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Drug Delivery to the Cardiovascular System: Application and Future Prospects 349
Fig. 3 Application of nanomedicine in the treatment of cardiovascular diseases
demonstrated that nanoparticles encapsulating the thiazolidinedione (TZD) pioglitazone can inhibit macrophage activation in
hyperlipidemic mice, thereby helping to prevent the formation of
atherosclerotic plaques in these animals [
PLGA nanoparticles encapsulating the statin pitavastatin have
demonstrated the ability to deliver the drug to the vascular endothelium, promoting effective therapeutic neovascularization. Further investigations into the use of these pitavastatin-loaded PLGA
nanoparticles focused on their potential to deliver compounds to
the heart following a myocardial infarction, aiming to prevent
ischemic tissue damage in patients. These nanoparticles successfully
mitigated ischemic-reperfusion (I/R) injury in the heart by activating the AKT/PI3K kinase signaling pathway. Additionally, they
were found to reduce inflammation, which is responsible for the
secondary tissue damage often observed after a myocardial infarc-
43]. These pitavastatin nanoparticles have the potential to be
tion [
beneficial in treating organ ischemia across various disease states,
serving as an exemplary case of cardiovascular drug delivery
through nanoformulations [
44].
Various metal nanoparticles-based treatments are also found to
be beneficial against cardiovascular ailments, as depicted in Table
42].
1.
5.6 Liposomal Delivery Systems
Liposomes are vesicle-based systems frequently utilized in drug
delivery. They are formed when lipids and surfactants are suspended
in an aqueous environment, leading to the self-assembly of spherical liposomes. The lipophilic core of these liposomes naturally
accommodates compounds, such as drugs, that have a similar lipophilic nature. One of the primary reasons for formulating small
350 Pankaj Kumar Umar et al.
Table 1
Application of nanoparticles in cardiovascular therapy
Serial
no.
1 Gold nanoparticles CV disease therapy
2 Silver nanoparticles Anticoagulation agent for thrombotic and CV disease
3 Copper nanoparticles Cardioprotection in ischemic reperfusion-induced
4 Platinum nanoparticles Mimic catechol oxidase for CV disease prevention
Metal nanomedicines Applications in cardiovascular system
treatment
myocardial infarction
5 Hamelia patens leaf extract gold
nanoparticles
molecules into liposomes has been to enhance their oral bioavailability. In a study by Patel et al. [
sive agents targeting the angiotensin II receptor—specifically
telmisartan and irbesartan—was improved. Both drugs are poorly
soluble in water, but by using castor oil alongside surfactants like
Tween 20 and Carbitol as co-solvents, a self-emulsifying drug
delivery system (SEDDS) was created, which increased the oral
absorption of these compounds by more than 7.5 times [
5.7 Delivery of Biologicals
Historically, treatments for cardiovascular diseases primarily relied
on small organic molecules. However, several challenges are associated with using these drugs, including the chemical properties of
the compounds, which may hinder adequate distribution, as well as
the pathological conditions of the affected tissues. Currently, there
is a significant shift in the therapeutic landscape for cardiovascular
diseases, expanding the range of treatments to include biological
agents such as antibodies, proteins, peptides, siRNA, and DNA.
5.8 RNA-Based Delivery
Silencing RNA (siRNA) has been effectively delivered to animals
through nanoformulations, offering the potential for precision
medicine. In a study by Leuschner et al. [47], siRNA was
encapsulated in liposomes composed of cholesterol, C12–200
lipid, distearoylphosphatidylcholine, and PEG-DMG, resulting in
spontaneously formed micellar liposomes. These siRNA liposomes
successfully knocked down the expression of CCR2 in monocytes
of atherosclerosis-prone animals [
emerged as a promising means for delivering therapeutic siRNA.
They play a significant role in cellular communication, allowing
cells to transfer various cytosolic components, including RNA and
microRNA, to one another. Exosomes derived from humaninduced pluripotent stem cells (iPSCs) have been shown to deliver
siRNA to pulmonary microvascular endothelial cells, effectively
reducing inflammation [
Pro-angiogenic
application
47].
properties for CV
wound healing
45], the delivery of antihyperten-
46].
Additionally, exosomes have
48].
Drug Delivery to the Cardiovascular System: Application and Future Prospects 351
5.9 Therapeutic Proteins and Peptides
Therapeutic peptides have emerged as significant strategies for
treating cardiovascular diseases. However, their delivery poses challenges due to susceptibility to enzyme degradation in the bloodstream, reduced permeability through vascular endothelial cells,
and limited tissue distribution [
enhance their circulation time in the blood is to attach polyethylene
glycol (PEG) linkers to the peptides [50]. Another strategy involves
creating a cyclic version of the linear peptide, which is less vulnerable to metabolic degradation in circulation. For instance, the peptide HYD1 was cyclized to produce MTI-101, which demonstrated
improved efficacy in animal models. Additionally, peptides can serve
as targeting agents to direct nanoparticles to specific tissues or
organs [
51].
6 Future Perspectives and Challenges
Given the increasing number of patients affected by cardiovascular
disease (CVD), there is an urgent need for novel drug delivery
systems and targeted strategies for therapeutic agents. Innovative
experimental methods have been reported, such as the targeted
delivery of small molecule drugs, biologics, RNA-based therapeutics, and stem cells, all of which have shown promising results in
preclinical studies. However, these scientific advancements and
technological innovations have yet to be fully integrated into clinical practice. It is becoming increasingly evident that additional
efforts, commitment, and investment are required to accelerate
the testing, translation, and commercialization of these new and
effective cardiovascular therapies. Ongoing initiatives to tackle the
challenges in this field, particularly those highlighted by the Specialty Section on Cardiovascular Drug Delivery, are essential for
translating new therapeutics and reducing the global impact of
cardiovascular diseases [
Despite significant
responsive drug deliver y systems (DDSs), a critical challenge
remains: the efficiency of gene transfection and cell engraftment is
often inadequate, failing to produce meaningful biomedical effects
for clinical therapy in cardiovascular disease (CVD). The primary
objective of DDSs should be to create clinically viable for mulations
for patients. Although sonothrombolysis has shown promise in
early clinical trials, many investigations into gene or cell therapy
remain in the preclinical phase due to structural and physiological
differences, as well as maximum dose limitations between animal
models and humans. These factors present substantial obstacles for
clinical application. To enhance clinical viability, gene or cell therapy should be used alongside existing pharmacological or interventional treatments as complementary therapies. Furthermore, past
studi
have often overlooked secondary endpoints, such as
es
49]. One traditional method to
52]
.
advancements in external stimulus-
352 Pankaj Kumar Umar et al.
microvascular perfusion, collateral blood flow, and metabolic rates,
which are critically influenced by the integrity of endothelial walls
and require validated measurements of novel parameters.
Additionally, while many previous studies have conducted thorough safety assessments of drug delivery systems (DDSs), there is
still a limited understanding of how nanostructures interact with
different biological systems in vivo, as well as the mechanisms
underlying their potential toxicity. Issues related to nanotoxicity,
such as cytotoxicity and carcinogenicity, are believed to arise from
the physicochemical properties of magnetic nanoparticles (MNPs),
including their size, shape, composition, and surface coatings
[
53]. Recently, researchers introduced the concept of the protein
corona phenomenon, which describes how magnetic nanoparticles
(MNPs) become coated with various serum proteins through different adsorption mechanisms. This structure is believed to significantly impact the pharmacodynamics and pharmacokinetics of the
nanoparticles, presenting a promising area for the design of new
drug delivery systems (DDSs) [
candidates like circRNAs and exosomes are expected to benefit
from the advancement of innovative drug delivery systems
(DDSs), enabling the translation of drugs with short half-lives
and low water solubility into preclinical applications [
Further research is essential to enhance the design of delivery
vehicles and the parameters for external stimuli to ensure effective
drug delivery while minimizing adverse effects. Given that dual
stimulus-responsive delivery systems have demonstrated significant
utility, fostering collaboration among various drug delivery strategies will be crucial for developing more innovative approaches.
Additionally, it is important to showcase the cost-effectiveness
and practicality of these techniques to achieve broader acceptance
among cardiologists in clinical settings. Overall, external stimulusresponsive drug delivery systems hold great promise for advancing
the treatment of cardiovascular diseases in the near future.
Continued efforts are needed to create optimal delivery systems
that facilitate greater drug accumulation and uptake at target sites,
while also effectively reducing toxicity.
54]. In the future, emerging drug
55].
7 Conclusion
Cardiovascular diseases (CVDs) pose a significant threat to human
health and well-being. Despite the availability of various drugs on
the market that operate through different mechanisms, conventional formulations for treating CVDs often fall short of expectations. This is primarily due to challenges such as poor water
solubility, low biological efficacy, lack of targeting, and the emergence of drug resistance. Effective therapeutic delivery to the cardiovas
system is crucial for successfully managing a range of
cular
Drug Delivery to the Cardiovascular System: Application and Future Prospects 353
conditions, including atherosclerosis, ischemic-reperfusion injury,
and other microvascular disorders like hypertension. To address
these challenges, several innovative technologies have been developed for both targeted and sustained delivery of new therapeutic
agents, encompassing both chemical compounds and biological
therapies. The field of specifically targeted drug delivery to the
cardiovascular system holds significant promise, offering several
a
dvantages that could enhance treatment efficacy. In this review,
we explore various options for creating effective delivery systems,
including nanoparticles, peptides, and small interfering RNA
(siRNA), that can be directed toward the
cardiovascular system.
The development of effective formulations utilizing nanotechnology has the potential to surmount physiological barriers and significantly improve therapeutic outcomes for patients. However, this
are
a is still in its early stages compared to more established fields
such as cancer or brain drug delivery. These novel delivery methods
open up a multitude of opportunities for achieving the necessar
tissue specificity and minimizing systemic exposure, paving the way
for the use of new pharmacological agents that could lead to better
patient outcomes in the future.
y
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Chapter 16
Drug Delivery to the Musculoskeletal System: Localized
Therapies and Repair
Khumtya Debbarma, Dilip K. Deka, Jadav Sarma, and Arjun Kafle
Abstract
The quality of life for patients and those caregivers can be greatly reduced by muscle disorders that results in
a loss of function and mobility. For abnormalities and disorders of the muscles, there are limited therapy
choices. One of the barriers to the creation of novel treatment approaches is the “blood-muscle barrier,”
which refers to the slow rate at which drugs diffuse from blood vessels to muscle. Consequently, the efficient
therapy of muscle disorders depends on drug delivery methods and techniques that specifically target
muscles. Musculo-targeted drugs and their delivery strategies to the musculoskeletal system are comprehensively covered in this chapter. Basic information regarding the morphology and molecular biology of
muscle is also described to improve our comprehension of the existing musculoskeletal targeted drug
delivery systems.
Key words Blood-muscle barrier, Musculoskeletal system, Musculo-targeted drugs, Delivery strategies, Drug delivery systems, Therapy
1 Introduction
Skeletal muscle is one of the most prevalent tissues in the human
body. It makes up about 40–50% of the body’s total mass and is
required to produce movement-inducing forces [21]. The body
depends on the musculoskeletal system for support, stability, and
mobility, and musculoskeletal disorders can have a major negative
impact on public health and the global economy [
movement or musculoskeletal functions of the human body can be
impacted by musculoskeletal disorders, which typically entail a
variety of aberrant physiologies in the muscles, joints, and bones
(e.g., Sarcopenia, Osteoporosis, trauma) [
41]. Owing in part to the aging of the world’s population, the
World Health Organization has projected a sharply rising burden of
musculoskeletal disorders [5, 10]. Many treatments, including systemic medication treatment and surgery, have been developed to
12, 39, 44]. The
17, 18, 22, 29, 30,
357
358 Khumtya Debbarma et al.
prevent and treat musculoskeletal disorders. In addition to systemic
drug delivery, local drug delivery has gained a lot of interest in the
treatment of musculoskeletal disorders. This is primarily because
local drug delivery has the potential to reduce toxicity or unwanted
side effects while delivering therapeutic agents to the desired site of
action and maintaining an optimal drug level for predetermined
amounts of time [
This chapter provides in-depth information, step-by-step
instructions for the use of localized therapies and repair for musculoskeletal disorders by targeting injured tissues, in order to demonstrate the application of local drug delivery. Additionally, local drug
administration can minimize systemic toxicity and unwanted side
effects while precisely controlling and maintaining high drug concentrations at the intended area.
2 Materials
15, 24, 28, 34, 40,
44, 48].
2.1 Equipment
The experimental apparatus is described in detail; however, any
model with a similar capacity can be used interchangeably.
1. 3D bioprinter (envisionTEC): A 3D PCL (polycaprolactone)
scaffold grafted with bone morphogenetic protein-2 (BMP-2)
attached via polydopamine chemistry.
2. Capsule-integrated polypeptide multilayer films were prepared
using a dipping machine (Riegler and Kirstein GmbH, Berlin,
Germany)—these films were capable of loading multiple oppositely charged drugs.
3. Confocal laser scanning microscopy (CLSM) (Nikon Ti-E,
Tokyo, Japan), equipped with LU4 four-laser module with
AOTF, a plan Fluor 40x DICM N2 objective, and a DS-F1
camera.
4. Bilayered microparticle-mesh scaffold (BMMS) was developed
using an electrospinning technique.
5. Scanning electron microscopy (SEM) produces image of a
sample by scanning the surface of a focused beam of electrons.
6. Transmission electron microscopy (TEM) is an analytical technique used to visualize the smallest structures in matter (ultrastructural characteristics).
7. Polyethylene glycol-modified
single-walled
carbon nanotubes
(PEG-SWCNTS) are hollow graphitic cylinders that have
recently been explored as unique nanoscale particles with
potential pharmaceutical applications such as gene transfection.
8. Electrosprayed microcapsules
(CHEERSONIC)—electrody-
namic spraying is capable of creating living cell factories.