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Stimuli-Responsive Drug Delivery Systems: From Concept to Clinical Translation 149
different wavelengths of light, have been extensively studied as
light-responsive groups [
99]. To disassemble catanionic vesicles,
the azobenzene moiety’s configuration has been changed
[99, 100]. A light-responsive catanionic self-assembly system (multilamellar and unilamellar vesicles) was created from sodium dodecyl sulfate (SDS) and 4-cholesterocarbonyl-4′-(N,N,Ntriethylamine butyloxyl bromide) azobenzene (CAB). Rhodamine
B and doxorubicin were released from the vesicles as a result of
reversible isomerization of CAB under UV light exposure, which
increased the interlamellar spacing.
To release medication without photolysis, another tactic is to
alter hydrophilicity. For instance, photooxidation serves as the basis
for the release mechanism in unsaturated phospholipids. When
unsaturated phospholipids are oxidized using singlet oxygen,
their hydrophobicity is decreased, which causes instability and
increases the permeability of the liposomes [
101, 102]. Lovell
et al. utilized the unsaturated phospholipid dioleoylphosphatidylcholine (DOPC) for the controlled release of doxorubicin loaded in
porphyrin-phospholipid (PoP) liposomes under NIR [
103]. PoP,
acting as the photosensitizer, generated active singlet oxygen,
which led to an acceleration of DOX release when exposed to
light at 665 nm. Singlet oxygen was confirmed to be involved in
the mechanism by the inhibition of drug release in the presence of
an oxygen scavenger or antioxidant.
5.6 ElectroResponsive Drug
Delivery Systems
In the electro-responsive gel erosion mechanism, polyelectrolyte
gels can be disintegrated in the presence of an electric field. These
gels are made up of two water-soluble polymers that combine to
form a hydrogel through ionic or hydrogen bond interactions. The
formation of these materials is depended on pH of the environment. For instance, a polyallylamine and heparin complex can form
over a pH range of 3–10, but it breaks down at pH 11
104]. Hydrogen bonds in the polyelectrolyte gel are broken by
[
hydroxyl ions produced during the electrolysis of water when a
cathode is positioned near it and an anode is positioned away
from it [
105]
he loaded drug is released as a result of the polymer
. T
complex eroding.
Hydrogels generally
have low poor conductivity, which hinders
their performance as electro-responsive drug delivery systems
(ESDSs). In order to improve the electrical conductivity of these
hydrogels, conductive substances like graphene-based nanomaterials, conducting polymers, and carbon nanotubes can be mixed into
the polymer gel. Both single-walled and multi-walled carbon nanotubes have been mostly used to enhance the mechanical strength
and electrical properties of hydrogels [
106, 107].
For instance,
Yang et al. created conductive polypyrrole-reinforced hyaluronic
acid hydrogels, which improved their electrical conductivity and
biocompatibility for use in biomedical applications
150 Manisha et al.
[108]. Moreover, to enhance the functionality of an electroresponsive delivery system, reduced graphene oxide (rGO) has been composited with polyethylene glycol diglycidyl ether and Jeffamine
polyetheramine [
109]. When rGO is present, the electrostatic
repulsion increases at a negative applied potential, hastening the
release of the drug from the composite.
5.7 EnzymeResponsive Drug
Delivery Systems
6 Conclusion
Enzyme-responsive polymeric nanoparticles have been created for
the treatment of diseases such as diabetes and cancer. For example,
4-hydroxymandelic acid was utilized as the framework to construct
enzyme-responsive linkers [
110]. The drug and enzyme substrates
were attached to the hydroxyl groups in the mandelate core. An
enzyme found in the infected cells caused the linker to break,
releasing the conjugated drug spontaneously. The work of Wong
et al. provides another illustration of enzyme-responsive DDS utilizing polymeric nanoparticles [
111]. Liposomes have garnered
significant interest as superior drug delivery vehicles due to their
numerous benefits, such as their large surface areas, appropriate
sizes, and distinct chemical characteristics. By conjugating with
targeting ligands that interact with receptors on the surface of the
treated cell, liposomes can either passively or actively accumulate in
target tissues. For example, Wan et al. reported a matrix metalloproteinase (MMPs)-responsive liposomal formulation for gene
delivery. An MMP-cleavable peptide was used as the linker to
functionalize PEG chains into anionic liposomes containing
adenovirus [
112].
Recent studies on the differences between pathological areas,
including tumors, and normal areas have observed that pathological regions exhibit abnormal conditions such as changes in pH,
temperature, and redox states, along with the downregulation or
overexpression of certain receptors and transporters. These significant alterations provide novel opportunities for creating smart drug
delivery systems (DDS) that are stimuli-responsive. Medications
can be put into specialized car riers that react to external stimuli
such as magnetic and electric fields or to the abnormal conditions of
pathological areas. The smart carriers have the ability to change
physically and chemically in response to these stimuli, which can
lead to the controlled and selective release of the drug payload. To
avoid or reduce unintended off-target effects on non-target tissues,
a deeper comprehension of the stimuli sensitivity of these designed
DDS is still required. One of the upcoming challenges in the
development of new DDS is creating systems that can react to
particular biomarkers at extremely low concentrations. Future challenges in developing new DDS include investigation of cutting-
7 Notes
Stimuli-Responsive Drug Delivery Systems: From Concept to Clinical Translation 151
edge nanotechnology-based personalized medicine techniques,
combination therapies, and new stimuli. Additionally, the design
and development of multifunctional DDS for simultaneous diagnosis and therapy of diseases will be another important approach.
Improve the biocompatibility, stability, and specificity of systems
that respond to stimuli in order to make them more suitable for
clinical use.
1. Definition: Stimuli-responsive drug delivery systems are
synthesized to release therapeutic drugs in response to specific
physiological triggers or stimuli.
2. Types of Stimuli: Common stimuli include pH changes, redox,
temperature variations, enzymatic activity, light exposure, and
magnetic fields.
3. pH-Responsive Systems: Modify the release of drugs according
to changes in pH in various body compartments, such as the
acidic environment found in tumors.
4. Temperature-Responsive Systems: Modify drug release based
on temperature changes; this is helpful for targeted therapy in
the treatment of hyperthermia.
5. Enzyme-Responsive Systems: Releasing medication in reaction
to the enzymatic activity found in pathological states, like
cancerous tissues.
6. Light-Responsive Systems: Drug release can be triggered by
light exposure by using light-responsive molecules such as
azobenzenes or nitrobenzyl groups.
7. Magnetic-Responsive Systems: Under the effect of an external
magnetic field, use magnetic nanoparticles to direct and release
medications in particular tissues.
8. Redox-Responsive Systems: Make use of redox-responsive
bonds, like disulfide linkages, to cause drug release in reaction
to the intracellular environment that is reductive.
9. Electrically Responsive Systems: To enable controlled drug
release, use materials that react electrochemically or change in
conductivity when exposed to electric fields.
10. Advantages: Target drug release to diseased tissues or organs
specifically to increase drug efficacy and decrease side effects.
11. Materials Used:
properties in response to stimuli include metals, polymers,
lipids, and hybrid materials.
Substances that change their physicochemical
152 Manisha et al.
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12. Controlled Release Mechanisms: Involve stimuli-induced
reversible changes in material structure, such as conformational
changes or degradation.
13. Current Research Trends: Improve the biocompatibility, stability, and specificity of systems that respond to stimuli in order
to make them more suitable for clinical use.
14. Challenges: One of the upcoming challenges in the development of new DDS is creating systems that can react to particular biomarkers at extremely low concentrations.
15. Future Directions: investigation of cutting-edge nanotechnology-based personalized medicine techniques, combination
therapies, and new stimuli.
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