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Introduction to Drug Delivery System: Past, Present, and Future Perspectives 19
noted the spontaneous formation of circular structures resembling
bags. Gerald Weissman, a colleague of Bangham, coined the term
“liposomes” to describe these structures. This discovery proved to
be highly versatile and found applications in various fields including
biology, biochemistry, and medicine. Liposomes became popular in
vesicular research due to their biocompatibility and structural similarities to biological cells [
within liposomes and the size of the liposomes are
10
]. The quantity of drug encapsulated
critical factors
influencing the pharmacokinetic and pharmacodynamic properties
of the drug. Liposomes typically range in size with an average
diameter of around 100 nm. Because of their size and the combination of hydrophobic and hydrophilic characteristics, liposomes
represent promising platforms for drug delivery. Liposomes have
demonstrated significant commercial signifi
cance, starting from the
earliest product, “Doxil,” which was a PEGylated doxorubicin
liposomal
formulation, to the most recent product, “Marqibo,”
which is a vincristine sulfate liposomal formulation. The properties
of liposomes vary greatly depending on factors such as lipid composition, surface charge, size, and preparation method. The composition of the phospholipid bilayer dictates the rigidity or fluidity
of the vesicles, as well as their charge [
through various methods, involving the entrapment of drugs
8]. Liposomes are created
via
either passive or active loading techniques. In the passive loading
technique, drug molecules are loaded or encapsulated either before
or during the formation of liposomes. During the preparation of
liposomes, when the lipid film is dissolved in a buffer containing the
drug, hydrophilic or water-soluble drugs are loaded into the center
of the liposome vesicle. Lipophilic drugs, on
added to the lipid phase of the liposome components,
the other hand, are
allowing
them to be loaded in between the lipid bilayers. Any unentrapped
drug is typically removed using gel-filtration chromatography or
dialysis for liposomal dispersion. Passive loading encompasses four
distinct methods, which are:
1. Mechanical Dispersion: Involves physical techniques to disperse the drug within the liposome matrix.
2. Solvent Dispersion Method: Involves replacing organic solvents with an aqueous phase to entrap the drug within
liposomes.
3. Size Change or Combination Vesicle Method: This involves
altering the size of vesicles or combining them to encapsulate
the drug.
4. Detergent R
emoval M
ethods: Involves removing detergents
used in liposome preparation to encapsulate the drug.
The remote
or active loading method involves loading compounds with both aqueous and lipid solubility, along with ionizable
groups, after the formation of vesicles. This technique allows for
20 Santanu Pal et al.
10 Dendrimers
the loading of dr ug molecules post-formation. Several methods
exist for preparing liposomes using this active loading approach.
Doxil™ is an example of a liposomal product prepared using this
method. Extended treatment with anticancer medications often
results in numerous toxic effects. However, using liposomal formulations specifically targeted at tumor cells has shown reduced
side effects. Studies have demonstrated that liposomes can effectively target tu
durations due to enhanced vascular
PEGylated liposomal formulation of doxorubicin designed for
intravenous administration using stealth technology, received
approval for the treatment of hematological tumors. Additionally,
Caelyx and Myocet are other liposomal preparations of doxorubicin
utilized for advanced breast cancer treatment.
Dendrimers are intricate molecular structures composed of a central core surrounded by well-defined branches, formed through a
series of methodical reactions. Each successive reaction iteration
results in a dendrimer of higher generation, corresponding to its
layer count [
mers have epitomized controlled hierarchical synthesis, enabling
the creation of intricate systems. Notably, dendrimer synthesis
allows precise control over size, composition, and chemical reactivity, akin to a finely tuned machine.
Almost any polymer can ser ve as the basis for dendrimer synthesis. The first extensively characterized dendrimer structure was
polyamidoamine dendrimers (PAMAM dendrimers) [
structed through a repetitive sequence of steps (Table
ers have successfully obtained PAMAM dendrimers up to
generation 10. Over the past decade, numerous novel dendrimer
variants have emerged and undergone exploration, demonstrating
promising applicability in various fields.
mor cells and circulate in the bloodstream for longer
permeability. In 1995, Doxil, a
11]. Since their inception in the early 1980s, dendri-
12], con-
4). Research-
11 PEGylated Drug Delivery System
PEG (polyethylene glycol) is widely regarded as the preferred polymer for drug conjugation due to its exceptional properties. Nevertheless, a significant drawback of PEG lies in its limited
biodegradability. Therefore, there is considerable interest in modifying the structure of PEG to enable its fragmentation, addressing
this issue (Table
like paclitaxel or proteins serve to improve water solubility. Among
these carriers, PEG is frequently employed due to its ability to
extend the drug’s plasma half-life, thereby averting interactions
5). Hydrophilic polymers linked to small molecules
Introduction to Drug Delivery System: Past, Present, and Future Perspectives 21
Table 4
The structural elements of dendrimers [
Sl.
Structural
No.
components
1. Focal point (core) The center of the dendrimer can be a small molecule, nanoparticle, or
2. Free (void) spaces These are empty spaces between the core and interior branchings to be used as
3. Interior branching Multibranched globular units with internal functional groups have a covalent
4. Exterior groups These are the outer hydrophilic or hydrophobic surface groups that construct
Description/function
polymeric material
a room for drug encapsulation or carrying
framework connecting the dendrimer core with the outer-surface groups
the cover of the dendrimer–drug complex
17]
5. Dendrimer–
linkage
dru
g
Covalent or
noncovalent bond between the dendrimer and the drug.
with plasma proteins and masking the molecule. PEG-based drug
delivery systems are widely regarded as the benchmark in the pharmaceutical sector for addressing various diseases including cancer,
hemophilia, pain, and diabetes. Among these clinical applications,
the creation and advancement of PEGylated nanocarriers for containing anticancer agents hold significant importance. Recent
advancements in nanosystems designed for tumor treatment
exhibit limite
therapeutic efficacy [
d accumulation at the target site and inadequate
13]. Present methods for attaching PEG mole-
cules to conjugates typically involve the PEGylation process. This
process primarily for
other molecules
ms a connection between proteins, peptides, or
and a carrier through covalent bonding. In 1990,
Adagen (ADA) became the first therapeutic protein PEGylated in
this manner. Adagen is utilized in the treatment of various immune
disorders stemming from a congenital deficiency of the enzyme
adenosine deaminase [
9
]. There are currently three generations of
PEGylation methods. The first generation relies on glycosylation
reactions. However, this process lacks control, which can lead to
multisite PEGylation
due to the interaction between the hydroxyl
group of PEG and the carboxyl group of the amino acid. The
second generation of PEGylation introduces a diverse array of
potential conjugates, ranging from gene technology applications
to modification with thioacid or employing ch
emical ligation strategies. Additionally, it includes N-terminal protein modification
through biomimetic transamination reactions. These methods
offer advantageous characteristics such as
high molecular weight,
activated molecules, and branched PEG structures. However, they
often result in reduced biological activity. Consequently, efforts are
underway to develop the third generation of PEGylation methods,
which seek to preserve bioactivity while reta
ining the benefits of the
22 Santanu Pal et al.
Table 5
Classification of various polymeric excipients along with their benefits and drawbacks in the context
of PEGylation
Sl.
Conjugate Advantages Disadvantages Ref.
No.
1. Dendrimers Good water solubility, improved plasma
half-life, and changed biological
distribution
2. Nanoliposomes Immunogenicity and antigenicity
reduction, prolonged half-life
3. Nanomicelles Biocompatible, biodegradable, low
toxicity, high half-life, and good
penetration properties
4. Nanoparticles Good biodistribution, extended
capacity
5. Polymer-
protein
6. Polymer-small
molecule
drug
circulation, and drug load
No recognition by the immune system,
and increased half-life
Excretion of PEG through the kidney
due to lower molecular mass, no drug
degradation, enhanced permeability,
and intracellular uptake
previous generations. There exists various methods for releasing
pharmaceutical agents, including enzymatic cleavage, pH gradient
modulation, temperature-triggered hydrolysis, surface modification activation, swelling mechanisms, and controlling the half-life
of the specific bond between the polymer and the drug. Since the
discovery of PEGylated technology in the 1990s, advancements
have occurred in several areas: transitioning from random to sitespeci
fic PEGylation (Phase I), from linear to multibranched PEGs
(Phase II), and from low to high molecular weights (Phase III).
Furthermore, PEGylation is now utilized in a broader spectrum of
therapies, leading to expanded clinical pipelines for numerous biotechnological firms. With PEG-based conjugates already
lished in medicinal treatments, the focus of PEGylation processes
is shifting toward achieving lower doses and longer-lasting therapeutic effects.
Large hydrodynamic radius,
leading to low renal clearance.
Steric hindrance of PEG chains
inhibits cellular uptake and
accelerates blood clearance
Low encapsulation efficacy [16]
High sudden release
PEG is not degradable, causing
accumulation of the carrier
The structure of small molecules
influences the self-assembly of
the polymer
of the drug
[16]
[16]
[16]
[16]
[16]
estab-
12 Antibody-Drug Conjugate System
Antibody-drug conjugates (ADCs) represent a swiftly developing
category of treatments, merging the targeted specificity of a monoclonal antibody (mAb) with the cytotoxic potency of cellular
Introduction to Drug Delivery System: Past, Present, and Future Perspectives 23
poisons. As drug engineering progresses and new biological understandings of drug mechanisms emerge, the field of ADCs is still in
its early stages of evolution. More than a century ago, the concept
of targeted chemotherapy was proposed by German scientist Paul
Ehrlich. He envisioned a “magic bullet” that could deliver cytotoxins specifically to targeted structures within diseased cells while
sparing healthy tissues [
14]. The essential elements of an ADC
include a monoclonal antibody (mAb) targeting a tumor-associated
antigen, a cytotoxic payload, and a connecting linker. Each of these
components and their interactions are pivotal in determining the
effectiveness and potential toxicity of an ADC [
10]. T
he antibody
component of an ADC influences its duration in plasma circulation,
potential for immunogenic responses, immune-related functions,
and specificity to the target. Presently, ADCs primarily utilize
immunoglobulin G (IgG) as the antibody format, with IgG1
being the most commonly employed. IgG1 provides an extended
serum half-life and robust Fc-mediated immune functions, which
encompass antibody-dependent cell-mediated cytotoxicity
(ADCC), antibo
dy-dependent c
ellular phagocytosis, and
complement-dependent cytotoxicity. HER2 and trophoblast cell
surface antigen 2 (TROP2) are being targeted for ADC development in breast cancer (BC) because they are highly expressed on the
surfaces of tumor cells while showing limited expression in normal
tissues [
10]. P
ayloads are the chemotherapeutic agents responsible
for exerting cytotoxic effects on the tumor cells targeted by ADCs.
Typically, these agents function by binding to microtubules or
inducing DNA damage, which can involve DNA cleavage or alkylation. With advancements in linker conjugation chemistry and a
better understanding of the in vivo mechanism of ADCs, there is
now a wider range of anticancer agents being incorporated into
newer ADC designs. The main mecha
nism o
f action for ADCs
involves targeting the cytotoxic payload specifically to tumor cells.
Upon binding of the monoclonal antibody (mAb) to the target
antigen, the ADC is internalized within the tumor cell. The
subsequent breakdown of the linker leads to the release of the
payload inside the cell, where it can then exert its cytotoxic effects,
such as damaging microtubules or DNA. The process of antibody
binding and internalization may be further manipulated or
enhance
hrough pharmacological interventions. Besides the con-
d t
ventional mechanism of payload release and action, the antibody
component of ADCs can also exhibit anticancer effects independently of the payload. By binding to the target antigen, the antibody can disrupt the antigen’s downstream functions by inhibiting
its interaction with binding partners or promoting its degradation.
Moreover, ADCs can exert antitumor effects through the activation
of immune resp
onses, s
cytotoxicity (ADCC), as seen with trastuzumab [
uch as antibody-dependent cell-mediated
10]
. The intro-
duction of ADCs for treating metastatic cancers in the last decade
24 Santanu Pal et al.
has notably enhanced outcomes across various solid tumors. However, patients undergoing these therapies eventually encounter disease progression, often due to resistance. Given that ADCs
represent a relatively recent addition to oncology treatments, the
mechanisms underlying resistance are not yet fully understood.
Resistance may arise from various factors related to the components
of ADCs, such as modifications in target cell surface expression or
gene muta
counteract payload toxicity,
nalization rates of the ADC, or simply resistance to the payload
itself.
tions, increased expression of drug efflux transporters to
13 Mesoporous Silica-Based Drug Delivery
Kresge et al. have demonstrated a method that combines sol-gel
chemistry with liquid crystal templating to create ordered porous
molecular sieves characterized by regularly spaced mesopores
(ranging from 2 nm to 50 nm) embedded within a silica matrix.
Mesoporous silica nanoparticles (MSNs) have emerged as a
promising and innovative drug delivery vehicle due to their distinctive mesoporous structure, which preserves a degree of chemical
stability, surface functionality, and biocompatibility. This structure
ensures controlled and targeted delivery of various active pharmaceutical ingredients (APIs) [
covered by the Mobile Oil Corporation in 1992, have garnered
significant attention due to their outstanding properties, including
high surface area, large pore volume, tunable pore diameter, and
adjustable pore size distribution. The low toxicity and high drugloading capacity of mesoporous silica nanoparticles make them
particularly advantageous for controlled and targeted drug delivery
applications. Mesoporous silica exhibits unique properties, particularly in its ability to load high amounts of drug nanoparticles and
facilitate subsequent delivery. Due to the strong Si-O bond, silicabased mesoporous nanoparticles are more resistant to external
reactions such as degradation and mechanical stress compared to
niosomes, liposomes, and dendrimers. This characteristic reduces
the necessity for external modifications during the synthesis
of MSNs.
alterations in the trafficking and inter-
15]. Mesoporous silica materials, dis-
14 Transdermal Drug Delivery System
Transdermal drug delivery (TDD) is a noninvasive systemic delivery approach where drugs are applied to healthy and intact skin.
The dr ug initially permeates through the stratum corneum, followed by passage through the deeper epidermis and dermis without
significant accumulation in the dermal layer. Once the drug reaches
Introduction to Drug Delivery System: Past, Present, and Future Perspectives 25
the dermal layer, it becomes accessible for systemic absorption
through dermal microcirculation. Over time, first-generation transdermal delivery systems have advanced and become established in
clinical practice. They are typically utilized for administering small,
lipophilic, and low-dose drugs. Second-generation delivery systems, employing different designs incorporating chemical enhancers, non-cavitational ultrasound, and iontophoresis, have
also
resulted in clinical products. Third-generation delivery systems
focus on targeting
the stratum corneum using methods such as
microneedles, thermal ablation, microdermabrasion, electroporation, and cavitational ultrasound. Presently, transdermal drug delivery systems utilizing microneedle and thermal ablation technology
have been developed and are progressing through clinical trials for
the delivery of macromolecules, such as insulin and parath
hormone. A transdermal drug delivery system
(TDDS) typically
yroid
consists of essential components such as a polymer matrix, membrane, drug, penetration enhancers, pressure-sensitive adhesives
(PSA), backing laminates, and release coatings. Types of TDDS
are as follows
1. Single-layer (unilayer): Fabricated with three layers, including a
temporary liner at the bottom, an adhesive in the middle, and a
backing on top, this design is referred to as a single-layer
system. In this setup, the adhesive layer serves a dual purpose:
providing adhesion to the skin and serving as a container for
the active molecule.
2. Multilayer: Similar to the single-layer design, this system features an adhesive layer that doubles as the drug-containing
layer. However, it differs by incorporating an additional layer
of drug adhesive, typically separated by a membrane. Additionally, it includes a temporary liner and a permanent backing.
3. Reservoir: In contrast to both the unilayer and multilayer
designs, this system incorporates a distinct drug layer. This
layer comprises a liquid compartment containing the drug in
either solution or suspension, separated by an adhesive layer.
Additionally, the patch includes a backing and a temporary
liner. The release kinetics of this system follow a zero-order
pattern.
4. Matrix: This system features a drug layer consisting of a semisolid matrix containing a solution or suspension of the drug.
The adhesive layer partially surrounds the drug layer, effectively
enveloping it.
5. Vapor:
The adhesive layer of the patch is infused with oils or
another solution that vaporizes for release. Some patches
release essential oils for over 6 hours, useful for decongestion
purposes, while others aim to enhance sleep quality.
26 Santanu Pal et al.
15 Hydrogel-Mediated Ocular Drug Delivery
Hydrogels consist of a mesh-like structure of water-loving polymer
chains that can hold a significant amount of water. When applied,
these gels start as a liquid but turn into a gel once they come into
contact with the eye. The three main types of responsive materials
commonly used to create gel systems for administering eye medications are those sensitive to heat, pH, and ions. Recent advancements in hydrogel technology present promising prospects for
delivering drugs to treat eye conditions effectively [
advancements in hydrogel technology present promising prospects
for treating ocular diseases through improved delivery of ophthalmic drugs. Hydrogels can enhance drug efficacy by (1) extending
drug retention duration at the delivery site, (2) maintaining sustained drug release at the desired location, and (3) facilitating the
simultaneous delivery of multiple drugs to their respective functions. Fang et al. created a polypseudorotaxane hydrogel to address
anterior uveitis. This was achieved by blending Soluplus micelles
(with a size of 99.4 nm) with cyclodextrin solutions [
et al. devised an in situ hydrogel composed of Bevacizumab (Bev)
and hyaluronic acid cross-linked with poly(ethylene glycol) diacrylate. This hydrogel was slowly released after Bev injection into the
suprachoroidal space of the eye using microneedles (MNs). The
Bev-hyaluronic acid hydrogel formed in situ was well tolerated and
exhibited sustained Bev release for more than 6 months in rabbit
eyes, suggesting its potential for treating posterior ocular diseases
in upcoming applications [
injectable antibody-loaded supramolecular nanofiber hydrogel by
blending betamethasone phosphate with CaCl2. This hydrogel,
based on betamethasone phosphate, can release anti-VEGF agents,
which can effectively inhibit retinal vascular proliferation, diminish
choroidal neovascularization (CNV) over an extended period, and
mitigate reactive oxygen species (ROS) to alleviate local
inflammation [
11].
16]. Recent
11]. Jung
11]. Gao et al. recently created an
16 Challenges with Current Drug Delivery Systems
Recent advancements have shown the successful utilization of various delivery systems aimed at transporting drugs from diverse plant
sources to their intended sites within the body for treatment.
Despite significant progress, these systems still encounter numerous limitations and challenges in achieving their therapeutic objectives. The scarcity and inconsistency of information, which is crucial
for guiding industries, may hinder the future advancements of
nanomedicines and prolong the transition from research and experimentation to clinical application [
2].
Numerous researchers
Introduction to Drug Delivery System: Past, Present, and Future Perspectives 27
acknowledge the dual nature of nanoparticles—they can have positive or negative impacts. While the advantages of nanoparticles are
well established and acknowledged, there is a lack of comprehensive
information regarding their safety, their interactions with
non-specific proteins, and their behavior and interaction with
organs other than their intended targets [
tems employ
as limited absorption and solubility, instability in vivo, low bioavailability, difficulties in achieving target-specific delivery, and various
adverse side effects upon administration. Utilizing significantly
smaller particles for delivery into the human biological system
offers a solution to these challenges associated with larger particles.
Achieving target-spec
systems. While
tial to reduce toxicity and enhance treatment effectiveness, its
efficacy relies on ensuring sufficient amounts of the therapeutic
reach the intended site. This challenge is evident when administering siRNA systemically, as they often fail to reach their target cell or
organ due to degradation by bodily enzymes. Additionally, administering siRNA in l
negative charge
no uptake by the body [
liposomes, categorized
delivery. However, their effectiveness may be compromised due to
interactions with the body. These interactions, such as phagocytic
absorption and hepatic filtration, have the potential to impede
target delivery and may also result in toxicity associated with the
nanoparticles. The kidney and liver possess inherent mechanisms
for detoxifying the body, whic
potential waste.
causing obstruction and potentially resulting in the buildup of
nanoparticles within these organs.
large particles as carriers, which pose challenges such
ific delivery poses a challenge for all delivery
target-specific delivery has demonstrated the poten-
arge quantities presents another hurdle, as their
impedes absorption by cells, leading to minimal or
2]. Research is investigating micelles and
as lipid nanoparticles, for targeted drug
h may perceive nanoparticles as
This natural function can hinder drug delivery by
2
]. Certain delivery sys-
17 Future Direction and Conclusion
Although challenges have impeded the clinical implementation of
these delivery systems, the latest advancements in drug delivery
show significant promise. Realizing this potential would necessitate
collaboration spanning academic theory, laboratory research, medical knowledge, pharmaceutical expertise, and extensive research
efforts to effectively transition findings from experimental stages
to practical clinical applications. According to Vargason et al., the
integration of cell therapies holds the potential to address
bio-acceptability challenges encountered by drug deliver y systems.
They refer that cell therapies could offer a solution by providing a
single effective dose, thus mitigating the issue of excessive drug
accumulation within the body. Furthermore, cell therapies offer the
28 Santanu Pal et al.
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