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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5604_Библиотеки_им_академика_М_И_Перельмана.pdf
Drug Delivery System and Technologies 75
Fig. 2 Limitations of conventionaldrug deliverysystems. Reproduced with permission from MDPI
[1]
advantages over traditional methods, primarily owing to their improved properties,
safety, stability, accuracy, and effectiveness. Traditional and advanced drug delivery
systems and technologies under development are designed to accelerate the targeted
delivery of drugs to specific areas, maximize the therapeutic effect, and minimize
off-target events in vivo [3].
2 Drug Delivery System
2.1 Conventional Drug Delivery System
Conventional drug delivery system mainly contains tablet, capsules, ointment,
syrups, granules, and suppositories. After the drug undergoes formulation into
various dosage forms, it becomes more convenient and acceptable for the patient
to use. This not only ensures accurate dosage of the drug, but also enhances the
stability of the drug. Additionally, it may reduce the occurrence of toxic side effects,
and easy to store, transport, and carry the drug.
2.1.1 Tablet
Tablets are solid formulations created by blending and compacting raw materials
and excipients into various shapes, such as round and oval. Tablets are the most
commonly used formulation of oral medications, which account for more than half
76 W. G uo e t al .
of all dosage forms [4]. Various factors, including drug solubility, drug particle size,
and tablet porosity, determine the drug release and effect of a given tablet. Therefore,
high-quality tablet products are successfully developed, which are determined by a
clear understanding of their structure, such as molecular structure, crystal structure,
particle properties, and tablet structure [5]. Oral ulcers were treated with ammonia
lexanox oral adhesive tablets. Adhesive oral tablets are chosen as delivery vehicles
for recurrent aphthous stomatitis (RAS) drugs such as ammonia lexanox due to they
are easy to administer and havegood taste. The interaction on the surface of the mouth
will lead to sustained release of the medication for an extended duration [6]. Clinical
studies have demonstrated the efficacy of this novel tablet system in reducing lesion
size and degree of erythema, as well as reducing the level of exudation of ulcers and
reducing pain.
2.1.2 Capsules
Capsules are solid formulations consisting of pharmaceuticals and dressings encapsulated in hard shell capsules or enclosed within soft capsule materials. Hard capsules
are primarily employed for encapsulating dry powdered ingredients, while soft
capsules are mainly used for encapsulating oily drugs, such as Vitamin E. Typically, capsule systems exhibit a core–shell structure wherein the core and shell can
be loaded with drug molecules or equipped with bio-functional ligands and stimulus–
response functions to facilitate targeted delivery or controlled release [7]. The drugs
contained within capsule shells are typically medications that can cause irritation
to the esophagus and stomach lining, or medications that have a strong, unpleasant
taste and are easily vaporized. By using capsule shells, these medications are able to
conceal their own unpleasant smell, safeguard the medication from degradation,
and prevent irritation to the esophagus and stomach. Capsules offer an alternative to tablets for the oral administration of therapeutic compounds. Compared to
tablets, capsules can transport various components, including non-aqueous liquids,
semi-solid, and solids.
2.1.3 Ointment
Ointment is a semi-solid topical preparation made by uniformly mixing drugs
and matrices. Common ointment bases include water-soluble bases (gel), absorption bases (water-in-oil emulsion), hydrocarbon bases (oleaginous ointment bases),
and water-removable bases (cream) [8]. Ointment is administered through different
routes, including topical, intranasal, transdermal, ocular, and vaginal.Intranasal ointment acts as a lubricant to prevent the nasal mucosa and secretions from drying out
and forming scabs. For oral diseases like RAS, the oralbase paste is enhanced with
0.05% clobetasol propionate ointment, which acts as a binder to prolong the time of
the drug in the mucosal area. The adhesive is added to the ointment to increase the
Drug Delivery System and Technologies 77
adhesion, allow it to remain in place for a longer duration, and play a better role in
protecting the oral mucosa [9].
2.1.4 Syrups
Syrup is a concentrated aqueous sugar solution, where active pharmaceutical ingredients (APIs)are dissolved. Syrups are widely used as cough medicine. Almost
all contemporary cough remedies are formulated with sweet syrup. The primary
mechanism by which cough syrups suppresses cough is attributed to the properties
inherent in the syrup itself, rather than its active ingredients (e.g., dextromethorphan).
The sweetness and viscosity of syrup seem to be indispensable attributes of cough
medicines. The sweet taste of cough syrups may employ to mask the bitter flavor of
drugs, and the physiological effects might aid in suppressing cough and facilitating
expectorant [10].
2.1.5 Granules
Granules are dry solids in the form of single-dose sachets, usually dissolved in water
for ingestion. Koukining is a traditional Chinese medicine that has been widely
applied for the treatment of oral ulcers. It is made using a combination of Chinese
herbs such as coptis and scutellaria. The complete wet granulation procedure for
preparing koukining granules necessitates continuous monitoring to ensure consistent quality of the final product. The use of these granules for therapy of RAS ulcers
shows promise and should be further investigated in clinical trials. The granules act
as a delivery method for the herbal extracts, allowing them to be transported directly
to the site of the ulcer. This technique is specifically designed to prolong the half-life
of the medicines [11].
2.1.6 Suppositories
Suppositories are solid unit dosage forms containing an active compound dissolved
or suspended in a suppository base, which melts or dissolves under body temperature
and releases the drug substance to act locally or throughout the body [12]. The rectal
mucosa is rich in blood vessels, and since suppositories belong to the rectal delivery
system, drugs are more easily absorbed. Although oral and parenteral routes are the
most commonly used methods, the rectal route has also been used for centuries,
especially in post-operative cases when the patient is unconscious, vomiting, and
unable to swallow.
78 W. G uo e t al .
2.2 Advanced Drug Delivery System
Healthcare has advanced with the discovery and development of new drug delivery
systems. Cancer has a high morbidity and mortality rate among diseases caused by
diverse factors worldwide. Chemotherapy is the most common means of treating
cancer and inhibiting tumor recurrence. Because chemotherapy drugs cannot limit
cytotoxicity to tumor cells, adverse toxicity to healthy tissues limits their use. To
overcome these limitations, a large amount of localized DDSs have been investigated, such as hydrogels, micelles, liposomes, nanoparticles, and so on. Compared
to conventional chemotherapy, localized administration offers the advantageof minimizing toxicity to healthy cells, thereby preventingthe spread of chemotherapydrugs
throughout the body. Additionally, it can control t he release of chemotherapy drugs
at the site of treatment, resulting in improved treatment effectiveness.
2.2.1 Micelles
Micelles synthesized through the self-assembly of amphiphilic block copolymers in
water-based solutions have wide and bright application potential in drug delivery.
These micelles can effectively encapsulate drugs within their core, allowing them to
be transported at concentrations higher than what would normally be possible due
to their limited solubility in water. The hydrophilic blocks of the copolymer form
hydrogen bonds with the surrounding water, creating a protective shell around the
micelle. Thus, the hydrophobic core of micelles is well shielded against hydrolysis
and enzymatic degradation. Furthermore, the crown can hinder identification by
the reticuloendothelial system, effectively preventing the entry of micelles into the
bloodstream. Interestingly, overall molecular weight, the chemical composition, and
ratio of block lengths in micelles can be readily adjusted, enabling precise control over
their size and shape. By incorporating crosslinked groups into block copolymers, the
stability and temporal control of micelles can be enhanced [13]. Nanocarrier systems
based on curcumin micelle has successfully targeted for the treatment of glioma and
Alzheimer’s disease [14].
2.2.2 Hydrogel
Hydrogel is a biomaterial with a three-dimensional network structure that has high
water content and has mechanical properties similar to soft tissue extracellular
matrices. It is also biocompatible and exhibits the ability to swell in water. Therefore, hydrogels are able to easily encapsulate hydrophilic drugs. Hydrogels with
injectable and biodegradable properties can form gels through in situ methods and
have extensive applications in drug delivery. Moreover, there is a growing number
of macromolecular drugs, such as nucleic acid and proteins, being approved as new
drugs. The crosslinked network of hydrogel may protect these bioactive ingredients
Drug Delivery System and Technologies 79
from early degradation caused by enzymes that are diffusing inwards [15]. Hydrogel
also offers the advantage of providing spatio-temporal control over the release of
small-molecular drugs, nucleic acids, proteins, and even cells [15, 16]. Researchers
investigatedthermosensitiveand biodegradable poly(organophosphazene) hydrogels
and found that doxorubicin (DOX) release time in DOX-polymer conjugate hydrogel
was longer, and it was more effective in local accumulation of tumor site and better
inhibition of tumor growth [17, 18].
2.2.3 Dendrimers
Dendrimers are synthesized from natural or synthetic monomers that have a spherical three-dimensional structure. Dendrimers are used as materials for drug delivery
because of their spherical shape and porous structure. In 2018, a Janus dendrimer with
disulfide bonds, capable of forming both hydrophilic and hydrophobic regions, was
investigated as a delivery system for siRNA. The positively charged hydrophilic part
of the Janus dendrimer established a robust and stable connection with the negatively
charged siRNA through electrostatic interactions. The siRNA was then released from
the dendrimer within the tumor cells under conditions of redox potential, resulting in
a highly effective gene silencing effect [19]. Nacetyl-L-cysteine-based dendrimers
may become a feasible choice for the treatment of neuroinflammation [20].
2.2.4 Nanosponges
Nanosponges have a three-dimensional porous structure, a size below 1 micrometer,
and high encapsulation efficiency, which can easily load lipophilic and hydrophilic
drugs [21]. Porosity and tiny particle size are important properties of nanosponges,
which are essential to correct the shortcomings of drugs. Mendes et al. prepared
nanosponges based on hyper-branched cyclodextrin and found that they had high
encapsulation efficiency. They observed improvements in the physicochemical properties of norfloxacin and the efficiency of oral absorption when using the nanosponge
formulation. Moreover, the nanosponge formulation enhanced the antibiotic activity
in vivo sepsis model [22].
2.2.5 Liposomes
Liposomes are closed spherical structures formed by self-assembly of lipids. When
dissolved in water, liposomes form closed structures with phospholipid bilayer
membranes, creating internal environments. They are commonly used as drug
delivery systems because they can stabilize compounds used for therapy, overcome
barriers to uptake by cells and tissues, improve the targeting of drugs to specific sites,
and reduce accumulation in non-target areas. Liposomes were first discovered in 1961
by British scientist Alec Bangham and his colleagues. They accidentally found that
80 W. G uo e t al .
phospholipids have the ability to spontaneously form closed vesicles when dispersed
in a water-based medium. Water-soluble drugs are encased in the interior of liposome, where the hydrophobic end accumulates. Water-insoluble drugs, on the other
hand, are incorporated into the phospholipid layer. The first commercially available liposomal product was Doxil, a Doxorubicin hydrochloride liposomal injection
approved by the Food and Drug Administration (FDA) in 1995. Among the liposome products already on the market, they are mainly focused on tumor therapy,
but also involve other areas, such as infections, anesthesia, vaccines, lung diseases,
and photodynamic therapy. Liposomal anthracyclines, such as pegylated liposomal
doxorubicin and liposomal daunorubicin, have shown the capacity of anticancer. In
addition, liposomes can fuse with cell membranes to release their contents or drugs
into the cell. When phagocytic cells take up liposomes, organelles called lysosomes
act upon the phospholipid walls, leading to the release of the medication [13]. The
liposome suspension is combined with the ointment and gel base. In contrast to ordinary ointments, where the release rate drops rapidly, the system releases the drug at a
controlled rate every 24 h. The delivery of drugs through the human skin is very slow.
In vivo studies have shown that in the case of liposome formulations, the duration of
action is longer. Liposomes have enhanced permeability and retention and are often
used in tumor cell-targeted therapy. One of the examples of liposomes that have been
used in cell-targeted therapy is amphotericin B liposomal injection.
2.2.6 Nanoparticles
Nanoparticles are polymer particles made from natural or synthetic polymers, whose
sizes range from 10 to 1,000 nm. They can be used to deliver drugs in various ways,
such as forming solid solutions or dispersions, attaching to a surface, or chemically binding to the drug, which can enhance permeability and retention effects.
Nanoparticle drug delivery systems offersignificant potential in variousapplications,
such as gene therapy, anti-tumor therapy, HIV therapy, radiation therapy, protein
delivery, antibiotic delivery, viral inhibitor delivery, vaccine delivery, and crossing
the blood–brain barrier [23]. In 2010, researchers loaded gatafloxacin/prednisolone
into a mucoadhesive nanoparticle system for the treatment of bacterial keratitis [24].
Nanoparticles offer numerous advantages in drug targeting, delivery,and release, and
they also have the potential to combine diagnosis and therapy. The main purpose is
to enhance the stability of drugs in the body, control their distribution, and improve
drug solubility and bioavailability. However, it is important to address the potential
toxicity of nanoparticles and their degradation products. Therefore, future research is
primarily focused on improving the biocompatibility of these nanoparticles in order
to ensure their safety and efficacy.
Drug Delivery System and Technologies 81
2.2.7 Nanosphere/Nanocapsule
Nanospheres are a matrix type of drug delivery system composed of oligomers or
polymers. For example, the hybrid nanospheres formed by DNA molecules and metal
ions have shown great potential in delivering nucleic acid drugs due to their fast and
simple synthesis strategies. Nanocapsules are a type of system that acts as a reservoir
for lipophilic drugs, which are composed of an oil core surrounded by a polymer shell.
The size of nanocapsules is between 5 and 1000 nm, which can provide enhanced
protection and stability for the drugs they encapsulate.
2.2.8 Nanoemulsions
Nanoemulsions are composed of two immiscible liquids, with droplet sizes between
20 and 500 nm. They require energy input for their formation, and are stabilized by surfactants or emulsions [25]. Nanoemulsions are extensively employed
in hydrophobic drugs because of their numerous advantages such as easy production, improved loading capacities, long-term stability, enhanced bioavailability, and
the ability to control drug release.
2.2.9 Aptamer
Aptamers are single-stranded oligonucleotides (DNA or RNA) that fold into threedimensional structures and can bind to targets like proteins and phosphoribonucleic
acids with high affinity and specificity through intermolecular forces. They have
the ability to recognize their target with high affinity and specificity [26]. Aptamers
possess several desirable characteristics, including their small molecular weight,
ease of synthesis, and the ability to undergo multiple selection processes. These
features make them attractive for various applications, including targeting diseases
and serving as therapeutic agents. Aptamers have the potential to contribute to the
development of innovative nanotechnology applications in medicine.
2.3 Controlled and Sustainable Drug Delivery System
In a controlled and sustainable drug delivery system, a drug remains at a constant
level in blood and tissues over a specific duration. Through extensive research in
pharmacology and pharmacokinetics, scientists have uncovered the significance of
drug release in achieving therapeutic effects. This further contributed to the advancement of controlled release technology [2]. In 1952, the first controlled release agent,
D-amphetamine, was created for a duration of 12 h [27]. Since then, researchers
have delved deeper into the mechanisms of controlled drug release and found that
can be achieved through four mechanisms: dissolution, diffusion, penetration, and
82 W. G uo e t al .
ion exchange [3]. The controlled and sustainable drug delivery system remains unaffected by physiological conditions and has the capability to release drugs steadily for
several months. This system allows for reduced dosage and frequency of administration, reduces the fluctuations of drug levels in the bloodstream, enhances drug solubility and targeted drug accumulation, improves patient acceptance, and minimizes
the drug toxicity.
3 Drug Delivery Technologies
3.1 Active and Passive Drug Delivery
3.1.1 Active Drug Delivery
Because of insufficient uptake, the drug delivery system may lack enough efficacy,
and the drug pharmacokinetics may also be delayed. In order to improve the penetration and accumulation of drug carriers, it is necessary to consider the enhanced
penetration and retention (EPR) effect when designing drug delivery systems, especially nanocarriers, such as micelles and liposomes. Active drug delivery has shown
eye-catching behavior in drug delivery field and controlled release owing to the
improved efficacy, and decreased side effects in normal tissues. Micro/nano-robots
can convert other forms of energy into propulsion and movement, and such robots
can be used as active drug delivery systems that can be navigated to targeted locations, and the therapeutic drugs can be loaded, transported, and delivered efficiently
[28]. Ávila et al. [29] designed the magnesium micromotor that was used as a method
of active delivery of clarithromycin, a model antibiotic used to treat gastric bacterial infection caused by Helicobacter pylori. The micromotor is propelled in the
gastric medium and helps regulate the administration of antibiotics. Cancer cells
overexpress certain receptors frequently, such as transferrin and folate receptors,
for related cancer diseases in the areas of their membranes compared to normal
cells. Thus, the ligand-receptor-mediated targeting system is considered an active
drug delivery. The specific molecules can be attached to the drug carriers, such as
nanocarriers, as the targeted ligands. The efficacyand specificity can be increased via
receptor-mediated endocytosis due to the increased affinity and internalization. The
success of active drug delivery via ligand conjugated drug carriers mainly depends
on their conformation, pharmacodynamics, and pharmacokinetics. The selectivity
of nanoparticles, as nanocarriers can be improved by conjugating ligands, including
hormones, aptamers, nucleic acids, antibodies, peptides, and other small molecules
[30]. After the drug carriers reach the targeted tumor area through EPR effect,
the receptor will recognize the corresponding ligand, resulting in improved drug
concentration in the targeted tumor cells. For instance, for the cancerous cells in
breast cancer, the expression of human epidermal growth factor receptor 2 (HER2)
is abnormally high, such a situation occurs in around 25% of breast cancer cases. So,
Drug Delivery System and Technologies 83
some researchers have improved the binding and immunoliposomes internalization
using p185HER2, which can overexpress breast cancer cells including BT-474 and
SK-BR-3 [31]. The chemical binding and functional modification greatly influence
the recognition of ligands on drug carriers. Furthermore, some physical approaches
could also influence the targeted activity, such as the accumulation of therapeutic drug
carriers in the tumor area, which magnetic fields can guide greatly [32]. Thus, the
strategy of combining drug carriers with magnetic materials, including iron, cobalt,
and nickel, could endow the drug carriers with magnetic properties. For the active
drug delivery system used for cancer treatment, different targeting strategies need to
be considered, especially for different types of malignancies. The common targeting
strategies include targeting angiogenesis, targeting uncontrolled cell division, and
targeting specific malignancies. Several angiogenic factors like fibroblast growth
factors (FGF), extracellular matrix (ECM), and vascular endothelial growth factor
(VEGF) could regulate the angiogenesis process, so the corresponding specific receptors including vascular endothelial growth factor receptor (VEGFR), vascular cell
adhesion molecules (VCAM), and integrins have the potential to be employed in the
development of active drug delivery system. Furthermore, compared to normal cells,
uncontrolled cell division generally occurs in tumor cells, which is mainly caused
by the mutations of tumor suppressor genes, such as p53. Using the receptors in the
drug delivery system that can overexpress tumor’s distinct cell division would be a
good strategy, and the main receptors include transferrin receptors, human epidermal
receptors, and folate receptors. The active drug delivery has the advantages of high
efficacy and precision guided transport for applications of diagnostics, photothermic
therapy, and biological imaging [33–35].
3.1.2 Passive Drug Delivery
Passivedrug deliverycan be employed for therapeutic nanoparticle design to achieve
enhanced permeability and retention effects, and the drug bioavailabilityand efficacy
can be effectively enhanced. Generally, leaky vasculatures in the diseased region can
uptake drug-loaded particles, which will be released and accumulated at a higher
concentration than normal tissues. Small particles as drug carriers have to pass
through vascular endothelial cells’ barriers to arrive at the lesion location, and the
drug carriers were not functionalized using identified ligands, such drug carriers
were considered passive drug delivery with targeting properties. Many biocompatible nanoparticles, including carbon nanotubes (CNTs), gold nanoparticles, liposomes, mesoporous silica nanoparticles (MSNs), and polyelectrolyte capsules, were
exploited as passive drug delivery systems for disease therapy. For cancerous tissue,
passive targeting drug delivery is based on the inherent chemical and physical characteristics of cancer cells, and the design of the drug carrier system will influence the
efficacyof the passive targeting drug delivery [32]. The nanoparticles, as drug carriers
with a size range of 20–200 nm can effectively escape from the vascular endothelial
cells and accumulate in targeted areas. Furthermore, the aggregation of drug nanocarriers in the targeted tissue could be promoted due to the physiological variations in
84 W. G uo e t al .
blood vessels and dysfunctional lymphatic drainage. The drug delivery carriers using
stimulus-responsive delivery systems, as new approaches, are considered as passive
targeting delivery, the encapsulated cargo can be released depending on the specific
stimulus employed in the delivery system. The stimulus-responsive drug delivery
systems can be classified into inter-regulated stimuli and exter-regulated stimuli.
The pH, certain biomolecules, and ionic strengths belong to internally regulated
stimuli, and temperature, magnetic field, light, and ultrasound intensity belong to
externally regulated stimuli. Stimulus based passive delivery systems can also be
considered as smart drug delivery, which will be summarized and discussed in the
next section. Active and passive drug delivery with targeting properties displayed
promising results in related diseases treatment, especially cancers. The intravenous
and extraneous drug delivery technologies also play an essential role in efficacy.
3.2 Smart Drug Delivery
Conventional drug delivery systems usually have side effects such as nonspecific
biodistributionand uncontrollable drug release [36]. Advanced/smart controlled drug
delivery system can overcome these limitations by loading and releasing drugs at the
targeted place in a controlled spatial manner, resulting in reduced dosage frequency
effectivelywhile extending the duration of drug concentration. Based on the conventional drug delivery technologies, and loaded drug can be designed as acting smart.
For example, the stimuli-responsive biomaterials have the potential to control drug
delivery, resulting in the development of smart drug delivery systems that harness
the specific properties of biomaterials. The researcher defines smart drug delivery as
the process of drug release, that the drug only can be released at the proper rate at the
targeted sites [37]. A smart drug delivery system can be designed using endogenous
and/or exogenous stimulus, as shown in Fig. 3. The endogenous stimulus mainly
includes pH, enzymes, hormones, glucose, small biomolecules, and redox gradients. The exogenous stimulus includes light, temperature, ultrasound, magnetic field,
electric pulse, and so on.
Among several stimuli, pH is frequently used to trigger drug release in organs
with different pH values, such as intestinal tract (around 7) and stomach (pH around
2). The designed pH-responsive carriers can differentiate the change of pH values
in specific areas, like ischemic, inflammatory, tumor tissues, endosomes, and lysosomes. For instance, due to the high glycolysis rate, the pH in various solid tumors
is usually lower than 7.0 compared to normal tissue and blood (around 7.4). Redox
responsive stimuli are also extensively applied in intracellular drug delivery systems
for disease therapy, due to the fact that the varying redox potential within different
organs in microenvironments. For instance, the smart glutathione (GSH) targeting
drug delivery can be designed based on the GSH reduction system within cancer
cells [37]. The concentration of GSH (2–10 mM) in cancer cells is 100-fold higher
than that in blood and normal extracellular matrices (2–20 µM), and such differences