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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5398_Библиотеки_им_академика_М_И_Перельмана.pdf
Drug Delivery to the Cardiovascular System: Application and Future Prospects 339
toxicology (ADME/Tox). By incorporating these considerations
earlier in the dr ug development pipeline, researchers can ensure
that drug-like proper ties are built into new compounds from the
outset.
In some cases, standard medicinal chemistry approaches are not
enough to overcome the challenges associated with drug delivery,
especially when these compounds are tested in preclinical models or
administered to humans. In such instances, advanced formulation
technologies have been employed to enhance the drug’s ability to
reach its target site effectively. One of the main challenges in the
delivery of small molecule drugs is solubility, which can be
improved through the use of nanoformulation techniques. Nanomedicine offers distinct advantages in drug delivery by not only
enhancing the drug’s distribution to its target but also providing
protection against toxicity in non-target organs. For example, a
recent study led by Liu and colleagues demonstrated how the use
of a hyaluronic acid polymer nanoparticle combined with Intralipid
20% could significantly reduce the toxicity of platinum-based cancer drugs in organs, such as the liver, spleen, and kidney. Intralipid
is currently being tested in human clinical trials to evaluate its
effectiveness in cardiac reperfusion therapy.
In recent years, various types of nanomedicine have been developed to address different therapeutic needs. The choice of a specific
formulation depends on a range of factors, including the chemical
properties of the drug, such as solubility and molecular weight, as
well as the intended therapeutic goal. For example, if the objective
is to treat peripheral organ systems, the primary for mulation target
may be to protect the drug from metabolism. In other cases,
nanoformulation may be used to improve the distribution of the
drug to specific target organs, such as the brain. The blood-brain
barrier (BBB), which is highly selective, only allows certain compounds to pass through via transcellular or transporter-mediated
uptake. A recent study highlighted a novel approach to overcoming
this barrier by activating the A2A adenosine receptor (A2A AR),
which was shown to open the BBB, potentially allowing drugs like
chemotherapeutic agents—normally excluded from the brain—to
reach the central nervous system (CNS).
Various
nanoformulations have been developed for small
organic molecules, including liposomes, nanoparticles, nanocapsules, nanotubes, polymeric conjugates, and micelles. While these
formulations have been most extensively used in treating cancer
and central nervous system diseases, other therapeutic areas such as
orthopedics and cardiovascular diseases are now emerging as
promising fields for novel drug delivery strategies. The general
approach for nanoformulating small molecules involves encapsulating the drug within a polymer carrier system. In this method, the
lipophilic properties of the drug interact with the lipophilic regions
of the polymer, causing the polymer to self-assemble and form a
340 Pankaj Kumar Umar et al.
protective barrier between the drug and its aqueous environment.
Other nanoformulation methods include conjugating the drug to
the polymer or forming a complex with systems such as glutathione
or folate. These innovative approaches provide significant potential
for improving the delivery, efficacy, and safety of small molecule
therapies across various disease conditions.
3 Drawbacks of Conventional Drug Delivery System
Despite significant advancements in conventional drug delivery
systems (DDSs), there are still notable limitations, especially in
the context of cardiovascular applications. One of the primary
challenges lies in the extremely low efficiency of gene transfection
and cell engraftment at the target site. This inefficient delivery of
drugs often results in insufficient drug concentrations at the desired
location, which in turn leads to suboptimal therapeutic outcomes.
Furthermore, conventional DDSs are prone to off-target effects,
where the drugs may unintentionally affect surrounding tissues,
potentially causing adverse side effects.
Another major limitation of traditional drug delivery methods
is the difficulty in tracking drug movement and behavior in realtime within the body. Conventional systems often lack the capability to monitor how well drugs are retained at the target site and how
they are distributed throughout the body. Without this real-time
tracking, it is challenging to ensure the effectiveness of the treatment or make necessary adjustments during therapy.
To address these drawbacks, there has been growing interest in
utilizing external stimuli, such as magnetic fields (MF) and ultrasound (US), as part of novel drug delivery strategies. These methods offer a non-invasive approach to drug delivery and possess
intrinsic biomedical effects that make them particularly attractive.
The application of external stimuli allows for more precise control
over drug release and distribution, potentially improving therapeutic outcomes while minimizing side effects.
4 Factors Affecting Cardiovascular Drug Targeting System
The design and development of vascular-specific drug delivery
vehicles require careful consideration of several physical attributes,
such as particle size, shape, density, and how they behave in blood
flow. These characteristics are essential to ensure that the drug
carriers can travel effectively through the bloodstream and selectively bind to the target receptors on the endothelial lining of
vascular plaques and walls. Factors such as particle shape, size,
density, and their interaction with blood flow dynamics are critical
in the development of vascular-targeted drug delivery systems. By
Drug Delivery to the Cardiovascular System: Application and Future Prospects 341
optimizing these factors, drug carriers can be engineered to
improve their precision in targeting diseased areas within the vascular system, leading to more effective therapies for vascular-related
diseases.
4.1 Particle Shape
4.2 Particle Size
Spherical particles are often preferred due to their favorable hydrodynamic properties and ease of fabrication. The shape of the drug
delivery vehicle significantly impacts its ability to circulate in the
bloodstream, its internalization into target cells, and its efficiency in
binding to specific receptors. Spherical particles are typically cleared
more quickly by the body, which can reduce their overall effectiveness. However, non-spherical particles, such as those with disk- or
rod-like shapes, tend to remain in circulation for a longer time,
offering greater resistance to rapid renal clearance. This prolonged
circulation enhances their ability to target specific areas within the
vascular system. The oblong or elongated shape of these
non-spherical particles allows them to experience lower drag forces,
improve adhesion to the vascular walls, and provide more binding
sites for targeting ligands. As a result, non-spherical particles may
be more effective for targeted vascular drug delivery.
The size of the particles is also critical for successful drug delivery.
Particles that range from tens of nanometers to submicron sizes are
ideal for intravenous delivery through the microcirculatory system.
These small particles are less likely to trigger an immune response,
allowing them to circulate longer without being cleared. While
nanosized particles are advantageous in this regard, micropar ticles,
which are larger (ranging between 2 to 5 micrometers), tend to
exhibit stronger adhesion to their target, particularly in larger
vessels such as arteries, which are commonly affected by conditions
like atherosclerosis or peripheral artery disease. Microparticles,
regardless of their shape, demonstrate a higher binding affinity
compared to nanosized particles. However, particles should not
exceed 5 micrometers in size, as larger particles are subjected to
greater disruptive forces and increased wear and tear, resulting in
diminished adhesion efficiency to the targeted site.
4.3 Particle Density
The density of the particles plays an important role in how well they
can move toward and adhere to vascular walls. Different materials
used for vascular targeting have various densities based on their
composition. For example, FDA-approved biodegradable polymers
typically have a neutral buoyancy or a density slightly higher than
that of blood. In contrast, inorganic particles such as silica or gold
have much higher densities than blood, which can enhance their
performance in targeted delivery. Silica particles, for instance,
exhibit better adhesion to vascular walls than polystyrene particles
of the same size. This is largely due to the fact that silica is almost
twice as dense as blood, whereas polystyrene is neutrally buoyant.
342 Pankaj Kumar Umar et al.
The higher density of silica helps the particles marginate, or move
toward the vascular wall, more effectively, which increases their
ability to bind to the target site.
4.4 Flow Characteristics
Blood flow dynamics, or hemodynamics, are critical in determining
how well the drug delivery particles adhere to the endothelium and
interact with target receptors. Various factors, including shear
forces, flow patterns, the presence of red blood cells, and the height
of the blood vessel channels, influence these interactions. Interestingly, the pulsatile nature of blood flow, which involves periodic
fluctuations in velocity and pressure, and flow recirculation generally do not significantly affect the adhesion of nanoparticles. This is
because nanoparticles are small enough that they are less influenced
by the disruptive forces generated by blood flow. On the other
hand, microparticles (0.5–5 micrometers in size) are more susceptible to these flow dynamics. Their adhesion efficiency increases
when they have longer residence times in the bloodstream and
experience lower slip velocities, especially in pulsatile flows. Regardless of their shape, microparticles have been shown to adhere more
effectively in areas where blood flow is disturbed by shear forces.
5 Various Targeted Drug Delivery Systems
5.1 Application of Exosomes and EVs (Extracellular Vesicles)
There are various drug delivery techniques to the cardiovascular
system as described above (Fig.
introduced from the exterior of the cell to aid in the transport of
active pharmaceutical ingredients can be categorized into three
main types: apoptotic bodies, which range in size from
1). Primarily, vesicles that are
Fig. 1 Different techniques of drug delivery to cardiovascular system
Drug Delivery to the Cardiovascular System: Application and Future Prospects 343
Fig. 2 Application of extracellular vesicles in cardiovascular diseases
400 to 2500 nm in radius; ectosomes or microvesicles, with a radius
of 50–500 nm; and exosomes, which are the smallest at 15–50 nm
in radius. These extracellular vesicles (EVs) play significant pathophysiological roles in various cardiovascular diseases, influencing
key processes such as angiogenesis, tissue swelling, and the repair
of damaged cardiac tissues (Fig.
with a variety of molecules, including nucleic acids and cytokines,
which migrate to different cell types, such as immune cells and
fibroblasts. This highlights the complex interactions and contributions of EVs in the context of cardiovascular health and disease
[
18]. The proteins found on the surface of extracellular vesicles are
also critical for
effective cardiovascular drug delivery. These surface
proteins can facilitate interactions between the vesicles and target
cells, enhancing the specificity and efficiency of the delivery process.
By mediating recognition and binding to specific receptors on
target cells, these proteins help ensure that the therapeutic agents
carried by the vesicles are delivered accurately to the in
of action. This
feature not only improves the therapeutic efficacy of
the drugs but also minimizes potential side effects, making the
proteins on extracellular vesicles an essential component in the
development of advanced drug delivery strategies for cardiovascular
applications [
19].
For example, proteins such as CD14, Serpin F2, and G1, along
with cystatin C and various microRNAs, have been identified as
having functional roles in cardiovascular drug delivery. They can act
as “procoagulant” proteins or serve as biomarkers for the detection
and treatment of conditions like stroke and heart dysfunction. The
significant potential of proteins, lipids, and microRNAs in exosomes and extracellular vesicles (EVs) to enhance targeted drug
delivery to the heart and cardiovascular system has been
2). Their involvement is associated
tended sites
344 Pankaj Kumar Umar et al.
emphasized. Notably, microRNAs like miR-146a and miR-21 have
been linked to the progression of various stages of cardiovascular
diseases, including myocardial infarction, plaque buildup in
arteries, and heart failure [
The inherent properties and activities of extracellular vesicles
(EVs) and exosomes have been the focus of extensive research
aimed at uncovering their potential and functions as biotherapeutic
agents, especially in the context of cardiovascular diseases. For
example, exosomes derived from mesenchymal stem cells have
demonstrated the ability to promote blood vessel regeneration.
They play a crucial role in mitigating the damaging effects of free
radicals by reducing oxidative stress in the body. This capability not
only supports the healing processes within the cardiovascular system but also highlights the therapeutic promise of using exosomes
in treating various cardiovascular conditions. The exploration of
these vesicles continues to reveal their multifaceted roles in enhancing vascular health and providing protective effects against oxidative damage, paving the way for innovative treatment
strategies [
Extracellular vesicles (EVs) derived from cardiac progenitor
cells have been demonstrated to enhance blood vessel development, with their effects mediated by specific metalloproteinase
components. Additionally, EVs can be produced by endothelial
cells and blood platelets, offering a wide range of beneficial effects
for cardiovascular therapy. These effects include promoting angiogenesis, reducing plaque formation, and aiding in the restoration of
blood flow or revascularization processes [
attack, or myocardial infarction, the tiny size of extracellular vesicles
(EVs) has been demonstrated to be advantageous for targeted drug
delivery to the swollen myocardium. This effectiveness is largely
attributed to the “enhanced permeability and retention” (EPR)
effect, which allows these vesicles to penetrate tissues more easily
and remain in the targeted area for longer periods. For optimal
success in targeted delivery, it is crucial that the biotherapeutic
agents incorporated into the EVs do not undergo any changes to
their surface characteristics. Maintaining the integrity of the surface
ensures that the vesicles can effectively bind to the target cells and
deliver their therapeutic payload, enhancing the overall efficacy of
the treatment during such critical cardiovascular events [
Extracellular vesicles
targeted delivery of therapeutic agents such as microRNAs (miRNAs) that possess neuroprotective properties, particularly in the
context of cardiovascular conditions like stroke. One of the key
challenges in treating such ailments is the presence of the bloodbrain barrier, which typically restricts the entry of many therapeutic
compounds into the brain. However, EVs have the unique ability to
cross this barrier, allowing them to deliver miRNAs directly to the
affected neural tissues. This targeted delivery not only enhances the
21].
20].
22]. During a heart
.
23]
(EVs) offer significant benefits in the
Drug Delivery to the Cardiovascular System: Application and Future Prospects 345
effectiveness of the treatment but also minimizes potential side
effects by ensuring that the therapeutic agents reach the specific
areas where they are needed most. By utilizing EVs as carriers,
researchers can leverage their natural properties to improve therapeutic outcomes in stroke patients, thereby opening new avenues
for effective treatment strategies [
24]. While enhanced uptake of
drug-carrying vesicles by the liver can diminish the effectiveness of
this therapeutic approach, genetically modified extracellular vesicles
(EVs) have been demonstrated to help mitigate this issue [
25]. The
drawbacks associated with the intramyocardial delivery method can
be
addressed by modifying the surface characteristics of exosomes.
These alterations have resulted in improved blood vessel regeneration, better retention of exosomes in the hear t, and the promotion
of cardiomyocyte propagation. Additionally, the modified exosomes have been shown to decrease their uptake in the liver, effectively overcoming one of the main challenges in cardiovascular d
delivery [
26].
rug
5.2 UltrasoundMediated Drug
Delivery
The primary goal of this method of drug delivery across the cell
membrane is to improve the ability of substances to penetrate cells
or enhance their permeability. In the context of ultrasoundmediated cardiovascular therapy, there are three key aspects to
consider:
1. Cavitation: This phenomenon involves the
microbubbles,
which can be either inertial or stable. The result-
oscillation of
ing pulsing action generated by these oscillations helps to
propel drugs into blood clots, facilitating their targeted delivery and improving therapeutic outcomes.
2. Radiation Force
from Ultrasound
: This force plays a vital role,
particularly in cardiovascular treatments, as it helps to direct
microbubbles toward the intended cardiac or cardiovascular
tissues. By generating a sustained force, the ultrasound effectively guides the microbubbles to the targeted site, enhancing
the delivery of therapeutic agents [
3. Sonothrombolysis:
This represents t
27].
he most significant application of ultrasound combined with microbubble therapy. It
involves the non-invasive disintegration of blood clots and
the restoration of blood flow through the use of highfrequency ultrasound. This technique can be employed either
alone or in conjunction with the cavitation effect of microbubbles, offering a powerful approach to treating conditions like
thrombosis [
28].
Together
, these aspects underscore the potential of ultrasoundmediated therapy to enhance drug delivery and improve outcomes
in cardiovascular treatments. The application of sonothrombolysis
combined with targeted microbubbles serves two primary
346 Pankaj Kumar Umar et al.
purposes: first, to identify and localize the blood clot, and second,
to facilitate its breakdown through ultrasonic-induced cavitation
[29]. The effectiveness of the “ultrasound-targeted microbubble
destruction” (UTMD)
ering genes and genetic drugs to cardiac tissues and related organs.
For instance, in a mouse model of heart attack, the use of Perflutren
for transferring “stem cell factor,” “vascular endothelial growth
factor,” and “green fluorescent protein” via UTMD resulted in
improved restoration of cardiac tissues and enhanced migration of
stem cells to t
The UTMD procedure has shown the capability to increase the
engraftment of mesenchymal, cardiac, and endothelial progenitor
cells in animal models with reduced sizes. One notable advantage of
microbubbles is their ability to carry much higher concentrations of
gases compared to standard liquids, a feature that is especially
crucial during heart attacks, when cardiac muscles urgently require
elevated levels of oxygen [
When i
ery in cardiovascular therapy, sonothrombolysis remains a significant focus, particularly in the treatment of strokes and myocardial
infarctions. In the case of strokes, standalone ultrasound
interventions—without the use of microbubbles—combined with
tissue plasminogen activator have demonstrated positive results.
For heart attacks, the healing effects are primarily linked to the
ability to restore blood flow in both the epicardium and the myocardial microvascular bed [
However,
been noted. In advancing drug delivery for cardiovascular therapy,
the use of molecular contrast-enhanced ultrasound (CEUS) has
been documented for applications within both the heart and the
vascular system. Specifically, in the context of the heart, efforts
focus on identifying acute inflammatory responses after heart
attacks. This is achieved by directing microbubbles toward white
blood cells or by modifying the surfaces of microbubbles with
ligands that specifically recognize leukocytes [
system, research efforts are focused on the precise monitoring of
atherosclerosis progression and endothelial repair by targeting
microbubbles to specific markers such as vascular cell adhesion
molecule (VCAM-1), P-selectin, and junction adhesion molecule
(JAM-A), among others. One of the primary advantages of the
therapeutic molecular contrast-enhanced ultrasound (CEUS) procedure is its use of high mechanical index ultrasound, which facilitates the physical disintegration of thrombi and enhances
thrombolysis. This approach is particularly beneficial as it helps to
mitigate the hemorrhagic complications that are commonly associated with existing revascularization techniques. By effectively
combining targeted delivery with controlled ultrasound application, CEUS holds promise for improving the management and
technique has been documented for deliv-
he heart.
30].
omes to utilizing ultrasound for targeted drug deliv-
t c
31]
.
complications following sonothrombolysis have
In the vascular
32].
Drug Delivery to the Cardiovascular System: Application and Future Prospects 347
treatment of vascular conditions while reducing the risks of adverse
effects typically seen in traditional methods [
33].
5.3 MagneticResponsive Drug
Delivery Systems
Magnetic nanoparticles (MagNPs) are already in use in clinical
settings. Magnetic resonance imaging (MRI) can provide both
structural and functional insights for diagnosing and validating
cardiovascular disease (CVD) through the use of contrast agents
made from superparamagnetic iron oxide nanoparticles (SPIONs).
MagNPs have distinct characteristics that make them suitable for
various biomedical applications. These complexes are biocompatible and can effectively guide therapeutic agents to specific target
sites, enhancing treatment efficacy while allowing for real-time
tracking via MRI. The use of magnetic nanoparticles represents an
innovative strategy for developing targeted drug delivery systems
(DDS), which offer numerous advantageous features [
34].
First and foremost, the magnetic nanoparticle (MagNP) complexes that have received clinical approval are designed to be biocompatible. Given that bare iron oxide can be cytotoxic, researchers
have developed a core-shell model for MagNPs, utilizing various
materials for the shell, including silicon oxide, liposomes, polyethylene glycol, polyethyleneimine, and derivatives of dextran—all
known for their favorable biocompatibility [
35]. The choice of
shell material is crucial, as it significantly influences the final size
and geometry of the MagNPs, which in turn affects their distribution throughout the body and their kinetics of cellular uptake.
Additionally, it is possible to directly attach negatively charged
nucleic acids to the surfaces of MagNPs coated with cationic polymers through electrostatic interactions. This capability enhances
the versatility of MagNPs in biomedical applications, particularly
in targeted drug delivery and gene therapy [
Second, t
he m
agnetic properties of magnetic nanoparticles
36].
(MagNPs) enable targeted drug delivery when an external magnetic field (MF) is applied. For effective site-specific delivery, it is
essential for the magnetic field to generate a strong enough attractive force to counteract the hydrodynamic drag that occurs in
flowing fluids. While permanent magnets can be used for this
purpose, they are limited by their effective range and depth of
penetration. To address this limitation, researchers have developed
electromagnets and magnetizable stents that can maintain a stronger and more consistent magnetic force over greater distances.
These innovations enhance the ability to capture and direct
MagNPs to specific sites within the body, thereby improving the
efficacy of targeted drug delivery systems. By employing these
advanced magnetic technologies, the potential for localized treatment and better therapeutic outcomes in various medical applications can be significantly enhanced [
37]
.
Third, the targeted accumulation of drugs at the site of interest
facilitates therapeutic treatment at lower doses. This technique,
348 Pankaj Kumar Umar et al.
known as magnetofection, involves combining cells or nucleic acid
vectors with magnetic nanoparticles (MagNPs) to accelerate transfection rates by magnetically concentrating the therapeutic agents
at the desired location. Numerous studies have also shown that the
application of an external magnetic field can enhance the penetration of magnetic cells and vectors into tissues, further improving
the efficacy of the treatment. This approach not only increases the
l
ocalized concentration of therapeutic agents but also reduces the
potential for systemic side ef
effective drug delivery [
Fourth, the real-time tracking of drugs can be detected and
visualized noninvasively through magnetic resonance imaging
(MRI) in live subjects [39].
fects, making it a promising strategy for
38].
5.4 Nanomedicines in Cardiovascular Therapy
5.5 PLGA-Based Nanoparticles
Nanomedicines encompass nanosized particles or specially formulated drugs with high surface energy, and they are increasingly
employed in cardiovascular (CV) treatments due to their unique
properties, such as heightened reactivity, an enhanced ratio of
surface area to volume, and improved roughness and wettability
40]. These nanomedicines are utilized in two primary ways for
[
addressing cardiovascular conditions. The first approach involves
using nanomedicines as standalone agents to directly activate specific enzymes that can alter cardiovascular metabolic states. This
method often employs nanoparticles made from materials like
metals, metal oxides, carbon, polymers, and nanocomposites. The
second approach focuses on using nanomedicines as carriers to
enable regulated and targeted delivery of traditional cardiovascular
drugs. In this case, formulations such as polymeric liposomes,
micelles, and dendrimers are commonly used. Ongoing research is
also exploring the integration of nanocarriers into drug-eluting
stents and cardiovascular implants, aiming to enhance the effectiveness of nanomedicine in treating cardiovascular diseases (Fig.
3). By
improving the delivery and action of therapeutic agents, nanomedicine holds significant promise for advancing cardiovascular
41].
care [
Polymers have been utilized and advanced for application in nanoformulations, which primarily consist of nanoparticles typically
measuring less than 300 nanometers in diameter. One notable
example is poly(lactic-co-glycolic acid) (PLGA), a polymer derived
from the combination of polylactic acid (PLA), and polyglycolic
acid (PGA). PLGA is recognized as an FDA-approved biomaterial
13]. PLGA nanoparticles loaded with pitavastatin can effectively
[
prevent the rupture of atherosclerotic plaques by modulating the
recruitment of monocytes to these vascular lesions. Additionally,
PLGA nanoparticles have been utilized for delivering the antidiabetic drug pioglitazone, which acts as an agonist for peroxisome
proliferator-activated receptor-γ (PPARγ). Research has