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164
Nano Physical Pharmaceutics of Nanogel Delivery System
is added, the product of which can respond to the acidic environment
in the cell to achieve targeted drug release behavior [8, 9]. In
addition, the reversed-phase microemulsion system can also be
used for synthesizing stable cross-linked nanogels from watersoluble polymers by atom transfer radical polymerization [10].
cell, which facilitates the release of the nanogels inside the cell and
endows the nanogels with the property of reduction-responsive
degradation.
The polymerization reaction of nanogels can also be carried
out in oil-in-water microemulsion or water-based suspension.
Moreover, the polymerization reaction can be initiated by
hydrosoluble monomers in a homogeneous aqueous solution
For example, researchers synthesized a suspended nanogel by
precipitation polymerization using polyethylene glycol (PEG) and
polymethacrylic acid (PMA) as main ingredients [11].
In addition to these polymerization methods, covalent crosslinking between polymer chains provides a good solution for
producing nanogels with large voids [12] and has been widely
functions. With this method, PEG branch was combined with PEI
in the oil-in-water microemulsion environment, the solvents were
in the aqueous solution. As in the case of the polymerization
reactions mentioned earlier, the cross-linking connections
between nanogel polymers can be opened by various designs in
order to release the load. For example, a segmented PEI cross-
nanogels loaded with polynucleotides, which greatly reduced
biotoxicity [13]. In another work, hydrosoluble PEI was crosslinked on microglia composed of double-active PEG-b-PPG-bPEG triblock copolymers [14] to prepare hydrophobic core of
PPO and cross-linked shell of PEI/PEO (PEG-cl-PEI). In addition,
Tatiana et al. cross-linked the amphiphilic block copolymers
with oppositely charged shortening agents to obtain preliminary
particles, then chemical cross-linking of ionic bonds occurred
Mechanism of Nanogel Formation
165
obtain the gel, thereby controlling the spatial distribution of
polymer chains in the nanogel [15]. In addition, the spatial
distribution of polymer chains in the nanogels was controlled by
cross-linking amphiphilic block copolymers with counter-charged
condensing agents to obtain preliminary particles, followed by
removal of condensing agents to obtain nanogels.
5.2.3 Template Method
nanogels with precise and controllable size and shape (Fig. 5.4).
imprinting” for the preparation of nanogels and received
much attention. This method can strictly control the size,
shape, composition and particle surface function of nanogel
particles, allowing the loading of accurate small-molecule active
substances or biological macromolecules. For example, taking a
shapes, and chemical compositions. Using template imprinting
and UV-induced cross-linking, mono-dispersed PEG nanogels with
technology also provides a method for preparing chemically or
physically cross-linked nanogels. The advantage of this method
is that it can prepare nanogels with a variety of sizes, shapes
improve the preparation scale of nanogels.
5.3 Mechanism of Nanogel Formation
The essence of nanogel generation is the moderate cross-linking
between polymers. Inorganic substances or metal alkoxides are
used as precursors, and these materials are uniformly mixed,
hydrolyzed and condensed to form a stable transparent sol system
in solution. The solute is aged and the slow polymerization between
the colloidal particles gradually forms a three-dimensional spatial
166
Nano Physical Pharmaceutics of Nanogel Delivery System
loses its mobility to obtain nanogels. The preparation of solid
nanogels is relatively simple: it can simply be made by dry gel
absorbing liquid and expanding, which is a usually elastic nanogel.
However, the preparation of nanogels must meet two basic
conditions: (1) reduce solubility, so that the solid matter will
precipitate out of the solution in a “colloidal dispersion state”;
(2) the formed solid particles neither subside nor move freely,
but form a skeleton and continuous network structure.
5.3.1 Cross-Linking of Nanogel
In the cross-linking system of polymers, the conversion rate or
gel point [17], and gelation is an important feature of the crosslinking system.
5.3.1.1 Gelation theory of nonlinear polycondensation
The viscosity of most nonlinear polycondensation systems
increases suddenly and insoluble gel is produced when they reach
a certain stage, which is called gelation phenomenon. In
production, if gel appears in the reactor, it will bring great trouble
to the operation. Therefore, it is important to predict the critical
condition of gel theoretically.
Flory [18] introduced the concept of bifurcation point and
obtained the critical condition of gelation for a special case
critical condition by using the degree of average polymerization
polycondensation systems, thus advancing the theory to a new
stage. Take the Aa– Bb reaction as an example, Aa represents a
monomers of A group, and Bb represents b monomers of the B
group that can react with the A group. NA and NB are the
corresponding number of molecules, and pA and pB are the
corresponding degrees of reaction. Then the ratio range of gel in
Aa– Bb polycondensation reaction can be expressed by the
following formula:
Mechanism of Nanogel Formation
167
(5.1)
( 1)1 ( 1)
a
Therefore,
a and b
certain
r a b( 1)(b
A
for
A
a
is more
ratio
than
2 Bcan b produce gel can only
range, beyond this range, no matter
1 )
the idea that one of
reaction can only produce sol.
5.3.1.2
Compared
statistical
addition polymerisation
with
Free radical addit
with
condensation
io
method. This is
time and the
lengths
n polymerizat
polymerization,
due
to the fact
the
number
of the
of
reactive
ion
it is much more
that
during
reactive
polymer chain
deactivated polymer molecules.
was
studied
by statistical
method [21,
22],
and the
of active chain distribution was obtained as follows:
i
1
a
a t
()
t
p()t
()
V
( ))d
i
[1 ( )]
Pi p t
t
a a t
0
t ()
(
)
i 1
()
!
e
·
1
be
realiz
ed in
how
much
the
free
radical
groups
varies
and
expression
a
where
is
P
i
the raising
chain past ta – given time, and i ( )
in the time
The chain length M
chain length is the number of tactive tradicals,
procedure.
a
Vit dt
the
average
denotes
length
the
initiation
t + dt.
distribution
i
of active
rate
be obtained by the reaction equation of chain termination process:
i
1
)
Vtd
i
·
1(p
)
!
)
(t )
p
(tt )
t
1
(1 ) )
2
0
g dp (t
(1)
f t
t
V
0
(t)
i
d
t
p(t
M
pt
i
0
gdp t
( )
t
a(t
a t
)1(
i
(
0
(5.3)
where
g denotes a mono-radical termination fraction and (1 – g)
is a mono-radical termination fraction.
V
i
)
168
Nano Physical Pharmaceutics of Nanogel Delivery System
nanogel formed from graft copolymers.
In addition, assume that the charged fraction is small ( ≪1),
i
1
t
a t t
a
f
t
5.3.2 lectrolyte Nanogels
(( )
i 1()!
0
j
Properties of Polye
)
a a t
e
·
1p (t )
t
( ) ( )
t
a t a t
(
·
(i ) j ((1))! · 1p (t)
0
i
1
a t a t
e
( ) ( )
dt
N
nanogel,
the end n of
length
Bjerrum length is l
of
the system,
temperature
the
length of
the
number
branch
of the chain,
k
of B the
of
chains,
and a
= e2/(4
B
Boltzmann
system.
each
branch
R
is
is pethe
Figure
branch
chains,
the
radius r of
charged
k
T
), where is T the permittivity
B
constant,
5.2 illustrates
chain
in
the
the
distance
gel, b
fraction
e
and is
polyelectrolyte
between
is
the
Kuhn
of
the
the
absolute
the
sample
of
Figure 5.2 The mechanism of structure and properes tunning of nanogel
carrier in-suit formed from gra copolymers in water. The formula inserted
here is shown in Equaon 5.7.
a
Mechanism of Nanogel Formation
169
polyelectrolyte gels, the charged fractionation is constant; for
adjustable, for example, by pH. Bjerrum length lB= e2/(4pekBT) is
in the same order of magnitude as the Kuhn length of the chain,
that is, the dimensionless coupling parameter u = lB/b
characterizing the strength of the Coulomb interaction, which
interaction such as Manning ion condensation. The case of good
solvents is qualitatively similar to that of q solvents. The volume
change of the gel is not taken into account here, so the inferior
solvent case is not taken into account for the moment. The
volume fraction of gel can be expressed as:
3 3
Nb nNb
(5.5)
3 3
r R
The following equation is obtained:
R
(5.6)
r
1
3
n
5.3.3 Structure and Stability of Nanogel
The assembly behavior of copolymers is described by Equation 1.2
[23]. And the key parameter is the surface charge (also known
as zeta potential j), which can be adjusted by monomer ratio,
solvent mass or the pH value of the medium. The diameter of
such particles is determined by the number of nanoparticles (N
part
).
.
N k
R
i
04
(
aS
)
06.
(5.7)
part s
u
where k is a constant from 0.37 to 0.53, Ri, u, as and S represent
the rate of free radical generation, the rate of increase in
particle volume, the surface area of the surfactant, and the total
amount of surfactants, respectively. The amphiphilicity of a
copolymer can be determined by the balance of hydrophilichydrophobic relationship (HLB = 7 + SHLB
group
). This hydrophilic-
monomer composition [M], and [M] can determine as and S, and
170
Nano Physical Pharmaceutics of Nanogel Delivery System
then N
part
. A large number of colloidal nanoparticles in nanomicrogels can be connected to each other to form a large gel under
certain conditions due to the existence of active molecules on
the size of the gel is necessarily related to the number of crosslinked colloidal nanoparticles. At the same time, the cross-linking
reaction is also limited by the number of surfactant molecules
of the gel and other physical and chemical properties. For a
nano-hybrid system formed by homogeneous polymers, its
repulsion (E) [23].
kT
2
zej
hk
E 32psa
tanh
m
e
(5.8)
ze
4kT
where s is the electrostatic constant of the solvent, a is the
dielectric constant of the solvent, k is the Boltzmann constant,
T is the temperature, z is the number of electrons, e is the
solubility of the solvent, φm is the double-layer potential in the
k refers to the thickness of the layer, and h refers
to the distance between the two particles. For example, when
polyvinyl alcohol (PVA) and polylactic acid (PLA) are mixed in
aqueous solution, PLA is insoluble in water, and the electrostatic
repulsion force of the carrier mainly comes from the hydrophilic
polyvinyl alcohol polymer. This electrostatic repulsion force can
adjust the thickness of the double layer of the carrier. The greater
the electrostatic repulsive force, the less the thickness of the
the carrier can be adjusted by controlling the content of PVA in
the process of carrier synthesis, so as to design the carrier needed.
5.4 NPP of Nanogels in Drug Delivery
5.4.1 Physiochemical Properties of Nanogels
Nanogels have good hydrophilicity and dispersibility, and have
good performance to wrap small bioactive agents and biological
NPP of Nanogels in Drug Delivery
171
macromolecules. Swelling, shrinkage and thixotropy are unique
loading and release.
5.4.1.1 Expansion of nanogels
which increases their volume or weight by absorbing liquid or
the theory of gel expansion in 1943. Among many theories,
Flory–Rehner theory of gel expansion is one of the most classical
theories, which can successfully predict the swelling deformation
characteristics of polymer colloids [24]. In recent years, the
research on the swelling kinetics of nanogels has received more
and more attention and made great progress. It studies the
relationship of the swelling ratio of nanogels with time, which is
mainly controlled by the weak interaction of the gels. Good solvent
molecules swell by penetrating the nanogel network structure.
The volume expansion rate depends on the internal osmotic
pressure and the conformational transformation ability of the
nanogel molecular chain.
Compared with traditional hydrogels, nanogels have a faster
response speed [25]. Moreover, the swelling process is divided into
absorb a limited amount of liquid and the network structure of
the nanogels only swells without disintegration, it is called limited
swelling. If more and more liquid is absorbed and the network
structure of the nanogels swells larger and larger, which eventually
leads to its rupture, disintegration and complete dissolution, it
are not absolute, and changing conditions can also change the
nature of nanogel swelling.
Swelling degree S refers to the limit amount of liquid that
can be absorbed by nanogels per unit mass or volume under
m m
S
2 1
(5.9)
m
1
or
172
Nano Physical Pharmaceutics of Nanogel Delivery System
2 1
S
V V
(5.10)
V
1
In the equation, m1 and m2 are the mass of the nanogels
before and after the swelling of the nanogels, and V1 and V2 are the
volume of the nanogels before and after the swelling. The swelling
degree of the nanogels is related to the structure of the nanogels
and the solvent, and increases with the increase of temperature.
The occurrence of swelling is not instantaneous, and there
is a process to reach the equilibrium of swelling. The kinetic
nanogels:
dS
k
swell (Smax
S )
(5.11)
dt
In the equation, S is the amount of liquid absorbed by the
nanogels when the swelling time is t; S
max
is the maximum amount
of liquid absorbed (in equilibrium), and k
swell
is the swelling rate
constant.
5.4.1.2 Swelling mechanism
The swelling process of hydrogels with cross-linked structure
is actually a balance of two opposite trends. On the one hand,
the solvent tries to penetrate into the gel network structure to
expand its volume, leading to the expansion of the network
structure; on the other hand, the extension of the molecular chains
between the cross-linking points reduces the conformational
entropy of polymers, and the elastic contraction force, generated
by the three-dimensional network subjected by stress, causes
the molecular network to contract. When these two opposite
ratio of nanogels is related to the temperature, pressure, the
degree of cross-linking of polymers, and the properties of the
solute and solvent. The quantitative relationship between them
is derived from the lattice-like model solution theory and the
high elastic statistical theory:
NPP of Nanogels in Drug Delivery
173
the external solution of the hydrogel, (1/2 – 1
of the hydrogel to the deionized water or solution, and e/0 is
the cross-linking density of hydrogels.
molecules quickly occupy the nanogels and interact with the
nanogel macromolecules to form solvation layers. This stage is
very short and rapid. It has the following characteristics: (1) The
vapor pressure of the liquid is very low. This is because the degree
solvation layers, so the vapor pressure of the system is very low.
This part of the liquid is tightly bound with the gel macromolecules,
Although the volume of nanogels increases, as a whole, the
increased volume of nanogels is smaller than the volume of the
absorbed liquid, thus the volume shrinks. (3) There is a thermal
of liquid and swells is called swelling heat, which can be directly
measured; (4) Solvent entropy decreases, which is due to the
ordered arrangement of liquid molecules in solvation layers.
The second stage is the penetration and absorption of liquid.
In this stage, the absorption of liquid is several times or tens of
times of that of dry gel plasmids, and there is no obvious thermal
solvent molecules to penetrate into the core of nanogels, this
stage takes a long time. At this time, the pressure exhibited by
nanogels is swelling pressure.
2
1
5
3
P
x
i
1
2
2
V
S
u
V
e
V
0
1
2
v
1
In the equation,
non-swelling network structure,
i/2V
u
S is
the ionic
concentration
of
x
V V