Colloids and Surfaces B: Biointerfaces 151 (2017) 280–286

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Colloids and Surfaces B: Biointerfaces

journal homepage: www.elsevier.com/locate/colsurfb

Application of mesoscale simulation to explore the aggregate

morphology of pH-sensitive nanoparticles used as the oral drug
delivery carriers under different conditions
Yan Wang a,b , Bo Zhi Chen b , Yue Jin Liu a , Zhi Min Wu a,∗ , Xin Dong Guo b,∗
a
School of Chemical Engineering, Xiangtan University, Xiangtan 411105, PR China
b
Beijing Laboratory of Biomedical Materials, College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, PR
China

a r t i c l e i n f o a b s t r a c t

Article history: The pH-sensitive nanoparticles are selected as the potentially promising oral protein and peptide
Received 11 September 2016 drug carriers due to their excellent performance. With the poly (lactic-co-glycolic acid)/hydroxypropyl
Received in revised form 6 December 2016 methylcellulose phthalate (PLGA/HP55) nanoparticle as a model nanoparticle, the structure-property
Accepted 18 December 2016
relationship of nanoparticles with different conditions is investigated by dissipative particle dynamics
Available online 20 December 2016
(DPD) simulations in our work. In the oral drug delivery system, the poly (lactic-co-glycolic acid) (PLGA) is
hydrophobic polymer, hydroxypropyl methylcellulose phthalate (HP55) is pH-sensitive enteric polymer
Keywords:
which used to protect the nanoparticles through the stomach and polyvinyl alcohol (PVA) is hydrophilic
pH-sensitive nanoparticles
Oral drug delivery
polymer as the stabilizer. It can be seen from DPD simulations that all polymer molecules form spherical
Dissipative particle dynamics core-shell nanoparticles with stabilizer PVA molecules adsorbed on the outer surface of the PLGA/HP55
matrix at certain compositions. The DPD simulation study can provide microscopic insight into the for-
mation and morphological changes of pH-sensitive nanoparticles which is useful for the design of new
materials for high-efficacy oral drug delivery.
© 2016 Elsevier B.V. All rights reserved.

1. Introduction the drugs [13,14]. Therefore, several necessary strategies should

In these years, protein and peptide drugs are used to treat vari-
ous human diseases due to their low toxicity, few side effects, high
efficacy and good pertinence [1–3]. For now, Protein and peptide
drugs (i.e., insulin) are administered mainly by injection because
of their quick degradation in gastrointestinal tract [4,5]. But injec-
tion has some disadvantages such as tissue injury, pain, potential
complications, adverse reactions, poor patient compliance [3]. To
facilitate the use of protein and peptide drugs in clinical practice,
the non injection administration is investigated [6–8]. For all non-
injective delivery systems, oral administration is one of the most
desirable ways due to its safety, simplicity, efficacy and high patient
compliance [9–12]. However, for oral administration, the trans-
port of protein and peptide drugs should cross membranes of the
epithelial cells in the gastrointestinal (GI) tract, which can lead to
rapid enzymatic degradation and the poor intestinal absorption of
∗ Corresponding authors.
E-mail addresses: xdwuzm@xtu.edu.cn (Z.M. Wu), xdguo@buct.edu.cn
(X.D. Guo).
be applied in order to enhance the stability of protein and pep-
tide drugs and increase the absorption of the oral drugs [15–17].
Biodegradable polymeric nanoparticle as a novel carrier in pro-
tein and peptide peroral drug delivery is a promising approach,
which can significantly improve drug efficacy [18–21]. In partic-
ular, pH-sensitive nanoparticles as the oral drug delivery system
can be more adapted to the GI tract environment due to their
pH-sensitive. These nanoparticles can protect protein and peptide
drugs against degradation in the gastric juice and facilitate the
absorption through a paracellular or a transcellular pathway in the
intestinal juice [22–25].
Insulin is an effective drug for diabetes mellitus in clini-
cal practicel [26,27]. And for people with type 1 diabetes, they
must take insulin every day [28–30]. Therefore the development
and applications of the oral insulin delivery systems have enor-
mous application value. Recent polymeric nanoparticles in the
oral insulin delivery have been reviewed [20,31–33]. PLGA/HP55
nanoparticle, a kind of pH-sensitive nanoparticles, is potential as
oral insulin carry. In previous work, our team has explored the
preparation and structure performance of PLGA/HP55 nanoparti-
cles as oral insulin carriers through some experimental techniques

http://dx.doi.org/10.1016/j.colsurfb.2016.12.027
0927-7765/© 2016 Elsevier B.V. All rights reserved.
 Y. Wang et al. / Colloids and Surfaces B: Biointerfaces 151 (2017) 280–286 281

[34]. But it is rather difficult to explore the microstructure of action between a bead i and its neighbor bead j. The three forces
nanoparticles and distribution of polymers in nanoparticles due are given by:
to the limitation of the available experimental conditions, which  
FCij = ␣ij ␻C rij eij (3)
is disadvantageous to the further improving the stability and
the bioavailability of insulin. Thus, it is necessary to explore the   
FD
ij = ␥ij ␻
D
rij vij · eij eij (4)
structure formation, kinetic mechanism and structure-property
relationship of PLGA/HP55 nanoparticles with the help of computer   1
simulation. FRij = −␴ij ␻R rij ␨ij √ eij (5)
t
Dissipative particle dynamics (DPD)[35] is a coarse-grained sim-
ulation method proposed by Hoogerbrugge and Koelman [36], where aij is the maximum repulsion between beads i and j, rij is
which can reveal the mesoscopic-level information in the for- the distance between beads i and j, eij is the unit vector (ri − rj )/rij ,
mation of polymeric nanoparticles [37–39]. So in this work, DPD  ij is a friction coefficient, vij = vi − vj is the velocity difference,  ij
simulation technique is employed to investigate the morphology is the noise strength and was set as 3 in our simulations, t is the
and microstructure of PLGA/HP55 nanoparticles, and the effects of time step of simulation,  ij is a random number with zero mean
the relative ratio between the polymers, the proportion of stabi- and unit variance, the r-dependent weight function ω(r) = 1–r for
lizer and water, and pH value on the aggregate morphologies of r < rc and ω(r) = 0 for r ≥ rc (rc is the cutoff radius whose value is
PLGA/HP55 nanoparticles would be studied. The results provide set to be 1 unit of length in simulations). In the DPD scheme, the
valuable mesoscale structural information of PLGA/HP55 nanopar- reduce units are expressed in terms of m, and kB T, where m is the
ticles that can further improve the bioavailability and the adsorb mass, kB is Boltzmann’s constant, and T is the absolute tempera-
ability of the oral insulin. Meanwhile, DPD simulation method con- ture. The bead density  = 3 has been used in a previous work[43]
tribute to the development of the new oral drug delivery systems and kB T = 1 has been used[36]. In addition, when modeling stimuli-
with high efficient. responsive diblock copolymers, the integrity of the chain is ensured
by an additional spring force between neighboring beads given

2. Simulation model and method by FSi = Crij, where the spring constant C = 4, resulting in a
i=
/ j
2.1. Dissipative particle dynamics method slightly smaller distance for bonded beads than for non-bonded
ones [42]. The parameter aij of conservative force is referred as the
We study the pH-sensitive nanoparticles with the help of the DPD repulsion parameter and its value depends on the underly-
DPD simulation technique. DPD is a simple but intrinsically promis- ing atomistic interactions and is related with the Flory- Huggins
ing simulation method for particle dynamics [40]. The motion interaction parameter ij by means of the following relationship
of particles is calculated by solving the so-called equations of [44]:
motion over a certain time span. The equations of motion describe kB T␹ij (T)
how particles move under the influence of forces. In DPD the ␣ij = ␣ii + (6)
0.306
motion of the particle is simulated at constant temperature, and
the forces include those of a special thermostat. DPD uses a stochas- Here, the values of ij can be calculated from the solubility
tic and momentum conserving thermostat, which distinguishes the parameter by the equation[45]
method from Brownian or Molecular Dynamics. vbead  2
␹ij = ␦i − ␦j (7)
RT
2.2. Theory where Vbead is the molar volume of beads, ıi and ıj are respec-
tively the solubility parameters of two kinds of beads which can be
The DPD model, a set of soft interacting particles are used to obtained from experiments or molecular dynamics simulations, R
simulate a fluid system. Each particle, named bead, represents a is gas constant whose value is akin to 8.314.
group of atoms or a volume of fluid that is large on the atomistic
scale but still macroscopically small [41]. All beads comply with 2.3. Models and simulation parameters used in DPD
Newton’s equations of motion [42,43]:

dri dv We adopt the DPD simulation method to study the structure-

= vi , mi i = fi (1) performance relationship of nanoparticle. Within the DPD
dt dt
approach, the polymer nanoparticle in our study is repre-
where ri , vi , mi , and fi denote the position vector, velocity, mass, and sented by a coarse-grained model. In this article, the poly
total force on the particle i, respectively. For simplicity, the masses (lactic-co-glycolic acid)/hydroxypropyl methylcellulose phthalate
of all beads are set to 1 DPD unit [43]. The total force fi is the force (PLGA/HP55) nanoparticles will be chosen as an ideal subject. The
on bead i due to interaction with the other beads. In general, this poly (lactic-co-glycolic acid) (PLGA) is a hydrophobic polymer and
force can be written as [42,43]: hydroxypropyl methylcellulose phthalate (HP55) is pH-sensitive
  enteric polymer which used to protect the nanoparticles through
S A
fi = FCij + FD R
ij + Fij + fij + fij (2) the stomach. In addition, the oral delivery system also includes the
i=
/ 1
polyvinyl alcohol (PVA) and water. Simple coarse-grained models
of components are shown in Fig. 1. The polymer structure of PLGA
The term in brackets is the force due to the interaction of bead is divided into two types of beads (A and B). The structure of HP55
i with its neighbor bead j, whether bonded or not. This term has is separated into three types of beads (C, D and E). Each monomer
three components: conservative (C), dissipative (D), and random of PVA is considered as one bead named V. one molecule of water is
(R). The remaining terms are forces due to bonded interactions: represented as a bead W. Moreover, the HP55 as pH-sensitive poly-
springs (S) and angles (A). The conservation force for non-bonded mer exists in different forms at different pH conditions. At pH > 5.5,
particles is defined by soft repulsion. The dissipative force corre- the pH-sensitive segment E in the HP55 polymer is hydrophilic,
sponds to a frictional force that depends both on the position and represented by E-1 (Fig. S1 Supporting information). By using Eq.
relative velocities of the beads. The random force is a random inter- (7), the Flory-Huggins parameters ij are calculated from solubility
282 Y. Wang et al. / Colloids and Surfaces B: Biointerfaces 151 (2017) 280–286

Fig. 1. Coarse-grained models of (a) PLGA, (b) HP55, (c) PVA and (d) water.

Table 1 the physical size of the cut-off radius, rc = 6.58 Å. Thus, the box
The interaction parameters used in DPD simulations (unit: kT).
size in our simulation was characterized by effective dimensions
ɑij A B C D E V W of 197.4 Å × 197.4 Å × 197.4 Å, which can be used to calculate the
A 25.00 length of the simulated structures. The temperature was set con-
B 25.15 25.00 stant at 298.15 K. All the simulations were performed using DPD
C 27.01 26.06 25.00 program incorporated in the Material Studio 6.0 software (Accel-
D 31.55 35.27 39.08 25.00
rys).
E 28.01 31.10 30.06 36.20 25.00
V 27.61 26.97 26.20 25.27 26.14 25.00
W 98.86 112.71 72.73 65.05 76.79 48.77 25.00
3. Results and discussion

Table 2 3.1. The aggregate morphology of PLGA/HP55 nanoparticles

The interaction parameters between E-1 and other beads at pH > 5.5.

ɑij A B C D V W In general, the copolymer can self-assemble to form nanopar-

E-1 98.01 89.1 23.06 25.2 18.14
parameters. In this work, solubility parameters are calculated using
Amorphous Cell and Discover modules in Materials Studio soft-
ware (Accelrys Inc.) with the COMPASS force field. The interaction
parameters aij , shown in Tables 1 and 2, are calculated according
to Eq. (6). It should be noted that pH-sensitive block E changes
from hydrophobic to hydrophilic with the decrease of the pH from
pH < 5.5 to pH > 5.5 due to the protonation of imidazole groups
in block E, resulting in the change of the interaction parameters
between the pH-sensitive beads and other beads (the protonated
bead is represented by E-1). To obtain DPD parameters of E beads at
different pH values, we calculated the DPD parameters for nonpro-
tonated E bead (i.e. E) at pH < 5.5. At pH > 5.5, the DPD parameters for
protonated E bead (i.e. E-1) were calculated by attaching a positive
charge to bead E-1 in DPD simulations.
A cubic simulation box with periodic boundary condition was
applied in all three directions. In our previous study, a box of
20 × 20 × 20 is sufficient to avoid the finite size effects, and the
integration time step of 0.05 is small enough for our system to
get thermodynamic equilibrium [46]. In this work, the box size of
30 × 30 × 30 rc 3 (rc is the DPD length unit or the cut-off radius)
was used, which is large enough to avoid the finite size effects.
In each DPD simulations, the dimensionless time step of 0.05 was
employed. And simulation steps of 30000 have been adopted to
get a steady phase [47]. In this work, we calculated the volumes of
all the coarse-grained molecules and they have an average volume
of 95 Å3 . The bead density used in this work is 3, so the corre-
sponding volume of one bead is 285 Å3 [43]. Then we can find
27.79
ticles in aqueous solution. Hydrophobic polymers aggregate and
form an inner hydrophobic core of the nanoparticle, due to repul-
sive effect with water. Hydrophilic polymers arrange orderly
around the core and form an outer shell of hydrophilic groups. The
core-shell structure provides a perfect delivery tool for insulin. In
present work, DPD simulation can be used to model the formation
of the PLGA/HP55 nanoparticles.
The interaction parameters in Table 1 are used in DPD simu-
lations to investigate the formation of PLGA/HP55 nanoparticles.
Several snapshots of configurations of the studied system at dif-
ferent simulated steps are shown in Fig. 2. The system comprises
of 2% PLGA, 2% HP55, 3% PVA and 93% water. To show aggregate
morphologies clearly, water molecules are not displayed.
At the beginning of the simulation (Fig. 2a), all components are
randomly distributed in water. With the development of simula-
tion process (Fig. 2b), some polymer molecules aggregate and form
clusters of small size, due to the interactions among beads. With the
increase of the simulation step, the small clusters crash and form
large aggregates (Fig. 2c,d). Hydrophilic PVA spread around the sur-
face, while hydrophobic PLGA and pH-sensitive HP55 distribute
inside the core randomly. But also, there are some PLGA/HP55
clusters which have no PVA molecules surrounded dispersed in
aqueous solution individually. As simulation progresses, these
PLGA/HP55 clusters gradually diffuse into the core of large aggre-
gates. With the continuing increase of simulation steps (Fig. 2e,f),
adjacent large aggregates can combine to form larger aggregates.
The Aggregates are compact and close to spherical in shape, while
there is still the PLGA/HP55 cluster dispersed in aqueous solution.
At the simulation step of 20,000 (Fig. 2g), the PLGA/HP55 clus-
ter disperse into the aggregate totally, and a complete PLGA/HP55
 Y. Wang et al. / Colloids and Surfaces B: Biointerfaces 151 (2017) 280–286
Fig. 2. Change of aggregates with increasing simulation steps.
Fig. 3. Section view of a PLGA/HP55 nanoparticle.
nanoparticle forms with stabilizer PVA molecules adsorbed on the
outer surface of the PLGA/HP55 matrix. At the simulation step of
30,000 (Fig. 2h), the PLGA/HP55 nanoparticle have stabilized, and
the aggregate morphology does not change significantly with extra
simulation steps. All the following simulations are set to run 30000
steps.
To observe the distribution of the PLGA/HP55 nanoparticle more
distinctly, a section view of a nanoparticle at the simulation step
of 30,000, is shown in Fig. 3. We can see clearly from the figure
that hydrophilic PVA coats around the core formed by hydrophobic
PLGA, producing a core-shell spherical structure. The pH-sensitive
HP55 mostly distributes between the core and the shell. In this
paper, the inner core of nanoparticles can be used to entrap insulin.
So, the PLGA/HP55 nanoparticles are chosen as the oral insulin
delivery.
According to the above results, we the formation of PLGA/HP55
nanoparticles undergoes four stages: (I) Components distribute
randomly. (II) Polymer molecules start to aggregate and form small
clusters. (III) The small clusters form large aggregates. (IV) A com-
plete polymeric nanoparticle forms and stabilizes. In the third stage,
some PLGA/HP55 clusters which have no PVA surrounded disperse
283
in aqueous solution and gradually diffuse into the core of large
aggregates with the increase of simulation steps.
3.2. Effect of the polymer proportion on the aggregate
morphology of nanoparticles
During the formation of polymeric micelles, many factors can
affect the final morphology, such as the relative ratio between the
polymer, the proportion of stabilizer and water, and pH value. Here,
different ordered structures as the molar ratio of PLGA and HP55
are studied using DPD method.
All the simulations start from a random disordered state.
With the evolution of simulations, the morphological changes are
observed and finally formed different ordered structures under dif-
ferent ratios of PLGA and HP55, as clearly shown in Fig. 4. The
molar ratio of PVA and water is fixed at 3:93. The morphologies of
the polymeric nanoparticles vary with the different ratio of PLGA
and HP55. A stable nanoparticle is observed with stabilizer PVA
molecules adsorbed on the outer surface of the PLGA/HP55 matrix
when the molar ratio of PLGA and HP55 is 1:1 (Fig. 4a). When the
molar ratio of PLGA and HP55 is increased from 1:1 to 2:1 (Fig. 4a,b),
all molecules in the system still can form a stable nanoparticle with
larger average particle size. When the molar ratio of PLGA and
HP55 is up to 3:1, the nanoparticle cannot encapsulate all poly-
mer molecules and some excess PLGA and HP55 molecules form
small aggregate in the water phase, which leads to the average
particle size decreases, as shown in Fig. 4c. When the molar ratio
of PLGA and HP55 is decreased from 1:1 to 1:2 to 1:3 (Fig. 4d,e),
much smaller nanoparticles are obtained in aqueous solution due
to the surface tension. Meanwhile, it can also be observed that many
HP55 molecules have distributed in the outer surface of nanoparti-
cles. This change will have an adverse effect on the stability of the
structure of nanoparticles.
In summary, when the molar ratio of PLGA and HP55 ranges
from 1:1 to 2:1, all molecules in the system can form a complete
and stable nanoparticle with PVA molecules adsorbed on, which
can result in a high drug loading and encapsulation efficiency.
284 Y. Wang et al. / Colloids and Surfaces B: Biointerfaces 151 (2017) 280–286

Fig. 4. Aggregate morphologies of polymeric nanoparticles at different molar ratio of PLGA and HP55.

Fig. 5. Aggregate morphologies of polymeric nanoparticles with different mole fraction of PVA.

3.3. Effect of the mole fraction of PVA on the aggregate
morphology of polymeric nanoparticles
The aggregate morphologies of polymeric nanoparticles at dif-
ferent mole fraction of PVA are investigated. In these simulations,
the molar ratio of PLGA, HP55 and water is fixed at 2:2:93. The
results of simulations are shown in Fig. 5. As discussed above, PVA
molecules play the key role of stabilization. When only a few PVA
molecules are added to the solution (Fig. 5a), a stable nanopar-
ticle with small particle size can be observed, but most of the
PLGA/HP55 matrix contacts with water phase directly because the
PVA molecules too few. With the increase of mole fraction of PVA
(Fig. 5b), a more complete nanoparticle forms with PVA molecules
absorbed on. When the mole fraction of PVA is up to 12% (Fig. 5c), a
stable nanoparticle, with large particle diameter, can be observed
with all PLGA and HP55 molecules distributed inside the nanopar-
ticle. When more PVA molecules are added to the solution (Fig. 5d),
much smaller nanoparticles are obtained due to the surface tension.
With the further increase of mole fraction of PVA (Fig. 5e), spher-
ical aggregates disappear, while columnar structure forms. With
the further increase of PVA content, columnar and lamellar struc-
tures are observed (Fig. 5e,f), because the density of polar groups
distributed outside nanoparticles is higher and higher, which leads
to stronger interactions among nanoparticles. Therefore, some of
them contact together to minimize the outer surface of nanoparti-
cles and make the whole system more stable.
3.4. Effect of the mole fraction of water on the aggregate
morphology of polymeric nanoparticles
In order to further explore the oral insulin delivery system,
the aggregate morphologies of polymeric nanoparticles at differ-
ent mole fraction of water are also investigated. The molar ratio of
PLGA, HP55 and PVA is fixed at 2:2:3. The results of simulations
are shown in Fig. 6. When the mole fraction of water is high, only
some small nanoparticles could be observed (Fig. 6a). This is most
probably because a large distance between polymer molecules. The
interactions among them are too weak to form a complete nanopar-
ticle. With the decrease of mole fraction of water, the molecules
are closer and interactions among them are stronger. All of the
polymer molecules aggregate together and form a stable and com-
plete nanoparticle (Fig. 6b). When the molar fraction of water is
decreased to 85%, there is still a stable polymeric nanoparticle with
large particle size (Fig. 6c). When the mole fraction of water con-
tinues to decrease to 78%, the structure of polymeric nanoparticle
has a significant change from spherical structure to columnar struc-
 Y. Wang et al. / Colloids and Surfaces B: Biointerfaces 151 (2017) 280–286 285

Fig. 6. Aggregate morphologies of polymeric nanoparticles with different mole fraction of water.

ture. The columnar structure ensures a minimum contacting area

of hydrophobic groups and water, so as to keep the system stable
(Fig. 6d). A lamellar structure is gradually formed when the mole
fraction of water is further decreased (Fig. 6e and f). The simula-
tions indicate that the morphology of the polymeric nanoparticle
changes from sphere to column, to layer with decreasing the mole
fraction of water.

3.5. Effect of pH on the aggregate morphology of polymeric

nanoparticles

The carboxylic group in bead E is capable of releasing protons

in response to environmental pH changes, thus the repulsive force
between polymer molecules increases and the solubility of poly-
mer in water improves, contributing to the release of insulin in the
intestine. The aggregate morphologies of polymeric nanoparticles
at different pH are studied by DPD. The simulation system com-
prises of 2% PLGA, 2% HP55, 7% PVA and 89% water. The results of
DPD simulation are shown in Fig. 7. At pH < 5.5, the pH-sensitive
bead E remains a hydrophobic molecule, and polymer molecules
Fig. 7. Aggregate morphologies and section views of polymeric nanoparticles with
self-assemble into a normal spherical core-shell structure with PVA
different pH value.
coating around the core of PLGA and HP55 (Fig. 7a1). We can see the
distribution of the polymer in nanoparticle more clearly from the
corresponding section view (Fig. 7a2). PLGA molecules distribute ticle. And in the process of structural change insulin can be released
in the center of the nanoparticle and PVA molecules adsorb on the into the intestine, which improves the utilization of insulin.
outer surface of the nanoparticle. The pH-sensitive HP55 molecules
disperse between PLGA and PVA. The core-shell structure is con- 4. Conclusions
ducive to the loading of insulin. At pH > 5.5, the carboxylic acid
on bead E loses proton and ionize, leading to structural change of The computer simulation is used to investigate the phase behav-
the nanoparticle (Fig. 7b1). Fig. 7b1 shows that the nanoparticle ior of PLGA polymer and HP55 polymer in water. The formation of
has no significant morphological change, only the change of the PLGA/HP55 nanoparticles and effect of the relative ratio between
internal structure. The ionized bead E turns from hydrophobic to the polymer, the proportion of stabilizer and water, and pH value
hydrophilic, so HP55 molecules can move out from the inside of on aggregate morphology are studied using DPD simulation. The
the nanoparticle, and the structure is change, which may create formation of PLGA/HP55 nanoparticles undergoes four stages: (I)
favorable condition for the release of insulin. Section view of the Components distribute randomly. (II) Polymer molecules start to
nanoparticle in Fig. 7b1 can help us to understand the structural aggregate and form small clusters. (III) The small clusters form
change of the nanoparticle (Fig. 7b2). We can see in Fig. 7b2 almost large aggregates. (IV) A complete polymeric nanoparticle forms
all of the HP55 molecules distribute on the surface of the nanopar- and stabilizes. Under different ratios between PLGA and HP55, the
286 Y. Wang et al. / Colloids and Surfaces B: Biointerfaces 151 (2017) 280–286
morphology of nanoparticles would change which affects insulin-
loaded amount. The molar ratio of PLGA and HP55 ranging from 1:1
to 2:1 is optimal for our simulated system. Under different composi-
tions of PVA and water, different morphologies, like sphere, column,
and lamella, have been observed. Also, pH has an effect on the mor-
phology. At pH < 5.5, normal core-shell structural nanoparticle is
obtained, with PLGA and HP55 as the hydrophobic and pH-sensitive
core and PVA as the hydrophiphilic protective shell. At pH > 5.5,
HP55 is ionized, and almost all of HP55 molecules move out from
the inside of the nanoparticle, which can create favorable condition
for the release of insulin. DPD simulation could not only provide
insight into the mechanism of mesoscopic structures of polymeric
nanoparticles, but also serve as a complement to experiments and
more efficiently guide to the experimental preparation of the oral
drug delivery system with desired properties.
Acknowledgements
This work was financially supported by the national Natural
Science Foundation of China (21406187, 51473017, 51673019),
Hunan Provincial Natural Science Foundation of China (14JJ3080),
the China Postdoctoral Science Foundation Funded Project
(2014M552143) and the Fundamental Research Funds for the Cen-
tral Universities (buctrc201406).
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.colsurfb.2016.12.
027.
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