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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5919_Библиотеки_им_академика_М_И_Перельмана.pdf
Cell-Based Therapies and Drug Delivery: Advancements and Challenges 479
2.5 Genome Editing Technologies
2.6 Cell Plasticity Technologies
These powerful tools, including meganucleases, zinc finger
nucleases (ZFNs), and transcription activator-like effector
nucleases (TALENs), have been widely used to edit genomes in
various cell types and organisms. Recently, TALENs have become
widely accepted by scientists due to their simplicity compared to
meganucleases and ZFNs. Due to its high efficacy and costeffectiveness, the utilization of CRISPRCas9 systems for precise
genome editing has gained significant acceptance among researchers in the life sciences field [
11]. This is because these systems are
able to achieve a higher level of accuracy and effectiveness. Targeted
gene editing is a method that is currently in its early stages of
development, with promising potential applications in translational
research. However, its potential makes it a technology that could be
disruptive in the field of cell therapy. There is a high probability that
the initial concentration of these gene editing-based treatments will
be on conditions that are associated with blood cells and are
brought on by a single gene mutation.
The field of cell plasticity draws on findings over the past 50 years
that suggest some, if not most, cells are capable of differentiating
into cell types that were previously believed to be outside of their
usual spectrum of specialization. In 1962, a tadpole’s intestine
contained the nucleus of a fully developed cell, which John Gurdon
swapped with the nucleus of a fertilized frog egg cell. The fact that
the egg cell changed and matured into a new frog showed that the
fully grown cell still possessed the necessary genetic information to
generate all cell types. In the 1990s, scientists were able to successfully construct an animal known as “Dolly the sheep” by using
nuclear transfer technology [
This achievement
provided additional evidence of the cellular
12]
.
plasticity that was previously unknown. The creation of mouse and
human embr yonic stem cell lines was a huge step forward that made
it possible to conduct research on developmental biology and cell
plasticity in a laboratory environment. Not only are we able to
improve our capabilities to a greater extent through the utilization
of this technology, but we are also able to increase our access to
cellular treatments. Two examples of the kinds of important developments that have happened in the field recently are the identification of human and mouse-induced pluripotent stem (IPS) cells as
well as the discovery of trans differentiation, which is the process of
changing one type of specialized cell into another without going
through the pluripotency stage. There is a large amount of promise
in technologies that are based on cell plasticity, and it is expected
that these technologies will have a big impact in therapeutic contexts. This is mostly due to the high probability of having an
abundant supply of cells and the capability of partially matching
the cell product that is produced with the patient getting it.
480 Pradeep Kumar Ram et al.
3 Different Kinds of Cells Are Utilized in the Process of Cell Treatment
These cells include mature cells such as T cells or dendritic cells, in
addition to adult stem cells that are derived from a tissue source that
was collected not too long ago. The utilization of regulatory T cells
(Tregs) in therapeutic treatments is an application of mature cells
that is both promising and an emerging field of application. CD4+
Foxp3+ Tregs are long-lasting cells that block immune responses
in vivo in a manner that is both commanding and antigen-specific.
Treg cells have been shown to be effective in lowering all immunity
in graft-versus-host disease models. Tregs also provide long-lasting
protection against auto-inflammatory diseases in mice models. Preclinical trials involving human patients are now being conducted in
order to evaluate the efficacy and safety of the CD4+ Foxp3+ Treg
therapy. The dendritic cell is yet another fascinating fully mature
cell type that is now being researched for its potential applications
in cell therapy. Both innate and adaptive immune responses are
initiated and controlled by dendritic cells, which are specialized
antigen-presenting cells that arise from the bone marrow. Dendritic
cells play an important part in both sets of immune responses [
15]. The employment of dendritic cells as a therapeutic approach
for immunotherapy, in conjunction with the utilization of oncogene inhibitors, appears to be the preferable method of treating
patients. The effectiveness of targeted therapy for tumors in renal
cell carcinoma, prostate cancer, breast cancer, and melanoma is
currently being investigated in human clinical research. These
investigations are currently being carried out.
13–
4 The Practices of Regenerative Medicine and Cell Therapy
The discipline of regenerative medicine, which is a revolutionary
medical specialty, has the ability to repair and rejuvenate damaged
organs and tissues. The results of preclinical studies carried out on
laboratory animals suggest that stem cell therapy has the potential
to become a conventional treatment option for a variety of debilitating diseases that affect companion animals. On the other hand,
in order to determine whether or not something is safe and effective, comprehensive clinical trials performed on a large scale are
required before it can be adopted. The journey has begun with the
beginning of clinical research for illnesses such as osteoarthritis,
tendon repair, and chronic renal failure. These studies are now
being conducted.
4.1 Veterinary Medicine Therapeutic Uses
Douglas J. Hershel was the first veterinarian to use stem cell-based
technology for the treatment of equine suspensory ligament desmitis. He applied this technology in the field of veterinary
Cell-Based Therapies and Drug Delivery: Advancements and Challenges 481
medicine. Because of the nature of this application, it was necessary
to inject substantial volumes directly, ranging from 20 to 60 milliliters. In order to repair a damaged ligament, a bone marrow
aspirate was extracted from the sternum and then injected into
the area. The findings indicate that the technique demonstrated a
greater rate of progress in terms of returning to athletic function
when compared to traditional therapy. On the other hand, considering the limit
marrow
were described were completely attributed to the stem cells. In the
general population of nucleated cells that can be found in human
and cat bone marrow, mesenchymal stem cells (MSCs) represent a
minority. It is hypothesized that MSCs are also present in other
species, such as horses, at proportions that are comparable to those
seen in human bone marrow. Acco
investigations, the
that are present in mononuclear cells that have been isolated from a
Ficoll density gradient or bone marrow aspirate falls somewhere
between 0.001% and 0.01%. A further reduction in the number of
mesenchymal stem cells (MSCs) in the first bone marrow aspirate
would be achieved through the utilization of the Ficoll density
gradient separation technique, which eliminates a varie
types. Granulocytes
of the various types of cells that can be found in the sample. It is
possible that the potential therapeutic impact of bone marrow
aspirate is connected to the presence of a number of bioactive
compounds in the acellular fraction. These molecules include
growth factors that are released by platelets or other cells.
ed number of stem cells that were present in the bone
aspirate, it is highly implausible that the outcomes that
rding to the findings of these
percentage of mesenchymal stem cells (MSCs)
ty of cell
and immature myeloid precursors are just two
5 Advancements and Challenges in Drug Delivery
Targeting the cells that are implicated in the onset and progression
of diseases is now critically important due to advancements in
molecular pharmacology and a better understanding of the
mechanisms underlying most diseases. This is particularly true for
most serious illnesses that need to be treated with medications that
have a wide spectrum of side effects. As a result, accurate tissue
targeting is necessary in order to reduce the amount of systemic
exposure. Recent drug delivery systems are developed with the use
of cutting-edge technology in order to speed up the transport of
drugs throughout the body to the precise location where they are
needed [
simultaneously avoiding off-target accumulation in the body. The
term “drug delivery systems” refers to technological systems that
incorporate the formulation and storage of drug molecules into
appropriate forms for administration, such as tablets or solutions.
They accelerate the delivery of medications to the particular spot in
16].
This helps to maximize therapeutic efficacy while
482 Pradeep Kumar Ram et al.
the body that is being targeted, which results in the enhancement of
therapeutic efficacy while simultaneously reducing the buildup of
off-target substances in the body. Drugs can be administered to the
body through a variety of routes, including oral route, buccal and
sublingual routes, nasal and ophthalmic routes, transdermal and
subcutaneous routes, anal and transvaginal routes, and intravesical
routes of administration [
responsible
is consumed, and they are also responsible for the physiochemical
qualities that the medication possesses. Because of the improved
systemic circulation and the ability to modulate the pharmacological action of the drug, distributed drug delivery systems have been
utilized successfully in the treatment of diseases and the enhancement of health over the course of the p
the
development of pharmacology and pharmacokinetics, the
notion of controlled release came into existence. This was due to
the fact that the importance of drug release in determining the
success of therapeutic interventions was demonstrated. The controlled-release formulation of a drug was made available for the first
time in the 1950s, and ever since then, it has garnered a great deal
of interest due to the major advantages it possesses in co
to
traditional drugs. The rate at which it delivers medications is
predetermined, and it does so for a predetermined amount of time.
Furthermore, the lifespan of regulated drug delivery systems might
range from a few days to several years because they are immune to
physiological circumstances. Moreover, it provides spatial control
over the drug’s delivery, allowing for either constant or variable
release rates. Furthermore, it improves the drug’s solubilit
accumulation, efficacy, pharmacological activity, pharmacoki-
site
netic properties, patient acceptance, and compliance while concurrently lowering its toxicity. In order to provide more targeted, easy,
and controllable delivery, a number of drug delivery systems have
been created in the last few years using contemporary techniques.
Specific features that are exclusive to a given pharmaceutical delivery system dictate its release rate and mechanism
to
differences in the morphological, chemical, and physical characteristics, which will ultimately affect these substances’ affinities
for various pharmaceutical drugs. It has been determined that
diffusion, chemical reaction, solvent reaction, and stimuli control
are the most significant release mechanisms. Consider the majority
of cancer cells’ ability to proliferate via the lymphatic system and
permeable blood vessels.
This means that the medicine can simply penetrate through this
hole and reach the tissues that are being targeted. In the administration of a wide variety of chemotherapeutic drugs, EPR
(Enhanced Permeability and Retention) is a passive diffusion mechanism that has been extensively investigated and extensively utilized. Passive targeting may have its limitations in terms of
17, 18
]. The components of the drug are
for the changes that it causes in the body system when it
ast few decades. Because of
mparison
y, target
. This is mostly due
Cell-Based Therapies and Drug Delivery: Advancements and Challenges 483
specificity and selectivity, but these issues can be effectively
addressed by employing active targeting. For this process to
occur, all that is needed are attachments to the carriers, specific
ligands, and molecules that can actively bind to the surface of target
tissues. By preventing uptake by non-target cells, the chances of
experiencing adverse consequences and toxicity are significantly
reduced. Despite the advancements in the development of targeted
drugs, the
include issues such
of drugs in lysosomes after being taken up by macrophages, and the
need for ligands to selectively target specific cells. Through the
process of responsive stimuli targeting, these delivery systems
have the ability to precisely reach the desired cells by manipulating
the physical or chemical characteristics of the target cells. Quantities
such as pH, te
electric field are examples of these physical qualities.
re remain considerable challenges to address. These
as immunogenicity, the potential breakdown
mperature, ultrasonography, magnetic
6 Drug Delivery Systems and Applications
There has been significant progress made in recent years toward the
effective creation of drug delivery systems based on organic, inorganic, and hybrid nanoparticles as drug carriers for active targeting,
particularly in chemotherapy. Recent drug delivery systems (DDS)
have been developed with enhanced features, including small particle size, higher permeability, increased solubility, efficacy, specific
site targeting, stability, toxicity, and sustained delivery. These
improvements have been made possible by the formulation of
DDS. When compared to conventional dose forms, they have the
potential to dramatically improve the performance of therapeutic
agents. In the process of developing an optimal drug delivery
system, recent drug delivery systems are acknowledged as the
most recent developments and innovative understanding of the
pharmacokinetic and pharmacodynamic behavior of medicines.
Due to
maintain medicine concentrations within the therapeutic range for
an extended period of time while simultaneously delivering material
to the therapeutic site. The commercial and therapeutic success of
the invention is intimately related to the adoption of the delivery
mechanism via which the innovation is delivered. In order to
accomplish this, it would be necessary to involve patients at an
early stage in the development process and identify any potential
issues. Researchers have identified the potential benefits of nanotechnology in greatly enhancing medicine delivery methods over
the course of time [
delivery systems.
the fact that these DDS are transporters, they are able to
19, 20].
field, and
The following are some of the drug
484 Pradeep Kumar Ram et al.
6.1 Red Blood Cell
MembraneCamouflaged
Nanoparticles Drug
Delivery System
The nanoparticles that are hidden by the membrane of red blood
cells represent a novel category of medication delivery technologies. The characteristics of red blood cells (RBCs) and the
biological relevance of these cells make it possible for them to be
utilized as an effective system for the camouflaging of nanoparticles. Because red blood cells (RBCs) are the most abundant circulating cells in the body, they are an attractive vehicle for drug
delivery. Their biocompatibility (non-immunogenic), biodegradability, and longer circulating half-life make them an ideal vehicle
for drug delivery. Several types of bioactive chemicals, including
enzymes, medicines, proteins, and macromolecules, have been
found to be transported by engineered red blood cells, which
have been found to be efficient transporters for these substances
21]. Due to the fact that they are so abundant, red blood cell
[
membranes act as a “camouflage,” which enables nanoparticles to
combine the advantages of native red blood cell membranes with
those of the nanomaterial. With the goal of loading therapeutic
substances onto red blood cells (RBCs) without compromising
their structure or the physiological function of RBCs, a number
of different techniques have been devised. By imitating red blood
cells (RBCs) and interacting with their surroundings, coated nanoparticles will be able to generate long-lasting systemic circulation
when administered. Creating nanoparticles that are camouflaged
with RBCs is typically accomplished through the use of sonication.
The in situ polymerization, microfluidic electroporation, and extrusion techniques are some more approaches that can be utilized for
the fusing of RBCs with nanoparticles [
22]. On the other hand,
each one has a number of benefits and drawbacks with regard to the
synthesis, the difficulties associated with scaling up, the repeatability, and the character of the end product. The RBC membranederived vesicle is obtained through hypotonic treatment (dialysis,
hemolysis, or dilutions) of fresh whole blood from an organism
prior to the fusion. Furthermore, because of the huge number of
cell membranes, red blood cell vesicles are intrinsically biocompatible and biodegradable. Furthermore, they are able to readily reach
high load capacity, which results in larger accumulation at the target
region. Nano-formulations that are coated with erythrocyte membranes have been utilized widely in the field of anticancer research
(with significant success), cardiovascular disorders, and
encephalopathy.
6.2 Drug Nanocarriers Based on Hyaluronic Acid
Hyaluronic acid is one of the strategies that can be used to deliver
drugs. Hyaluronic acid is a new polymer that has the potential to be
utilized in the production of medicine delivery systems. The linear
macromolecular mucopolysaccharide that it possesses is composed
of N-acetylglucosamine saccharide units and glucuronic acid units
that are proportionately coupled to one another [
23]. Additionally,
it is capable of being associated with a particular cell surface
Cell-Based Therapies and Drug Delivery: Advancements and Challenges 485
receptor, in addition to exhibiting biocompatibility, biodegradability, and high viscoelasticity values. As long as the integrated pharmaceuticals are delivered in a consistent manner, it makes sense to
employ hyaluronic acid as a carrier for ocular drug delivery. Hyaluronic acid is a natural component of eye tissue and plays a significant role in the healing process of wounds. In addition to
enhancing medication targeting, they contribute to the thickening,
su
stained release, and transdermal absorption of active pharmaceu-
tical ingredients.
The utilization of active targeted HA-based drug
nanocarriers resulted in a significant improvement in the distribution of several drugs to cancer cells. In addition, biocompatible
drug carriers consisting of lipid nanoparticles that have been coated
with a suitable HA have been produced. These nanoparticles have a
significant potential for targeted drug delivery to the target ti
while simultaneously
decreasing the risk of adverse effects and
ssue
hurting other tissues. Using HA-based nanocarriers for cancers
that have heightened expression of the CD44 receptor has a number of advantages, including improved drug delivery, increased
therapeutic efficacy, higher cytotoxicity, and a significant reduction
in the formation of tumors, in addition to a high potential for
targeted chemotherapy. When an HA-based nanocarrier is mixed
with doxorubi
a CD44-targeting
cin (DOX) and cisplatin (CDDP), it can be created as
anticancer drug delivery system. Additionally,
these micelles demonstrated higher cellular uptake and stronger
cellular growth suppression than free medications. An acid-sensitive
drug release, CD44-targeted delivery, high biocompatibility, and
biodegradability are some of the characteristics that make HADOX-CDDP micelles a promising candidate for a drug delivery
system.
6.3 Hexagonal Boron Nitride Nanosheet Drug Delivery System
Boron nitride (BN) is a crystalline substance that has a stoichiometry of nitrogen (N) and boron (B) atoms that is balanced. This
substance can be found in a number of different configurations,
including cubic BN (c-BN), hexagonal BN (h-BN), wurtzite BN
(w- BN), and rhombohedral BN (r-BN). In addition, it is sometimes referred to as white graphene, and also considered to be an
analog of graphite. As an alternative for the, the B–N atoms there is
a strong covalent link that holds the carbon atoms together, which
results in the formation of interlocking rings. Owing to the fact that
this combination is somewhat ionic, the B–N bonds that it contains
are polar. This is a distinctive property of the compound. Graphene
oxide (H-BN) is an insulator that has broad uses in a variety of
sectors, including cosmetics, dentistry, cement, ceramics, and most
importantly, medicine, where it is used as a drug carrier in a manner
that is comparable to graphene or graphene oxide. According to the
findings of the study conducted by Jedrzejczak-Silicka and her
colleagues, the proliferation of MCF-7 cell line cultures was
shown to be reduced when compared to the proliferation of normal
486 Pradeep Kumar Ram et al.
L929 cell lines after being exposed to H-BN that was loaded with
gold particles. Sonication treatment was used to exfoliate H-BN,
which was then functionalized with gold particles for the investigations and assessed using the Neutral Red (NR) uptake assay. H-BN
was exfoliated through chemical treatment utilizing a modified
version of Hummers’ procedure with sonication treatment. In a
different research investigation, the in situ deposition of Pd on the
surface of H-B
photothermal
able to have a high loading capacity for doxorubicin, which is a
medicine that is used to treat cancer, and it also operates very well as
a drug delivery carrier. During the course of the trial, the medicine
was administered to mice for a period of two weeks, and the results
showed a great reduction of tumor growth. The drop in pH, which
resulted in the release of do
concurrent increase in glutathione concentration and near-
as a
infrared radiation (NIR) made this possible. Another factor that
contributed to this was the presence of near-infrared radiation.
H-BN coupled with DNA oligonucleotide and copper
(II) phthalocyanine (CuPc) was shown to be effective as a therapeutic agent in photodynamic treatment (PDT), as well as in situ
monitoring. This was demonstrated by another successful
gation. Boron
chemotherapeutic dr ug that is considered to be successful. As a
result of their greater stability in storage, improved targeting ability
on disease cells, sustained drug release, and higher encapsulation
ability, these are finding widespread use as drug delivery systems
[
24, 25].
N nanosheets resulted in the nanosheets acquiring
characteristics. Because of this, the compound was
xorubicin from the nanohybrids, as well
investi-
compound is currently being acknowledged as a
6.4 Polymer-Lipid Hybrid Nanoparticles
Liposomes and polymeric nanoparticles are the nanoparticles that
have the most widespread acceptance among those that are now
being employed for medication delivery. Although liposomes,
which are lipid-based nanoparticles, exhibited excellent biocompatibility, they still experienced drug leakage and instability when they
were stored. On the other hand, polymeric nanoparticles, which are
polymer-based nanoparticles, were able to overcome this limitation
by demonstrating high encapsulation/drug loading ability as well
as stability. The fact that it demonstrated a lower level of biocompatibility was, however, one of its own shortcomings. In order to
overcome these deficiencies and get an effective nanomaterial,
researchers looked out and developed a hybrid system that will
integrate the distinctive characteristics of the two classes of nanoparticles. This hybrid system is referred to as polymer-lipid hybrid
nanoparticles (plhnps). With the help of this hybrid approach,
parameters of biocompatibility, high storage stability, prolonged
drug release, low drug leakage, tiny particle size, and high encapsulation were fulfilled. As a result of the ef fectiveness of this technology, it is currently being utilized for a variety of therapeutic
Cell-Based Therapies and Drug Delivery: Advancements and Challenges 487
objectives in addition to diagnostic applications. Plhnps is composed of three unique components, one of which is a polymeric
core that is capable of efficiently encapsulating both hydrophilic
and hydrophobic medicines. This is possible as a result of the
hydrophilic and hydrophobic nature of the core and results in a
high sustained release, a lipid shell that provides biocompatibility
and high stability and a lipid-polyethylene glycol (PEG) that is
found in the outer
increased steric
part and covered by a lipid layer to provide
stability, prevent immune recognition, and increase
time for circulation. There are many different applications for
plhnps, including the administration of different chemotherapeutic
drugs, the transfer of genes (sirna and DNA), as well as the application of plhnps in photothermal therapy, photodynamic therapy, and
ultrasound. A number of studies have demonstrated that they are
suitable for use in imag
as well
as in the administration of vaccinations and the activation of
ing and alternative magnetic fields (AMF),
the immune system. Because of this, it has a wide range of applications in the rapidly expanding medical environment [
26].
6.5 Selfmicroemulsifying
Drug-Delivery System
In recent times, there has been a significant amount of interest in
lipid-based pharmacological preparations, with a particular emphasis on self-microemulsifying drug-delivery systems (SMEDDS).
There are many challenges involved in the process of producing
oral dosage forms of pharmaceuticals, one of the most challenging
being inadequate bioavailability. Therefore, minimal hydrophilicity
is a critical criterion for bioavailability in this context. This is due to
the fact that medications cannot be absorbed through the gastrointestinal tract (GIT) unless they are in solution form. A significant
number of chemical compounds that have pharmacological effects
that are both remarkable and beneficial have an issue with their
solubility in water. Furthermore, about 30% of medicinal entities
that are extensively sold and nearly 50% of novel medication compounds that are available for product manufacture are hydrophobic
in nature, which means that they have low water solubility. The
employment of a carrier system that is based on lipids in order to
increase the bioavailability of drugs that are less water-soluble has
significantly increased in popularity over the past few years. The
primary objective of this formulation is to ensure that the hydrophobic components remain in solution throughout the entirety of
the digestive system. Suspensions, dry emulsions, microemulsions,
and self-emulsifying drug-delivery systems (SEDDS) are some of
the different types of lipid-based carriers that are available. It has
been reported in the past that SEDDS has the capability of incorporating hydrophobic medicines [
27]. Self-microemulsifying drug-
delivery systems (SMEDDS) and self-nanoemulsifying drug-delivery systems (SNEDDS) are two additional names that have been
given to SEDDS after it has been revised. There are three different
kinds of emulsions: water-in-oil, oil-in-water, and multiple
488 Pradeep Kumar Ram et al.
emulsions or combinations of the two. In addition, traditional
micro- or nanoemulsions behave differently from SMEDDS in
that, after being ingested orally, they self-emulsify. There are two
categories of emulsifying agents that are utilized in the production
of microemulsions: surfactants (S) and co-surfactants (CoSs). Surfactant, on the other hand, is primarily soluble in water, but CoS is
primarily soluble in the oil phase where it functions. In order to
bring th
down to
microemulsion, CoSs are absolutely necessary. For the creation of
nanoemulsions with droplet sizes that are smaller than 100 nm, on
the other hand, either mechanical or chemical energy is required.
Despite the fact that nanoemulsions are considered to be kinetically
stable due to the fact that their rate of destabilization is extremely
low, their st
noteworthy
mulsion globules are stable in a wide range of circumstances,
including a variety of dilutions and temperatures, whereas microemulsions are primarily affected by parameters such as dilutions and
temperature [
e tension that is present between the two liquid phases
the appropriate level that is necessary for the creation of a
ability over a lengthy period of time (in months) is
. Consequently, it has been demonstrated that nanoe-
28].
6.6 In Situ Gel Drug Delivery System
The primary objective of any drug delivery system is to alter the
pharmacokinetic properties of the medication and to alter the
distribution of the drug in the tissue in a manner that is significant.
One of the most cutting-edge methods of drug delivery is the in
situ gel medicine administration, which has become increasingly
popular. It is possible for the in situ gel drug delivery system to
assist in the prolonged and regulated release of drugs, as well as
increased patient compliance and comfort. This is made possible by
the unique property of transitioning from Sol to Gel. In the majority of instances, formulations that are normally in the form of a
solution undergo a transformation into a gel form under specific
physiological conditions prior to entering the body. In order to
turn a solution into a gel form, a number of different stimuli,
including changing the pH of the solution, modifying the temperature, and exchanging the solvent, are combined. Research has
utilized a variety of administration methods, including but not
limited to oral, nasal, injectable, vaginal, rectal ocular, intraperitoneal, and parenteral administration. There have been a great number of polymeric approaches developed that are capable of
delivering medications. A sol-gel transition takes place in these
polymers whenever they are exposed to physiological stimuli
when they come into contact with them. A wide range of natural
and synthetic polymers are utilized in the production of in situ gel
drug delivery systems. There are four processes that are known to
produce the for mation of in situ gel biomaterials. These processes
are as follows: (1) variations in temperature and pH; (2) variations
in the physical properties of the biomaterials, such as swelling and