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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5386_Библиотеки_им_академика_М_И_Перельмана.pdf
174
Nano Physical Pharmaceutics of Nanogel Delivery System
5.4.1.3 Affecting factors of nanogel swelling
The swelling of nanogels in aqueous solution is based on the
degree of dissociation of functional groups and the hydration of
of nanogels (chemical structure of polymers, degree of crosslinking, charge density of electrolyte gels, etc.); (2) Environmental
parameters, such as pH, ionic strength, temperature, composition
of swelling medium, etc. [28].
The pH value of the medium: The pH value of the medium
dimensional network structure containing ionizable groups
such as protein and cellulose. At a certain pH value, the groups
resulting electrostatic repulsion can promote the swelling
process of gels. For anionic hydrogels, the side chain groups
ionize when the pH of the medium is greater than its acidity
dissociation constant (pKa), and gels swell. The cationic hydrogels
ionize when the pH is less than pKa, promoting the swelling
process. Using 2-hydroxyethyl methacrylate, methyl methacrylate
or N-vinyl-2-pyrrolidone as comonomers, the equilibrium and
dynamic swelling behaviors of hydrogels containing methacrylic
acid or various acrylamide were studied. pH-sensitive gels with a
wide range of expansion ratios can be obtained through a series
of composition changes [29].
Solution ionic strength: Ionic strength also determines the
swelling of polyelectrolyte nanogel. For example, the swelling
linker under high ionic strength, but when under low ionic strength,
The general rule is that the cross-linking ratio of the cross-linked
gel will decrease when the number of cross-links increases [30].
Temperature: Under certain circumstances, the interactions
temperature, which can lead to swelling or collapse of the gel,
so nanogel is temperature responsive. when the system is in
equilibrium (limited swelling), the maximum swelling degree
decreases with the increase of temperature. This is mainly
NPP of Nanogels in Drug Delivery
175
because the swelling process is exothermic, and the increase in
temperature will lead to a decrease in the binding strength of
the particles in nanogels, and the maximum swelling degree they
can bear decreases.
Others: The aging degree and cross-linking degree of nanogels
aging nanogels are, the higher the degree of cross-linking and
the lower the degree of swelling.
5.4.1.4 Thixotropy and desizing effect of nanogels
Subject to an external force, the network structure of nanogels
will be destroyed, linear particles will be separated from each
other, and the system will show liquidity. If the external force is
removed and nanogel is left to stand for a period of time, particles
re-cross-link into a network structure, which is called thixotropy.
The mutual transformation between sols and nanogels can be
repeated.
During the placement process, the properties of the nanogels are
still changing. This phenomenon is called aging. Its manifestation
is the desizing phenomenon, also known as dehydration. In other
words, under the condition of basically not changing the principle
form of hydrogels, it makes the arrangement more orderly
through the contraction of the particles, and simultaneously
squeezes some liquid out to produce the “sweating” phenomenon
[31]. The syneresis of a gel can also be regarded as a process of
which is proportional to the concentration of the nanogels.
The swelling behavior of pH-sensitive gels is not only
related to the composition of gels, but also related to external
changes. For sensitive gels containing weak acid groups, such as
polyacrylic acid (PAA) and polymethacrylic acid (PMAA), when
the external pH is higher than pKa, gels swell. And for sensitive
gels containing weak base groups, such as polydimethylaminoethyl
methacrylate (PDMAEAM), polyvinylpyridine (PVP), etc., there are
one or more volume phase change points.
176
Nano Physical Pharmaceutics of Nanogel Delivery System
5.4.2 In vivo Circulation of Nanogels
Drug-loaded nanogels need to circulate in the body to transport the
drug to the target site (Fig. 5.3). Its circulation time and integrity
are essential to prevent the drug from being rapidly eliminated
by the body or degraded and metabolized. One of the most
important barriers to realizing long circulation of nanogels is
their opsonization, that is, it is readily cleared by organs of the
monocyte macrophage system such as the spleen and liver.
their hydrophilicity and reduce their interaction with serum
weight, and density of the surface PEG of the nanogels. The
softness and deformability of nanogels also help to avoid the
physiological conditions to pass through membrane pores that
are many times smaller than their hydrodynamic diameter. The
deformability of nanogels can be adjusted by changing the crosslinking density between particles and changing the size of the
cross-linked parts, and the introduction of electrolytes into the
hydrogel network can increase the gel swelling ratio.
According to the structure of the carrier, targeted behaviors
antigen or receptor expressed in the tissue or cell of the lesion
antibodies, cytokines, or ligand proteins on the surface of carriers.
or organs in in vivo circulation. For example, the particle sizes
of carriers reaching the human brain, bone marrow, and other
tissues and cells must be less than 50 nm; nanoparticles of
100 nm–200 nm are easy to be internalized by phagocytes of
reticuloendothelial system and accumulate in the liver and the
spleen; carriers with a particle size larger than 1000 nm will
intercepted by the lungs and mainly concentrated in the lungs
[32]. The last one is physical targeting, which mainly exploits
NPP of Nanogels in Drug Delivery
177
targeted movement. Nanogels are usually too large to pass through
tight junctions between normal endothelial cells, but they can
These sites have distinctive structural features, such as vascular
leakage defects and loose connections, and enhanced permeability
prolonging the retention time at target sites and promoting cell
uptake. Compared with non-targeted nanogels, ligand-mediated
targeted nanogels are mainly distributed in highly expressed
tissues, which can avoid excessive accumulation of gel at non-
Figure 5.3 In vitro carrier–drug complex formaon process (micelles and
nanogels), microstructural parameters of complex properes, cellular
interacon and intracellular fate. The physicochemistry parameters noted
here are also shown in Fig. 1.16 in Chapter 1.
After the nanogel is extravasated from blood vessels, it
and can be absorbed by target cells through various endocytosis
178
Nano Physical Pharmaceutics of Nanogel Delivery System
mechanisms, according to the surface characteristics of nanogels,
such as size, softness and charge, as well as the receptor type of
target cells. In general, nanogels enter endosomes via endocytosis
and then reach lysosomes. The low pH, high degradation enzyme
concentration, and reductive environment become the stimulating
factors to drug release behavior from gels, giving them the
5.4.3 Drug Release Behavior of Nanogels
The loading, transportation, and release process of drugs through
nanogels generally involves the following steps: (1) Dissolve
nanogels in the drug solution. (2) Because of the concentration
the surface of nanogels. (3) The drug is desorbed from polymers
or tissues. During the whole process, there are many complex
physical and chemical phenomena, and the release characteristics
of drugs depend on the interaction of these physical and chemical
phenomena [33]. Through the analysis of these phenomena and
the study of the kinetic and thermodynamic process involved, a
way to control and adjust the release rate of drugs can be found,
so that the release of drugs from preparations can meet the
expected requirements.
between reticular polymer chains to achieve drug release behavior.
For degradable drug-loaded nanogels, the release of the drug
is also related to the degradation rate of the polymer/chemical
bonds. Biological agents can often be combined with nanogels
through physical embedding and covalent binding. According to
the loading method of the drug, this type of gel can be divided into
the polymer; the second one is to bond the drug on a polymer
chain and the release of drug can be regulated by controlling the
polymer degradation mechanisms, the drug release behavior is
NPP of Nanogels in Drug Delivery
179
r
(1/ n1)
D
gel
D
1 e
(5.13)
solution
z
where D
solution
r is the size of a drug molecule, z is the dynamic correlation
length, or the mesh size between two cross-linking points, and
The drug release behavior of carriers mainly hinges on the
interaction of the drug, the carrier, and the release medium. If the
binding force between the carrier and the drug is greater than that
between the carrier and medium, then the drug release is mainly
decided by the degradation mechanism, and its release rate is
on the contrary, if the drug release behavior is dominated by
When the drug is bonded to the carrier material in the adsorption
manner, the release of the drug is a desorption process and sudden
release is easy to occur. For poorly soluble drugs, the release
process in some cases is controlled by the solvation process of the
drug-loading system, the release of the drug may be based mainly
on one mechanism and secondarily on multiple other mechanisms;
stages. For polymer nanoparticles, the multiphase release pattern
often appears, including the initial burst release period and the
subsequent sustained release period.
by its microstructure [34], and how to overcome the lack of
drug release is an important problem in drug delivery systems.
Wei Li’s [35] group studied a novel dual-controlled temperaturesensitive nanogel to improve drug release, and drug release
by the microstructure of nanogels. Therefore, establishing the
D
) inside
gel
the gel and the microstructure change during the phase transition
of nanogels contributes to the improvement of drug release
behavior. This relationship can be explained by the following
equation:
180
Nano Physical Pharmaceutics of Nanogel Delivery System
n is the volume swelling rate of the nanogels (n = V
swell
)/(V
collapse
).
z and n. As shown in
Fig. 5.8, when the temperature causes a phase transition, the
uneven collapse will cause a dense surface layer. Due to high
chain entanglement or overlap, z and n are relatively small and
the diameter in the collapse state is about 90 nm. Both z and n
are able to lead to a decrease in D
gel
, which indicates that the
irradiation, z and n are larger, and D
gel
is therefore larger (Fig. 5.4),
which means a large drug release (Q) and well explains the drug
Figure 5.4 The eects of structural collapse and microstructure (mesh size)
of the temperature-sensive nanogels during the phase transion process
on the drug release, which is described by the modied drug release funcon
shown in 5.13.
5.4.4 Factors Affecting the Release of Drug-Loaded Nanogels
When the nanogel drug delivery system reaches the diseased
tissue or cell, how to control the release and the releasing dose
is a key issue. The network of nanogel is sensitive to the
environment, can withstand rapid changes in volume, and can
be stimulated to control the release of bioactive compounds. In
delivery and release of the targeted drug. According to whether
the system responds to the signal or not, the release of nanogels
NPP of Nanogels in Drug Delivery
181
can be divided into the programmed pulsed-release system (PPRS)
and the intelligent pulsed-release system (IPRS). The release
manner of PPRS is achieved through the pre-designed structure
of the carrier, and the lag time and duration of drug release
behavior are controlled by the polymer degradation performance.
Butun et al. designed a release system similar to the core–shell
type. The system consists of alternate drug-containing and drug-
duration, release time, and pulse number of drugs are determined
by the composition and layered thickness of ossein [36].
IPRS requires external stimuli and the response of carriers. The
intelligent drug pulse release system can be divided into external
regulation and self-regulation according to the source of the
signals. The former is the release of drugs regulated by external
factors such as light, electricity and magnetism, while the latter
realizes the drug release behavior through the system itself
stimulated by pathological tissues. See the next section for details.
5.4.4.1 Drug-loading methods
drugs. The strategy and the process of drug loading are crucial for
the release of the system. The calcium pectate nanogels prepared
by the mixing method were faster in drug release behavior
than the adsorption method or the swelling method, and the
release time was shorter by 50%. The hydrogel prepared by
Mackiewicz M. based on poly (N-isopropyl acrylamide) has
improved in multiple properties [37]. First, cystine(BISS)acrylic
derivative containing carboxyl group is used to replace the
commonly used N,N-bis(acryloyl)cystamine (BAC) as the
cross-linking agent, giving hydrogel particles better stability
including drug molecule bonding. Second, the water precipitation
polymerization method, by using the semi-batch method to initiate
redox, greatly increases the content of BISS and reduces the size
of nanoparticles, which is conducive to endocytosis. In addition,
the prepared nanogels show a higher loading capacity than dry
nanogels (16%), showing better stability and enhanced drug
182
Nano Physical Pharmaceutics of Nanogel Delivery System
5.4.4.2 Medium pH
When anion or cationic groups that can be protonated or
deprotonated are included in the 3D network of nanogels, their
pH response to the medium is more sensitive. If the pH of the
these groups will change, leading to the change in hydrophilicity
gel. Anionic nanogels generally contain sulfonic or carboxylic
acid groups, and if the pKa of the polymer is greater than the pH
value of the solvent, its ionic structure results in an increase in
electrostatic repulsion within the network and eventually leads
to overall expansion. On the other hand, cationic nanogels
generally contain amino groups at the end, so when the pH value
of the environment around the gel is less than pKb, the amino
groups change from NH2 to charged NH3 group, thus its
electrostatic repulsion, hydrophilicity and expansion rate are
increased [39, 40]. The pH of healthy tissue (pH 7.4) and tumor
collapse of gel caused by the protonation or deprotonation of
be controlled.
5.4.4.3 Solvent
Nanogels work by loading hydrophobic drugs into polymer
nanonetworks in a solvent, and the details of this process can
have a profound impact on their properties. Earlier work [41, 42]
showed that when nanoparticles were in an aqueous solvent,
hydrophobic core reorganizing into approximately spherical and
dense regions, while the hydrophilic parts remained solvated.
but polymer nanoparticles may adopt conformations unfavorable
for drug loading. Therefore, in the process of drug loading,
solvents, such as tetrahydrofuran, which is conducive to the
formation of hydrophobic cores of nanoparticles [43]. Since the
by solvents, the particulars of the loading process, especially the
NPP of Nanogels in Drug Delivery
183
tetrahydrofuran and dimethylsulfoxide on the conformations
of two kinds of nanogels were studied by simulating real full-
tetrahydrofuran and toluene are used in the drug-loading step,
star polymer nanogels can load large drug molecules inside and
the drug-loading rate rises. However, the use of methanol mainly
leads to shallow or surface drug loading, so the drug release
rate is higher. Ether cannot be used as solvent because it cannot
5.4.4.4 Particle size
loading and drug release capacity. Researchers have investigated
the morphology, particle size and sustained release properties
of a drug-loaded nanogel, in which polymethacrylic acid (PMAA)
is the raw material, ethylene glycol dimethacrylate (EGDMA) is
the cross-linker and amoxicillin (AM) is loaded. All the samples
showed uniform spherical shape, and the particle sizes were
less than 500 nm. In addition, the particle sizes of nanogels
decreased with the increase in the content of the chain terminator
(EGDMA). Further, the nanogels can achieve prolonged drug
release, which indicates that nanogels can control and continuously
release drugs and have long-term antimicrobial activity [46].
the decrease in particle size. This may be because smaller nanogel
particles form a denser hydrogel network, hindering the release
of drugs from the nanogels.
5.4.4.5 Surface charge
The existence of electrolytes in suspension is crucial for the
charged nanogel in aqueous medium. In fact, moving ions are
distributed in and around the porous nanogel, forming a socalled electric bilayer, which may determine the degree of particle