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Polymer-Based Drug Delivery Systems: Design and Characterization 119
(f) Dynamic light scattering (DLS) is another technique for the
determination of CMC. The scattered light in the DLS
method is based on the molecular weight of the particles in
micellar solutions.
Morphological Characterization
Physicochemical Characterization
4.3 Liposomes
Various microscopic techniques can be used for the morphological
characterization of PMs. There are various microscopic imaging
techniques for micelle characterization. AFM is a high-resolution
microscopical technique that is useful for the analysis of the morphology and size of the micelles. It can also be used for the evaluation of redox or temperature-related morphological changes. CryoTEM is another powerful tool used to deter mine the morphology
of micelles. Compared to normal TEM, cryo-TEM allows the
evaluation of micelles in their solution state. As the liquid background is important for micelles, cryo-TEM is preferred for micelle
characterization [
logical characters [
60]. SEM is also used for the analysis of morpho-
61].
Structural aspects of the synthesized copolymer can be analyzed by
employing Fourier transform infrared spectroscopy (FTIR) and
nuclear magnetic resonance spectroscopy (NMR) [
62, 63]. Small-
angle neutron scattering (SANS) and small-angle X-ray scattering
(SAXS) are two powerful tools used for the structural analysis of
micelles.
Liposomes are spherical vesicles composed of phospholipids and
cholesterol, arranged in a bilayer structure. They are also amphiphilic in nature, with an aqueous core surrounded by a lipid bilayer.
Liposomes have an internal aqueous core suitable for encapsulating
hydrophilic drugs. This core provides protection to the
encapsulated drug and facilitates its delivery to target tissues. The
phospholipid bilayer of liposomes encapsulates hydrophobic drugs,
shielding them from the external environment and allowing controlled release over time. Surface modifications of liposomes, such
as attaching dextran or PEG to the phospholipid bilayer, can
enhance their circulation time in the blood stream and can also
enhance the stability and pharmacokinetics of liposomal formulations. This modification helps evade detection by the immune
system and prolongs the therapeutic effect of the encapsulated
drugs (Fig.
3).
Liposomal formulations can be classified into two categories:
(i) Rigid vesicles liposomes—conventional liposomes and
niosomes
(ii) Elastic or
somes [
ultra-deformable vesicles—transferosomes and etho-
64]
120 Afroz Jahan et al.
Fig. 3 Schematic representation of different types of liposomes
4.3.1 Ethosome Ethosomes are novel lipid-based nano-carriers used in drug deliv-
ery systems. They are similar to liposomes but are specifically
designed to improve the delivery of active pharmaceutical ingredients (APIs), especially those with poor skin penetration due to their
higher lipid content and ethanol presence.
The p
roduction o
f the ethosomal vesicles can be evaluated
using photomicrographs, transmission electron microscopy
(TEM), and scanning electron microscopy (SEM) micrographs
65]. The formulation’s zeta potential can be determined using a
[
zeta meter [
depending on the ethanol and phospholipid concentrations [
66]. The reduction in mean vesicle diameter can vary
67–
69]. The transition temperature of the vesicular lipid systems can be
measured using differential scanning calorimetry, a method that can
be used to detect ethanol-skin phospholipid interaction, a property
connected to the fluidizing impact of ethanol on the phospholipid
bilayers [
70]
.
The ultracentrifugation
method can be used to determine the
ethosomes’ degree of entrapment. The high level of lamellarity and
the presence of ethanol in the vesicles can be used to explain why
ethosomes can effectively entrap hydrophilic and lipophilic
medicines.
Polymer-Based Drug Delivery Systems: Design and Characterization 121
4.3.2 Transferosome
A transferosome is a type of vesicular delivery system used in
transdermal drug delivery, which consists of phosphatidylcholine
and an edge activator. It is a flexible, ultra-deformable liposome
capable of passing through the tiny pores of the skin to deliver
drugs directly into the bloodstream or target tissues.
Visualization of transferosomes can be performed using transmission electron microscopy (TEM) and scanning electron microscopy (SEM) [
71]. Particle size and size distribution can be
determined by dynamic light scattering (DLS) and photon correlation spectroscopy (PCS) [71, 72]. The drug entrapment efficiency
by transferosomes can be measured by the ultracentrifugation technique. Vesicle stability can be determined by assessing the size and
structure of the vesicles over time, and drug content can be quantified by high performance liquid chromatography (HPLC) or
spectrophotometric methods. In vitro drug release can be
measured using a diffusion cell or a dialysis method [
4.3.3 Niosome Niosomes (non-ionic surfactant vesicles) are microscopic lamellar
73, 74].
structures formed by hydrating a mixture of non-ionic surfactants
from the alkyl or dialkyl polyglycerol ether class and cholesterol.
These vesicles are created in aqueous media due to the amphiphilic
nature of the surfactants, which arrange themselves into closed
bilayer structures when subjected to energy sources such as heat
or physical agitation. The bilayer structure consists of the hydrophobic tails of the surfactants facing inward, away from the aqueous
solvent, while the hydrophilic heads faces outward, remaining in
contact with the solvent. The formation of the bilayer vesicle
requires energy input, such as heat or physical agitation.
Niosomes can be characterized by various methods to determine their size, shape, bilayer formation, number of lamellae,
membrane rigidity, and entrapment efficiency. These parameters
are crucial for understanding the properties and potential applications of niosomes in drug delivery systems.
1. Size and Shape: Niosomal vesicles are typically assumes spherical shape. The mean diameter of niosomes can be determined
using several techniques like laser light scattering method,
electron microscopy, molecular sieve chromatography, ultracentrifugation, photon correlation microscopy, optical microscopy, freeze fracture electron microscopy [
75].
2. Bilayer Formation: The assembly of non-ionic surfactants into
a bilayer vesicle is identified by observing an X-cross formation
under light polarization microscopy [
3. Number of
Lamellae: The number of lamellae in niosomes can
76].
be determined using nuclear magnetic resonance (NMR) spectroscopy, small-angle X-ray scattering, electron
microscopy [
77].
122 Afroz Jahan et al.
4. Membrane Rigidity: Membrane rigidity is assessed by measuring the mobility of a fluorescence probe as a function of
temperature [78].
5. Entrapment Efficiency: After preparing niosomal dispersion,
unentrapped drug is separated, and the drug remained
entrapped in niosomes is determined by complete vesicle disruption using 50% n-propanol or 0.1% Triton X-100 and analyzing the resultant solution by appropriate assay method for
the drug [
79].
4.4 Polyplexes or Polymer-Drug Conjugates
One of the most commonly studied areas of polymer therapeutics is
polymer-drug conjugates in which the low MW therapeutic and
polymeric carrier are most often an anticancer agent and HPMA
copolymer, respectively. This area was born from a landmark study
by Ringsdorf in 1975 [
80] and then further pioneered in the 1980s
by Duncan & Kopecek, who designed the first targeted synthetic
polymer-anticancer conjugates to progress to clinical trials
81, 82]. This work was comprehensively reviewed recently
[
83, 84].
[
In
contrast to free drugs, which usually distribute randomly throughout the body and thus exert deleterious side effects,
attachment of the therapeutic to polymer carriers limits cellular
uptake to endocytosis, extends circulation times to several hours,
and facilitates passive targeting of tumors [
85]. The different types
of polymer drug conjugates, viz., dendrimers, polymer-protein
conjugates, and polymeric nanoparticles, is discussed in detailed
below.
4.4.1 Dendrimers The word “dendrimer” derives from a Greek phrase of “dendron,”
which means tree or meros or branch [
86]. As early as 1978,
Buhleir and coworkers synthesized and reported the first “cascade”
and “nonskid-chain-like” molecules with molecular cavity topologies, which later were recognized as the early forms of dendritic
polymers [
87]. Dendrimers have emerged as an important group of
nanostructured carriers for the development of nanomedicine to
treat various diseases. Because of structural diversity and adaptability, dendrimers have been used to deliver drugs and genes in many
different ways. Dendrimer-drug conjugates could reduce systemic
effects and increase efficacy at the targeted site compared with free
drugs [
88, 89].
It is reported that the half-life of drugs can be
increased by conjugating with dendrimers. PAMAM dendrimers
are one of the most used dendrimers for drug delivery systems
90–92]. The dendrimer architecture has three main sites for
[
drug entrapment by using various mechanisms: (i) void spaces
(by molecular entrapment), (ii) branching points (by hydrogen
bonding), and (iii) outside surface groups (by charge–charge interactions) (Fig.
4).
Polymer-Based Drug Delivery Systems: Design and Characterization 123
Fig. 4 Schematic representation of dendrimer loaded with drug
Dendrimers can be characterized by various methods, viz.,
nuclear magnetic resonance (NMR), gel permeation chromatography (GPC), dynamic light scattering (DLS), and high-performance
liquid chromatography (HPLC). Recently, electrophoretic and
mass spectroscopy measurements have been developed to detect
the mono-dispersity features and the effective charge of dendrimers
93, 94].
[
4.4.2 Polymer-Protein Conjugates
The concept of PEGylation, which involves the covalent attachment of polyethylene glycol (PEG) to peptides and proteins, was
pioneered by Davis and colleagues in the late 1970s [95]. This
technique has since become the preferred method to enhance the
pharmacokinetic and pharmacodynamic properties of protein therapeutics [
96]. PEGylation helps in extending the circulation time of
protein therapeutics in the bloodstream, thereby maintaining drug
PEG is
concentrations at therapeutically relevant levels [
85].
non-immunogenic and non-antigenic, reducing the likelihood of
immune responses against the therapeutic proteins. PEG is
approved by the FDA for various pharmaceutical formulations,
including injectable, topical, rectal, and nasal applications. The
hydrophilic nature of PEG provides a protective shield around the
protein, reducing recognition and clearance by the immune system
[
97].
PEG can be synthesized to facilitate specific conjugation sites
without crosslinking the protein, allowing the therapeutic to be
released effectively. While PEGylation can protect proteins from
degradation and immune responses, it can also reduce or alter the
biological activity of the protein. PEG is not biodegradable, which
can limit its long-term use and lead to potential accumulation in the
body. Although the increased circulation time of PEGylated proteins can compensate for reduced activity, this balance must be
carefully managed to ensure therapeutic efficacy. Despite its limitations, PEGylation remains a critical technique in the development
Ongoing research aims to
of polymer-protein conjugates [
97].
address these challenges by exploring alternatives to PEG that
offer similar benefits with improved biodegradability and reduced
impact on protein activity (Fig.
5).
124 Afroz Jahan et al.
Fig. 5 Schematic representation of polymer-protein conjugate
4.4.3 Polymeric Nanoparticles
Certain chemical entities are either rapidly degraded and/or metabolized after administration (peptides, proteins, and nucleic acids).
This is the reason the idea that nanotechnologies may be employed
to modify or even to control the drug distribution at the tissue,
cellular, or sub-cellular levels has emerged. Thus, nanotechnology
may be employed to modify or even to control the drug distribution at the tissue, cellular, or sub-cellular compartment. Among the
technologies utilized for drug targeting are polymer-based nanoparticles, which have been developed since the early 1980s, when
progress in polymer chemistry allowed the design of biodegradable
and biocompatible materials. Nanoparticles may be defined as
being submicron (<1 μm) colloidal systems generally composed
of polymers. Thus, nanoparticles are colloidal systems with a size
7 to 70 times smaller than the red cells. They may be administered
intravenously without any risk of embolization.
Based on the method of preparation, these can be nanocapsules
or nanospheres. Nanospheres are matrix system in which the drug is
dispersed within the polymer throughout the body of particle.
Nanocapsules are vesicular systems in which cavity contains drug
(oily/aqueous core) and is surrounded by a single ultrathin membrane of polymer (reservoir systems for controlled release of drug)
as depicted in Fig.
6. Drugs are released from the nanosphere and
nanocapsule by diffusion through the polymer or by degradation of
the polymer. Nanospheres and nanocapsules can be injected or
taken orally [
21].
Polymeric nanoparticles (NPs) exhibit diverse physical properties such as composition, concentration, size, shape, surface properties, crystallinity, and dispersion state. Thorough characterization
of these properties is crucial for understanding the applicability of
NPs, assessing nanotoxicology, ensuring health and safety in workplaces, and controlling manufacturing processes. Several techniques
are employed for comprehensive characterization.
The common characterization methods include:
(a) Electron Microscopy:
It includes scanning electron micros-
copy (SEM) and transmission electron microscopy (TEM)
Polymer-Based Drug Delivery Systems: Design and Characterization 125
Fig. 6 Schematic representation of polymeric nanoparticle
for detailed morphology analysis. SEM provides highresolution images of NP surfaces to study shape and size.
TEM is capable of distinguishing between nanocapsules and
nanospheres, and measuring nanocapsule wall thickness.
Atomic force microscopy (AFM) provides three-dimensional,
high-resolution images of surface morphology at a nanometric
98].
scale [
(b) Dynamic light scattering (DLS): Also known as photon corre-
lation spectroscopy (PCS), it is used to determine size distribution and zeta potential.
(c) Near-Infrared Spectroscopy: It is employed for assessing
chemical composition.
(d) Electrophoresis: It is used to measure surface charge and zeta
potential.
(e) Chromatography: I
purity [
99].
Chemically nanopar
t i
s used for analyzing composition and
ticle comprises of constituent elements
along with native or formed functional groups. The measurement
of the formed nanoparticle can be done using an ensemble or
single-particle elemental analysis method. One of the most
126 Afroz Jahan et al.
5 Conclusion
common ensemble techniques used is atomic absorption spectroscopy which is based on the principle of atomic absorption, where
ground state electrons of the atoms jump to an excited state by
absorbing a certain quantity of energy from light at a specific
wavelength [
chemical composition of a single particle is time-of-flight mass
spectrometry (TOFMS) that consists of ionizing small to large
organic analytes into the gas phase with minimal fragmentation
and their subsequent separation/detection using a time-of-flight
mass analyzer [
nanoparticle may be organized into a
be amorphous. Generally, crystal structure is determined using
powder X-ray diffraction or selected area electron diffraction
using a transmission electron microscope [
Research in polymer therapeutics has seen significant progress over
the past few decades, demonstrating success in the safe and effective
delivery of bioactive agents for treating a wide range of medical
conditions. The initiatives reviewed show substantial promise in
enhancing drug delivery by ensuring drugs are distributed specifically to needed locations in therapeutically relevant quantities,
thereby reducing reliance on patient dosing efforts. Moving forward, research should focus on better understanding the interaction between polymers and biological systems. Many recent studies
have introduced novel chemical approaches for advanced drug
delivery systems, but biocompatibility studies are often delayed
until late in development. This oversight can lead to failures at
later development stages. Early cellular and animal studies will
help ensure that polymer-related innovations and in vitro successes
translate into effective and safe drug delivery platforms.
100]. One of the techniques used to determine the
101]. The arrangement of elemental atoms in a
crystal structure or it may
102–104].
6 Future Prospects
1. Future treatments will require delivery vehicles capable of
highly regulated and site-specific payload delivery to achieve
therapeutically relevant concentrations in subcellular
organelles.
2. Upcoming therapeutic
indicative of specific diseases. Through unique triggering
mechanisms, either physical or chemical, these systems will
deliver therapeutic agents. The optimization of these systems
will be significantly influenced by classical chemical engineering
principles, particularly control theory.
systems will recognize key bioanalytes
Declaration
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Polymer-Based Drug Delivery Systems: Design and Characterization 127
3. The blood–brain barrier, composed of tightly sealed endothelial cells, poses a significant challenge for the effective delivery
of therapeutics for neurological and psychiatric disorders.
PEG-grafted polymer nanoparticles show promise in facilitating transport into deep brain areas without damaging the
blood–brain barrier or other brain structures.
4. Targeted therapeutic delivery of high-potency drugs at relatively high payloads to specific sites, particularly tumor, is a
major focus area. Advanced delivery systems will combine
chemical and biological methods to achieve precise localization
and therapy at targeted sites.
All the images are created by using BioRender free software.
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