparticle Solid Lipid

198 providing information about the size of the particles in nanoemul- 12

4 D.J. McClements / Progress in Lipid Research xxx (2013) xxx–xxx

D.J. McClements / Progress in Lipid Research xxx (2013) xxx–xxx 5

Protein emulsifier Bile, lipase, phospholipids, fatty acids… Digestion

6 D.J. McClements / Progress in Lipid Research xxx (2013) xxx–xxx

Initial Mouth Stomach Small

D.J. McClements / Progress in Lipid Research xxx (2013) xxx–xxx 7

509 Evidence for alterations in the interfacial properties of lipid par-

-30 4.2.2. Stomach 570

-50 ach the ingested material is exposed to a variety of physicochem- 573

8 D.J. McClements / Progress in Lipid Research xxx (2013) xxx–xxx

586 pid digestion, while gastric proteases will initiate protein

625 lizing FFAs, MAGs, and oil-soluble vitamins, and nutraceuticals

D.J. McClements / Progress in Lipid Research xxx (2013) xxx–xxx 9

10 D.J. McClements / Progress in Lipid Research xxx (2013) xxx–xxx

867 chemical and physiological factors: F = FB FA FM. Here, FB is 50

D.J. McClements / Progress in Lipid Research xxx (2013) xxx–xxx 11

4.4. Post-absorption 1009

0 4.5. Potential toxicity of lipid nanoparticles 1022

12 D.J. McClements / Progress in Lipid Research xxx (2013) xxx–xxx

Differences in Solubility Differences in Surface Area

Larger particles Smaller particles

D.J. McClements / Progress in Lipid Research xxx (2013) xxx–xxx 13

The fabrication of lipid nanoparticles using some homogeniza- 1169

1145 4.5.4. Compositional effects

14 D.J. McClements / Progress in Lipid Research xxx (2013) xxx–xxx

D.J. McClements / Progress in Lipid Research xxx (2013) xxx–xxx 15

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