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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5386_Библиотеки_им_академика_М_И_Перельмана.pdf
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Nano Physical Pharmaceutics of Nanogel Delivery System
hand, an increase in the concentration of salt leads to a decrease
nanogel, reducing the absorption of the internal solute with the
opposite charge. In addition, the ions and the change in the local
the charged-polymer network, resulting in internal inhomogeneity
in polymer density [47].
Arturo et al. explored the charge distribution of charged
nanomaterials in electrolyte water suspensions through Monte
Carlo simulation and Ornstein–Zernike integral equation theory,
and considered the size of ions, the swelling or shrinkage state
of the gel, the valence state of the counterions, the type of charge
carried by the gel, as well as the interaction between electrostatic
contraction, electrostatic repulsion between charged groups
will lead to an uneven distribution of polymer and form a lowdensity pore structure surrounded by dense corona. The excluded
volume repulsion strongly inhibits the penetration of ions in the
concentration at the dense structure. In general, the properties
the valence of counter ions and the charge of nanogels. On the
one hand, with the increase of the valence of counter ions, the
charged monomer enters into the inner and outer layers near
the coronal structure, forming a shrunken-down nanogel. On the
other hand, increasing the charge of particles can promote the
radius of nanomaterials [48].
5.4.5 Drug Release Behavior of Stimulus-Responsive
Nanogels
Nanogels can integrate drugs, proteins and DNA through
physical and chemical methods, and also have adjustable chemical
framework, swelling rate, mechanical strength and other properties.
Nanogels are also known as smart materials because they can
respond to external stimuli (such as pH, temperature, light, etc.) by
changing their volume, hydrophilicity, refractive index, etc. [49].
NPP of Nanogels in Drug Delivery
185
a feedback mechanism. The drug-loaded nanogels are in a
contracted state under normal conditions. After receiving disease
information, they can respond and expand the volume to promote
the nanogel shrinks and prevents the continued release of the
drug, so as to achieve the intelligent and controlled release of
pH- and glucose-responsive nanomaterials have been developed
for applications in drug transport, biological imaging, etc. [50].
5.4.5.1 Temperature-responsive nanogels
Temperature-responsive nanogels are one of the most frequently
studied environmentally sensitive systems in drug delivery.
The structure of this type of nanogel contains a certain ratio of
hydrophilic and hydrophobic groups. Changes in temperature
promoting changes in the network structure and volume of the
hydrogels. In the hydrogel solvent system, there are generally two
kinds of temperature-responsive phase transitions, that is, lower
critical solution temperature (LCST) and upper critical solution
temperature (UCST). Between them, the LCST-type polymer
gel shrinks at a temperature above the critical value, while the
UCST-type polymer gel shrinks at a temperature below the
critical point. The former is widely used in the temperaturedriven drug release strategy.
Poly(N-isopropylacrylamide) is currently the most widely
used polymer with temperature stimulus responsiveness because
its LCST is close to human physiological temperature. While poly
(N,N-diethylacrylamide) has a slightly lower LCST at 25 °C–32 °C.
It can also be used for drug delivery. However, copolymers of
acrylamide (AAM) and N-isopropylacrylamide (NIPAAm) are used
to prepare temperature-responsive photothermally adjustable
drug delivery systems. The LCST of copolymers can be adjusted by
changing the concentration of AAM. For example, increasing the
ratio of AAM/NIPAAm can increase the LCST from 32 °C to 60 °C.
The gel is used to encapsulate gold nano sheet, which can cause
local temperature rise by absorbing near-infrared radiation (NIR),
186
Nano Physical Pharmaceutics of Nanogel Delivery System
leading to rapid contraction of the gel and the release of the
encapsulated drug [51].
5.4.5.2 pH-responsive nanogels
The swelling properties of pH-responsive nanomaterials mainly
originate from the ionizable acidic or alkaline groups on the
the apparent dissociation constant (Ka
the corresponding monobasic or monobasic Ka. The existence of
ionizable groups causes electrostatic repulsion between polymer
chains, and the swelling degree of the corresponding hydrogel is
much higher than that of the hydrogel formed by non-electrolyte
polymers. Therefore, the degree of gel swelling can be controlled
the pH, ionic strength, and type of counter ion of the medium.
Moreover, the swelling degree of hydrogels can be regulated by
co-polymerization of neutral monomers (e.g., methyl methacrylate),
At present, polyethylene glycol grafted anionic polymethacrylic
acid-based nanogels have been developed for oral drug delivery.
When the environmental pH is around 2, the pore size of the gel
is smaller due to the formation of hydrogen bonds between the
carboxylic acid groups and the oxygen atoms on the polymethacrylic
and polyethylene glycol respectively. When the pH increases to 7,
methacrylic acid is deprotonated, attracting water molecules to
enter and causing the hydrogel to swell. This phenomenon is
adapted to the conditions of the digestive system, that is, it can
protect the drugs in the stomach (low pH environment), while
intestine [52].
5.4.5.3 Glucose-responsive nanogels
Glucose-sensitive nanogels can swell or collapse in response
to changes in glucose concentration, and mainly used in the
NPP of Nanogels in Drug Delivery
187
sensitive materials are mainly divided into three types: glucose
oxidase (GOD), concanavalin (Con A) and phenylboric acid (PBA).
The GOD system is inherently pH sensitive. It generates gluconic
acid and hydrogen peroxide through the reaction of glucose
oxidase and glucose, which leads to a decrease in local pH, causes
agglutinin with four glucose-binding sites. Agglutinins interact
with various cells by reacting with glycoproteins and glycolipids
on the cell surface. Glucose-sensitive gel prepared by cross-linking
with concanavin (Con A) and carboxymethyl dextran, when
free glucose competes with the oligosaccharide site of Con A in
the external environment, the gel structure is loose and insulin
is released [54].
Although glucose-responsive nanogels have excellent
performance as an insulin delivery system, they still need
improvement in various aspects before clinical application. Their
application constraints include slow response to changes in
glucose concentration in the environment, and reducing the size
of nanogels may be a way to shorten the response time. Besides,
they lack a high repeatability and rapid response to the changing
glucose concentration, and the ingredients used may induce
adverse immune reactions [55].
5.4.5.4 Photoresponsive nanogels
Photoresponsive nanogel is a kind of gel that can change in volume
under the condition of light radiation, which is generally divided
groups, such as triphenylmethane and azobenzene, etc., which
will undergo photodissociation or isomerization under light
irradiation, resulting in swelling of the gel. The other type belongs
to hybrid systems, which are nanoparticles with metal and
temperature-sensitive groups in the nanogel structure [56]. The
principle is that metals such as gold and silver can convert light
into heat, so the temperature in the system increases, and
temperature-sensitive groups make the nanogel responsive [57].
A light and temperature-sensitive nanogel is shown in Fig. 5.4.
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Nano Physical Pharmaceutics of Nanogel Delivery System
5.4.5.5 Other stimulation-responsive nanogels
stimulus-responsive nanogels have been developed. Magnetic
responsive nanogel is a kind of magnetic-sensitive nanogel
system containing magnetic materials such as Fe3O4, Fe2O3. It
has good magnetic responsive drug release characteristics and
has great application prospects in the diagnosis and treatment of
tumors [58, 59]. Nanogels with double or multiple responses
have also gradually emerged, such as the magnetic/temperature
dual response system [60], temperature/pH dual response system
[61], pH/magnetic dual response system [59], and temperature/
pH/magnetic multiple-response system [62]. Double or multipleresponse nanogels combine the advantages of each response
monomer and have more potential, which is worthy of further
investigation.
5.4.6 Biological Applications of Nanogel Delivery
Systems
With the development of nanotechnology, biomedicine and smart
materials, nanogels have shown attractive application prospects
due to their excellent drug-loading properties and drug release
ability, so they have attracted great attention.
5.4.6.1 Delivery of small-molecule therapeutic drugs
The application of nanogels for drug delivery is an important
direction of current research, which mainly has the following
three advantages: targeted therapy, controlled release and long
circulation. Nanogels are prepared from amphipathic block
copolymers, PEG-b-polymethacrylic acid (PEG-b-PMA) can be
synthesized via ionic complexation and cross-linking reaction with
a swollen PMA cross-linking network as the core and PEG chain
as the shell. This synthesis method can adjust the macro
characteristics (e.g., size and swelling degree) of nanogels, by
changing the cross-links number or chemical structure [63].
Compared with other nanocarriers, this nanogel shows very low
Moreover, nanogels with such core and shell can load a large
NPP of Nanogels in Drug Delivery
189
amount of (50%) doxorubicin (DOX) through the electrostatic
adsorption of the carboxyl group of the core, which can not only
remain stable for a long time but also promote the release of DOX
after being protonated in an acidic environment. Meanwhile, it
shows good cytotoxicity to tumor cells. The author further used
the nanogel to contain the hydrophilic chemotherapeutic drug
cisplatin, which not only achieved pH-responsive release but also
degree of cross-linking of the inner core. The released platinum
drugs remained active and could form platinum adducts with the
DNA in the nucleus of the tumor cell. The experimental results
of the mouse model of ovarian cancer indicated that the nanogel
increasing the drug concentration at the tumor delivery site and
reduce the nephrotoxicity of platinum drugs to improve the safety
inhibited by modifying the drug-loaded nanogels with targeted
ligands (e.g., folic acid, LHRH peptide).
5.4.6.2 Delivery of oligonucleotides
Therapeutic oligonucleotides (e.g., small interfering RNA (siRNAs)
and antisense oligodeoxynucleotides (ODNs)), can diagnose and
treat tumors, neurodegenerative diseases, lethal virus infections,
mRNA sequences. Although some oligonucleotide-based treatment
deliver them to target cells is still an urgent concern. Because
oligonucleotides are hydrophilic molecules with a negative charge,
they cannot penetrate the cell membrane and can be degraded
by a variety of endogenous nucleases to stimulate the inherent
immune response. Therefore, oligonucleotides need a delivery
system to deliver them to the target site without causing side
composed of polymer polyelectrolytes or copolymers of ionic
monomers, giving the gel surface a certain charge. It is able to
achieve targeted delivery by adsorbing DNA fragments, bases
and other substances, wrapping or forming complexes, and
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Nano Physical Pharmaceutics of Nanogel Delivery System
same mechanism of action as that of drug delivery systems.
deliver nucleic acids such plasmid DNA, siRNA molecules. However,
endocytosis or binding of oligonucleotides is not enough to keep
Figure 5.5 shows the general process of DNA-nanogel polyplex
formation and release as conducted in our group. It is easily seen
that the polyplex formed by a positively charged chain like PEI is
not stable because the size and polydispersity (PDI) are large due
to the interparticle aggregation. On the other hand, in the polyplex
formed by the positively charged nanogel, the negative pDNA
is absorbed and trapped in the nanogel resulting in a stable and
uniform polyplex.
Figure 5.5 The mechanism of DNA complex and polyplex stability as
interacted with caonic nanogel (such as PNIPAM-PEI nanogel) and cationic
polymers (such as PEI).
Summary and Perspective
191
5.4.6.3 Delivery of therapeutic proteins
Nanogels can be used to encapsulate biological macromolecules,
such as proteins and peptides, to prevent them from being
amylopectin (CHP) gels can form a variety of complex protein
complexes through hydrophobic interaction. The complexation
proteins and protect them from enzyme degradation. The amount
of complexation is related to the hydrophobicity and of molecular
weight proteins [64]. However, the protein complexes are unstable
under high protein concentration. To improve the long-term
stability of the complexes, nanogels with strawberry-like structures
nanogels (40 nm–120 nm). The nanogels had a high encapsulation
rate of interleukin-12 (IL-12), and IL-12 level in plasma remained
stable after subcutaneous injection for 72 h. Shi et al. synthesized
acid-resistant nanogels of N-vinylformamide through inverse
emulsion polymerization, and the drug loading of lysozyme was
up to 60%. About 95% of lysozyme was released at pH 5.8 after
3 h; at pH 7.4; at the same time, only 15% of lysozyme was
released, while the released lysozyme retained about 50% of its
consistency, and stability after loading are still problems to be
considered.
5.5 Summary and Perspective
With the continuous improvement of biomedical technology, the
and treatment systems is also increasing. Nanogels show
water content and good biocompatibility. With the continuous
improvement of nanogel design theory, it is possible to design
more functional carrier systems according to the demand by
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Nano Physical Pharmaceutics of Nanogel Delivery System
and so on. However, how to improve the biocompatibility and
biodegradability of nanogels is still a huge challenge. With
the continuous improvement of synthesis and preparation
technologies, it is expected that extensive clinical application of
nanogels may be achieved, and new therapies for diseases may
be developed.
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