Article
pubs.acs.org/Langmuir
Cubosome Topologies at Various Particle Sizes and Crystallographic
Symmetries
W. T. Gózd́ ź*
Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
*
S Supporting Information
ABSTRACT: The nanoparticles built of bicontinuos lyotropic
phases of cubic symmetry are studied within the framework of
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the Landau−Brazovskii functional that correctly predicts the
structure of soft monocrystals and thin films of bicontinuos
lyotropic phases. A detailed description of the geometry and
topology of cubosomes is presented. This level of description
of the internal structure of cubosomes is not easily accessible
by experimental techniques. I show that the internal structure
of the cubosomes may be extremely rich.
■ INTRODUCTION
I investigate the properties of nanoparticles1,2 of lyotropic
bicontinuous phases formed in mixtures of lipids and water.
Bicontinuous phases are liquids with crystalline order and
periodicity in the x, y, and z directions having a length scale
much larger than the size of molecules. They can be observed
in systems with competing interactions,3,4 such as diblock
copolymers, ternary mixtures of oil, water, and surfactants, or
binary mixtures of lipids and water.5−8 They can be
encountered in biological cells in the endoplasmic reticulum
and organelles9 or arthropod biophotonic nanostructures.10
Lyotropic liquid-crystal phases are formed when lipid molecules
self-assemble into a bilayer with hydrocarbon chains isolated
from water molecules. The bilayer divides the space into two
disjointed networks of channels filled with water and behaves as
an elastic membrane. The midplane of the membrane forms a
triply periodic surface with the topology identical to that of an
infinite triply periodic minimal surface of cubic symmetry.
In physical systems, bicontinuous phases are bounded by
walls of a vessel or a surface of an electrode.11 The
monocrystals of cubic phases12,13 or a dispersion of nano-
particles built from a cubic phase can be immersed in an
isotropic phase.1,2,14,15 When a bicontinuous phase is in contact
with an isotropic phase, its structure at the interface has to be
deformed in order to avoid free edges of a bilayer exposed to an
isotropic phase because the free edges are mainly built of
hydrocarbon chains. Because of the hydrophobic effect, the free
edges merge and the bilayer in the bicontinuous phase forms a
closed surface, where the surface is defined by the midplane of
the bilayer.16,17 It has to be noted that the experimental
realization of dispersions of liquid-crystalline nanoparticles,
including cubosomes, requires an input of physical energy and
PEGylated surfactant agents (or other polymeric detergents)
for the fragmentation of the bulk amphiphilic phase and for
stabilization of the nanoparticle interfaces against aggrega-
tion.18−20
© 2015 American Chemical Society
The properties of nanoparticles of cubic lyotropic phases
(cubosomes) make them ideally suited as efficient drug delivery
vehicles. Cubosomes may be used as nanocontainers for drug
delivery in a manner similar to that for liposomes, but they have
many advantages over liposomes as drug carriers. They have a
high drug payload because of the large surface area of the
bilayer of the cubic crystalline structure. They have an
enhanced capacity for drug encapsulation and the capability
of encapsulating hydrophobic, hydrophilic, and amphiphilic
substances. The dispersion of cubosomes has a lower viscosity
than bulk cubic phases. Cubosomes can be used for the
controlled release of active ingredients through a slow diffusion
process from nanochannels assemblies. When decorated with
fluorophores, they can be used in theranostic applications.21
They are efficient in enhancements for therapeutic protein
stability against enzymatic degeneration.22 They can be used to
design vehicles for neuroprotection and neuroregeneration.23,24
Most of the work devoted to the study of nanoparticles of
cubic lyotropic liquid crystals is experimental.2,12,14,15 Unfortu-
nately, available experimental techniques are not sufficient for
the detailed observation of the structure of cubosomes and
monocrystals. The size of the unit cell of the cubic bicontinuous
phases is much smaller than the resolution of the optical
microscopes. Because the monocrystals are soft, the application
of AFM (atomic force microscopy) techniques is not trivial.
Despite that, the AFM technique has been applied with some
success to examine the surface of thin films composed of the
bicontinuous phase of monoolein and phytantriol.25 So far
cryo-TEM (transmission electron microscopy) is the best
technique for studying the structure of small, soft objects on the
order of 100 nm. From images obtained from cryo-TEM, it is
possible to infer some information about the internal structure
Received: October 12, 2015
Revised: November 16, 2015
Published: November 20, 2015
13321 DOI: 10.1021/acs.langmuir.5b03799
Langmuir 2015, 31, 13321−13326
Langmuir
of the nanoparticles and their shape. Unfortunately, the images
obtained from cryo-TEM experiments are generated by
electrons scattered throughout the whole sample. Thus, limited
information about the structure of the surface of the sample can
be inferred indirectly from cryo-TEM experiments.19,26
However, the cryo-TEM technique has been able to
demonstrate the generation of the smallest possible tetrahedral
channel in cubosome nanoparticles formed upon fusion of lipid
nanovesicles of nonlamellar lipids.26 The experimental cryo-
TEM data have confirmed the theoretical modelization of the
smallest cubosome of diamond symmetry, the formation of
nanochannel networks in small cubosome particles, and the
cubosome growth evidenced by the nodal surfaces approach.27
The theoretical description has been restricted to purely
geometrical models based on the properties of triply periodic
nodal surfaces28 and to lattice models.29−31 The mathematical
modeling based on the nodal surfaces allows for an
investigation of topological properties of the studied structures,
but the shape of the bilayer and the thermodynamic properties
of the examined object cannot be determined. In this approach,
it is assumed that the internal structure of a cubosome is
identical to the structure of the bulk phase, only the free edges
of the midplane are merged and the associated energy effect is
disregarded.
Detailed knowledge about the shape of the bilayer may be
obtained by the minimization of the appropriate free energy
functional. I have already used a Landau−Brazovskii-type
functional to study the stability of facets of lyotropic
monocrystals16 and the orientation of thin films of lyotropic
cubic phases with respect to the axes of the unit cell.17 The
results of the theoretical predictions are in very good agreement
with the results of experiments. I apply the same functional to
study nanoparticles formed of lyotropic cubic phases. To the
best of my knowledge, this is the first such study when the
structure and properties of cubosomes are described in such
high detail. I show that the structure of cubosomes obtained
from the minimization of the Landau−Brazovskii functional is
much more complex then the structure predicted by the simple
analysis of geometrical models based on nodal surfaces. Even
the topological properties of small cubosomes differ from the
results of simple geometrical considerations.
■ MODEL AND COMPUTATIONAL METHOD
I have performed the calculations within the framework of a
relatively simple Landau−Brazovskii-type model with one scalar
order parameter related to the local concentration of water.32,33
The free-energy functional for systems inhomogeneous on a
mesoscopic length scale can be written in the form
-[ϕ(r)] = ∫ d3r(|Δϕ(r)|2 + g[ϕ(r)]|∇ϕ(r)|2 + f [ϕ(r)])
(1)
where Δ and ∇ denote the Laplacian and gradient, respectively.
This functional successfully describes systems as diverse as
binary or ternary surfactant mixtures, block copolymers,
colloidal particles with competing attractive and repulsive
interactions of different ranges, and magnetic systems with
competing ferromagnetic and antiferromagnetic interac-
tions.3,4,32,34−37 Order parameter ϕ(r) in eq 1 depends on
the physical context. In the case of lipids in water, ϕ2(r)
describes the local concentration of water. The value of the
order parameter is zero in the center of the lipid bilayer, ϕ(r) =
0. The bilayer divides the space into two disjointed water
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channels, one of them on one side of the bilayer, where ϕ(r) >
0, and the other one on the other side of the bilayer, where
ϕ(r) < 0. The sign of ϕ(r) allows me to distinguish between
the two disjointed channels of water. The fluid in each channel,
however, has the same physical nature. For this reason in the
case of lipids in water, functional eq 1 must be an even function
of ϕ.
f [ϕ] is the free-energy density of the homogeneous phases.
In the case of the phase coexistence between water- and lipid-
rich phases, we can postulate for f [ϕ] the form with three
minima of equal depth, where ϕ = ±1 both represent the water-
rich phase, f [ϕ(r)] = (ϕ(r)2 − 1)2(ϕ(r))2. The inhomoge-
neous distribution of the components, in particular, the
formation of the bilayer, is possible when the corresponding
free energy is lower than for any homogeneous structure. When
the concentration ϕ(r) becomes position-dependent, (∇ϕ)2 >
0. - can decrease for (∇ϕ)2 increasing from zero when
g[ϕ(r)] < 0. On the other hand, Laplacian term |Δϕ|2 leads to
an increase in - , and the length scale of the inhomogeneities
(the size of the unit cell in the case of the periodic phases) is
determined by the competition between the terms supporting
and suppressing the spatial oscillations of ϕ(r). Unlike refs 3, 4,
and 35−37 where g[ϕ(r)] was approximated by a constant, we
assume from ref 32 the form g[ϕ(r)] = g2ϕ(r)2 + g0 with g2 =
4.01 − g0 and g0 = −3 because for these parameter values the
cubic bicontinuous phases in the bulk have already been studied
in detail.32
The stable or metastable phases of the system correspond to
the minimum of functional eq 1. To minimize the functional,
we discretize the field ϕ(r) on a cubic lattice. The discretization
and minimization procedures are described in detail in refs 16
and 32 (Supporing Information). After discretization, the
problem of minimization of the functional is converted to the
problem of minimization of a function of many variables, where
the variables are the values of field ϕ(r) at the lattice sites. I use
the conjugate gradient method to minimize the function
numerically.32,38,39
It is worth noticing that functional eq 1 gives results
consistent with the Helfrich functional.16 In the Helfrich
functional, only the shape of the bilayer is considered40
Fb = 2κ ∫ H 2 dA + κ ̅ ∫ K dA
where κ and κ̅ are the bending rigidity and the Gaussian rigidity
(2)
of the bilayer, respectively. H, K, and dA are the mean
curvature, the Gaussian curvature, and the infinitesimal area
element of the midplane, respectively. The first term in eq 2
takes into account the bending of the bilayer, and the second
term depends on the topology. For a fixed topology, the second
term is constant. From the integral of the Gaussian curvature
over a closed surface, the genus can be calculated. The genus
describes the topology of the surface. If the surface of the
bilayer is transformed without cutting it to a sphere with
handles, then the number of handles is the genus of the surface.
Functional eq 2 has the lowest value when the mean curvature
of the surface describing a bilayer is zero. Triply periodic
minimal surfaces and a plane have a mean curvature of zero at
every point on the surface. The mean curvature at a given point
is zero when the surface is a symmetric saddle or is flat. The
shape of the bilayer in a bicontinuous cubic phase closely
resembles the shape of a triply periodic minimal surface.41
Closed minimal surfaces do not exist. Thus, the bending energy
for a closed surface such as the surface formed by the bilayer
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that forms a cubosome will always be higher than the bending
energy of the triply periodic minimal surface.
I study cubosomes of different sizes built of different cubic
phases. The size of the cubosomes is determined by the size of
the computational box. I use a cubic computational box and
impose fixed boundary conditions at the faces of the box. The
fixed boundary conditions mimic the presence of the stabilizing
agents used in preparations of the cubosomes dispersions. The
value of the order parameter field ϕ(r) at the faces of the cube
is equal to the value that characterizes the isotropic phase.
Changing the size of the computational box in which the cubic
phase is confined causes the formation of different cubosomes.
I use the nodal approximation (eqs 3, 4, and 5) to triply
periodic bicontinuos phases P, I-WP, and D, respectively, to
build the initial configurations for field ϕ(r), r = (x, y, z) in the
computational box:
⎛ 2π ⎞ ⎛ 2π ⎞ ⎛ 2π ⎞
ϕP(r) = cos⎜ x⎟ + cos⎜ y⎟ + cos⎜ z⎟
⎝L ⎠ ⎝L ⎠ ⎝L ⎠
⎛ ⎛ 2π ⎞ ⎛ 2π ⎞ ⎛ 2π ⎞ ⎛ 2π ⎞
ϕIWP(r) = 2⎜cos⎜ x⎟ cos⎜ y⎟ + cos⎜ y⎟ cos⎜ z⎟
⎝ ⎝L ⎠ ⎝L ⎠ ⎝L ⎠ ⎝L ⎠
⎛ 2π ⎞ ⎛ 2π ⎞⎞ ⎛ ⎛ 2π ⎞ ⎛ 2π ⎞
+ cos⎜ x⎟ cos⎜ z⎟⎟ − ⎜cos⎜ 2x⎟+cos⎜ 2y⎟
⎝ L ⎠ ⎝ L ⎠⎠ ⎝ ⎝ L ⎠ ⎝L ⎠
⎛ 2π ⎞⎞
+ cos⎜ 2z⎟⎟
⎝ L ⎠⎠
⎛ 2π ⎞ ⎛ 2π ⎞ ⎛ 2π ⎞ ⎛ 2π ⎞
ϕD(r) = cos⎜ x⎟ cos⎜ y⎟ cos⎜ z⎟ − sin⎜ x⎟
⎝L ⎠ ⎝L ⎠ ⎝L ⎠ ⎝L ⎠
⎛ 2π ⎞ ⎛ 2π ⎞
sin⎜ y⎟ sin⎜ z⎟
⎝L ⎠ ⎝L ⎠
L is the linear size of the unit cell of the bulk bicontinuous
cubic phase,32 and for fixed model parameters, it is different for
each phase as shown in Figure 1. The linear sizes of the unit cell
Figure 1. Unit cells of P, I-WP, and D phases obtained by the
minimization of functional eq 1. The presented surface is given by the
equation ϕ(r) = 0 (the midplane of the bilayer). The colors represent
two sides of the surface. All images are drawn on the same scale.
of the I-WP and D phases with respect to the P phase are 1.49
and 1.59, respectively. I discretize field ϕ(r) in such a way that
we have at least 33 lattice points on length L. In the
calculations, the center of the unit cell of the cubic phase is
placed in the center of the computational box. I have also used
randomly generated field ϕ(r) as the initial configuration. In
this case, additional constraints were imposed on the symmetry
of the field in the computational box. Field ϕ(r) was minimized
in a tetrahedral volume element, and then the volume inside the
cubic box was filled by copying the tetrahedral element
according to the imposed symmetries. In a similar way, the
minimization was performed for the bulk cubic phases.32
■
RESULTS AND DISCUSSION
I have studied the relationship between the size of a cubosome
and its structure. Functional eq 1 was minimized for different
sizes of the computational box. Nodal approximations ϕP(r),
Article
ϕI‑WP(r), and ϕD(r) were used for the initial configuration of
field ϕ(r) for different phases. The calculations were performed
mainly for the simple cubic bicontinuous phase P (Figure 1).
The structure of this phase is the simplest among all of the
bicontinuous phases, and the most stable facets of the P phase
are perpendicular to direction [100]. I focused on small
cubosomes built of fewer than 100 unit cells.
In Figure 2, the results of the minimization of functional eq 1
for two different sizes of the computational cube are presented.
(3)
Figure 2. Cubosomes of the same shape but different sizes obtained by
the minimization of functional eq 1. The surface is given by equation
ϕ(r) = 0. The colors represent two sides of the surface. In the first and
the third columns, cubosomes of different sizes are shown. In the
second column, eight and four unit cells of the simple cubic phase are
shown. All images are drawn to the same scale. In the second row, the
interior of the cubosomes is presented.
(4)
The location of the bilayer is given by the surface where the
order parameter field is zero, ϕ(r) = 0. The colors represent
different sides of surface ϕ(r) = 0. The structure of the
bicontinuous phase used to build the initial configuration was
(5)
the same for each case. The initial configuration was calculated
from eq 3 with the size of the unit cell L obtained for the bulk
phase. Only the size of the computational box was different.
The surface area of the bilayer of the larger cubosome is 2.5
times larger than the surface area of the bilayer of the smaller
one. The topology of these cubosomes is the same, and the
genus is 28.
I obtained as a result of the minimization cubosomes with
the same topology for different sizes of the computational cubic
box. In Figure 2 only the smallest and the largest cubosomes
are presented, but we have also obtained cubosomes of the
same genus and intermediate sizes. For comparison, we also
present eight unit cells of the cubic phase obtained for the bulk
configuration. All images are drawn to the same scale. Further
increases in the size of the computational box lead to a
cubosome built of 27 unit cells. The period of the bicontinuous
phase inside a cubosome may be different from the period of
the bulk phase if there is a constraint on the size of the
cubosome. Such behavior is also observed for the cubosomes
that are built of hundreds of unit cells. Here, we have shown the
images of a small cubosome just to show in a clear way the
structure of the cubosomes.
In Figure 3, two cubosomes obtained from two different
phases, I-WP and P, are presented. The initial configurations
were calculated from eqs 4 and 3 with the size of the unit cell L
obtained for the bulk phase. In the first and second columns,
the cubosome obtained from the I-WP and P phases are shown,
respectively. The genera of these cubosomes are 23 and 28,
respectively, and the surface area of the bilayer of the cubosome
on the left is 0.56 times the surface area of the one on the right.
These cubosomes have the same symmetry (Im3m) but
different topology. These two different cubosomes look almost
the same from the outside and have almost the same size (see
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Langmuir
Figure 3. Cubosomes with the same symmetry and different topology
obtained by the minimization of functional eq 1. The surface is given
by the equation ϕ(r) = 0. The colors represent two sides of the
surface. In the first and the second columns, the cubosomes formed
from phases with the symmetry of the I-WP phase and the P phase are
shown. All images are drawn on the same scale. In the second row, the
interior of the cubosomes is presented.
the first row in Figure 3 for comparison), but their internal
structure is quite different (see the second row in Figure 3 for
comparison). It may also be possible that hybrid cubosomes are
formed. Such nanoparticles are built of two different phases and
have been called Janus nanoparticles.24,42
In Figure 4, two cubosomes with different structures of the
boundary layer are presented. The initial configuration was
Figure 4. Cubosomes with different structures of the boundary layer
obtained by the minimization of functional eq 1. The surface is given
by equation ϕ(r) = 0. The colors represent two sides of the surface. In
the first and the second columns, the cubosomes with similar internal
structure but different structure near the walls of the cubosomes are
shown. All images are drawn on the same scale. In the second row, the
interior of the cubosomes is presented.
calculated from eq 3 with the size of the unit cell L obtained for
the bulk phase. The genera for these cubosomes are 74 and 51,
respectively, and the surface area of the bilayer of the large
cubosome is 1.91 times larger than the surface area of the small
one. For these cubosomes the period of the bicontinuous phase
is comparable and close to the period of the bulk phase. For the
cubosomes presented in Figure 4, the passages are formed at
the edges of the cubosomes, and at the faces, the bilayer is kept
flat. Such a configuration minimizes the bending energy
because the curvature of the flat surface is zero. It should
also be noted that the passages in the outer layers are larger
than the passages in the inner layers.
From my calculation, it follows that the structure of small
cubosomes may be extremely rich. Examples of such
cubosomes are presented in Figure 5. These cubosomes were
obtained by starting from random configurations and imposing
constraints on their symmetry. All of these cubosomes have
Im3m symmetry. In this case, we noticed that some of the
minimized structures were the same as in the case when the
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Figure 5. Small cubosomes with different symmetry and topology
obtained by the minimization of functional eq 1. The surface is given
by equation ϕ(r) = 0. The colors represent two sides of the surface. All
images are drawn on the same scale. In the second and fourth rows,
the interior of the cubosomes is presented.
nodal approximation was used to build the initial configuration,
but we also observed many new structures of cubosomes, as
presented in Figure 5.
The first cubosome (a) is the simplest and the smallest. I
have observed that the internal structure of the cubosomes may
differ substantially from each other despite the very similar
structure of their faces. For small cubosomes, it is very often
encountered that they have four open channels at each face. I
have already presented such cubosomes in Figures 2−4. More
examples of such cubosomes are shown in Figure 5(b,f). Very
similar cubosomes with four open channels at the faces but
rotated by 45° are presented in Figure 5(d,e,g). The third (c)
cubosome is particularly interesting because it is formed from a
multiply continuous phase, where we have a small water
channel inside a large water channel. Finally, it is also
interesting that sometimes the cross section may look very
similar but the structure at the faces may be different, as it is in
the case of the cubosomes pictured in Figure 5(g,h).The small
cubosomes as presented in Figure 5 may be formed in early
intermediate states during the transition of the bilayer from
vesicles to cubosomes.26
For larger cubosomes, their internal structure closely
resembles the structure of the bulk bicontinuous phase. In
Figure 6, three relatively large cubosomes of regular shape and
different symmetry and typology built of the P, D, and I-WP
phases are presented. The initial configurations were calculated
from eqs 3−5 and with the size of the unit cell L obtained for
the bulk phase. The surface areas of the bilayer of the second
and third cubosomes are 1.08 and 1.28 times larger,
respectively, than the surface area of the first one. For larger
cubosomes, the surface of the faces to volume ratio decreases.
Thus, the deformation of the bilayer at the faces has a smaller
influence on the internal structure of the large cubosomes than
on the small ones. Moreover, the amphiphilic molecules may be
distributed in a more optimal way for large cubosomes than for
the small ones.
The richness of the potential structure predicted by
functional eq 1 is specific to the systems composed of
amphiphilic molecules. In solids, the building blocks of
monocrystals are atoms or molecules. In a lyotropic liquid
crystal, the element that is repeated periodically (a unit cell) is
DOI: 10.1021/acs.langmuir.5b03799
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Figure 6. Large cubosomes with different symmetry obtained by the
minimization of functional eq 1. The surface is given by equation ϕ(r)
= 0. The colors represent two sides of the surface. In subsequent
columns, the cubosomes formed from the phases with the symmetries
of the P, D, and I-WP phases are shown. All images are drawn on the
same scale. In the second row, the interior of the cubosomes is
presented.
built of thousands of molecules. There are many more ways of
deforming the structure of the interface with the isotropic phase
than in the case of the solid−liquid interface. In contrast to
solids, in lyotropic liquid crystals the unit cell is significantly
deformed at the faces and edges of monocrystals. The
deformation of the unit cell at the faces depends on the
orientation of the unit cell with respect to the direction of the
facet.16 The deformation of the unit cells at the faces of a crystal
costs energy because the unit cell at the faces is deformed in
such a way as to avoid the free edges of the bilayer, where the
hydrocarbon chains are exposed to water. There is always a
competition between two possible cases. In the first case, it may
be better to deform the bilayer at the faces (in such a way that
its mean curvature is much different from zero) and leave the
interior unaltered (the same shape as in the bulk). In the
second case, it might be preferable to deform the bilayer at the
interface such that its mean curvature is close to zero, at the
cost of deforming the interior. It is worth noting that small
cubosomes (nancubosomes) and proteins may form large
hierarchical nanoparticles called proteocubosomes43,44 where
the nanocubosomes may be ordered into periodic structures.
The cubosomes can be used as drug carriers. It is believed
that because of the porous structure of the bicontinuous phase
it may be possible to engineer such nanocontainers for drugs
where the drugs will be slowly released. This slow release is
achieved by slow diffusion due to the porous structure of the
bicontinuous phase. It should be taken into account that the
diffusion process may be changed for different porous
structures of cubosomes as presented in Figures 2 and 4.
■
SUMMARY
I have obtained and examined model nanoparticles built of
lyotropic liquid crystals. The nanoparticles were obtained by
the numerical minimization of the Landau−Brazovskii func-
tional. I have examined in detail the structure of the cubosomes
by analyzing the topology and geometry of the surface formed
by the lipid bilayer. It has been found that the internal structure
of the cubosomes can be extremely rich, much more complex
than the structure potentially predicted by the geometric
models. The cubosomes presented in Figures 2 and 3 could be
predicted by analyzing the geometric models by closing open
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water channels of a bicontinuous phase in a piece of the nodal
surface. It would be rather hard to obtain the cubosomes
presented in Figure 4 from the geometric models based on
nodal surfaces because the structure of the outer layers does not
follow from a simple deformation of the bulk phase. It is not
easy to imagine what would be the structure of a cubosome
with the optimal energy. However, such cubosomes can be
calculated by the minimization of the free-energy functional. I
hope that the presented results will be helpful in understanding
future experimental investigations and will be inspiring for
designing new experiments.
■
*
ASSOCIATED CONTENT
S Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.lang-
muir.5b03799.
Details of the numerical calculations (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: wtg@ichf.edu.pl.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
The support from NCN grant no. 2012/05/B/ST3/03302 is
acknowledged. I thank Paweł Pierański, Larisa Latypova, and
Alina Ciach for helpful discussions.
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13326 DOI: 10.1021/acs.langmuir.5b03799

Langmuir 2015, 31, 13321−13326