Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5615_Библиотеки_им_академика_М_И_Перельмана.pdf
15 Stimuli-Responsive PEGylated Nanocarriers
427
ability to apply stimuli directly at the targeted drug release site to trigger the delivery of the drug and reduce off-target effects on healthy tissues. Therefore, the effectiveness of this method relies on being able to discriminate differentiate healthy
from diseased tissue when applied (Yang etal. 2022).
Finding exogenous stimulus-responsive materials that can reach the desired tissue at the required depth and location for controlled, site-specic medication release
presents a signicant challenge. Two-photon methods or longer wavelengths of
light (such as a near-infrared laser) are being developed to treat a wider variety of
tissues to overcome this obstacle. Real-time monitoring of drug distribution, as well
as diagnosis and management of disease, can be performed with the injection of a
material activated by ultrasonic waves, cutting-edge light sources, or a powerful
magnetic eld; however, such treatments are not always feasible and/or costeffective and thus require elaborate and stringent protocols (Huang etal. 2023).
15.2 External Stimuli-Responsive Systems
The most important physical triggers from external sources are light, heat, magnetic
elds, and ultrasound waves. These stimuli signals rapidly trigger medication
release when interacting with external stimuli-responsive nanocarriers (Li etal.
2019). Smart nanocarriers enable the controlled release of the amount of drugs and
target timing and site for the release of encapsulated substances using external triggers as the remote, offering detectable regulation of nanocarrier-based drug delivery
system (Li etal. 2020).
15.2.1 Thermoresponsive Systems
Targeted medication delivery often involves one of the three methods: active, passive, or stimuli-based targeting. Passive targeting relies on physiological processes;
the combined application of thermoresponsive strategies for drug release and heat at
the target tissue (such as the tumor site) improves the passive targeting potential. The
basis for thermoresponsive drug delivery strategies is the use of custom polymers for
nanocarrier fabrication that retain the drug at systemic circulation temperatures
(37°C) but can release the drug rapidly at increased temperatures, such as at tumor
sites with increased local temperatures of 40–45°C (Dastidar and Chakrabarti 2019).
The ability of heat-sensitive polymers to react to temperature changes makes
them a valuable “smart material” with various applications; as a result, considerable
research interest has been shown in this eld (Gandhi etal. 2015). When the temperature changes slightly, the polymers in this innovative material transition reversibly from a hydrophilic to a hydrophobic state in aqueous solution. Thus, a sudden
globule-to-coil transition brought on by a temperature shift produces the release of
medicines integrated into the polymeric carrier (Gandhi etal. 2015).
The critical solution temperature (CST) is a crucial characteristic of thermoresponsive polymers. The CST represents the temperature at which solution phase
428
S. H. Almurisi et al.
separation of the solution happens (Sarwan etal. 2020). Thermoresponsive polymers with lower CST values (LCST) respond to increased temperatures by becoming insoluble, and upper CST (UCST) polymers become soluble (Dastidar and
Chakrabarti 2019). Poly(N-isopropylacrylamide) (PNIPAm) is studied extensively
as a thermoresponsive polymer because of its LCST in the water of around 32°C
(Bergueiro and Calderón 2015).
Additionally, polyethylene glycol (PEG) and its derivatives have been explored
as a major class of polymers with thermoresponsive properties for synthesizing
nanocarriers. In water, PEG displays an LCST greater than 90°C.The LCST may
be decreased by adding salt to the aqueous medium. As an example, its LCST
approaches 35°C when 450mM of K2SO4 is present (Bordat etal. 2019). The
LCST is signicantly inuenced by how many ethylene glycols repeating units are
present: For x=2, 3, and 8–9, the LCST is 28, 50, and 90°C, respectively (Lutz and
Hoth 2006). Additionally, as the molar mass rises, the LCST falls. This is explained
by the carbon polymer’s methyl-substituted backbone, which increases hydrophobicity and lowers LCST.The necessary LCST can be simply generated by selecting
the molar mass and the number of repeating units (Bordat etal. 2019). It has been
extensively researched how to lower the CSTs of “thermoresponsive” monomers
using poly(ethylene glycol) methacrylates.
Hydrogels with thermoresponsive properties are being studied for drug release
research, as they can change their structure with temperature change. During injection into the body, the change in temperature causes a phase change from sol to gel
to allow controlled drug release. Delivery of the hydrogel via injection is critical to
ensure minimally invasive applications and to ensure delivery of high drug loads at
the target site while avoiding entry into the circulatory system (Lencina etal. 2018).
Recently, studies on thermosensitive hydrogels using PEG and polycaprolactone
(PCL) polymers, varying molecular weight (Mw), and ratios of the polymers were
reported to design triblock copolymer sequences (Patel etal. 2019).
In the last 20years, numerous thermoresponsive nanocarriers have been studied,
but only ThermoDox® (Celsion) is currently undergoing a Phase III clinical trial
(Bordat etal. 2019). A thermoresponsive liposomal formulation called ThermoDox®
that contains doxorubicin (DOX) is used to treat primary liver cancer. The liposomes’ combination of normal lipids and lysolipids allows them to be thermoresponsive between 40 and 45°C.
15.2.2 Magnetically Responsive Systems
The rst magnet eld-based drug delivery system was developed in the 1980s.
However, there has been gaining interest in magnet-based targeting recently with
the availability of magnets with more extensive elds and sophisticated magnetic
probes for use in various elds, such as theranostic probes (Gu etal. 2018). The
probes enable the therapies to be delivered simultaneously, including precise drug
delivery via magnetic eld stimulation, hyperthermia, and diagnostic applications,
such as magnetic particle or magnetic resonance imaging (MRI) (Price etal. 2018).
15 Stimuli-Responsive PEGylated Nanocarriers
429
Typically, electromagnetic coils or permanent magnets can be used to direct magnetic drug targeting (Price etal. 2018). Nanoparticle magnets metal (such as iron,
gadolinium, and manganese) or superparamagnetic oxides, such as superparamagnetic iron oxide (Fe3O4), are typically the main components of magnetic nanoparticles (MNPs) (Gu etal. 2018).
Our immune system combats pathogens by enlisting a variety of immune cells
that discharge different inammatory substances, producing heat (fever). Utilizing
MNPs that have been externally energized by an alternating magnetic eld (AMF)
to generate heat has gained popularity in magnetic hyperthermia (MHT). The MHT
can be used to activate MNPs that are deeply embedded in tissues or organs at frequencies (f) and eld settings (H) that are safe for humans and provide direct damage, which can also trigger drug release (Mai etal. 2018). PEGylated liposomes
activated magnetically by loading citrate-coated Fe3O4 magnetic NPs to carry DOX
were produced in a recent study (Hardiansyah etal. 2019). Using a high-frequency
magnetic eld, DOX-loaded PEGylated magnetic liposomes could inductively heat
surroundings to 56 °C from baseline physiological temperature. The results of
invitro studies of the liposomes indicate effectiveness against HeLa cell proliferation while not presenting cytotoxic effects in healthy broblast L-929 cells. The
combination of MNP and DOX functionality in these liposomes has created a novel
system for effective delivery and action of anticancer drugs.
Magnetic force has the potential to direct the site of a drug delivery system
besides managing drug release. For instance, Li etal. produced platelets coated with
L-arginine and Fe2O3 magnetic nanoparticles (PAMNs). The amount of PAMN at
the lesion could increase by two times with the placement of a magnet that produces
a static magnetic eld above the lesion. The study of immunohistochemical slices
demonstrated that PAMNs could more effectively access the region of the brain
injury when the magnetic eld was present (Ma etal. 2022). However, creating
large gradients over enormous distances for applying this technology in the human
body is still a challenge (Shamsi etal. 2018).
Therefore, micromotors and nanomotors are considered the latest innovations for
personalized, precise drug delivery, with signicant benets compared to nonmotion, passive delivery strategies (Medina-Sánchez etal. 2018). Magnetic force for
targeting drug delivery using micro−/nanomotors is very promising because the
motor is adaptable to diverse conditions due to its amenability to be controlled
(Choi etal. 2021). In contrast to superparamagnetic iron oxide nanoparticles, magnetically propelled helical nanomotors are typically activated by 5–10 mT rotating
elds in a range of media. Additionally, it has been demonstrated that nanopropellers can spontaneously move through the tissues via biopolymeric networks (Kadiri
etal. 2020). A widespread use for nano- and micromotors is the delivery of DNA or
other pharmacoactive cargo (Li etal. 2017). A magnetic eld is typically applied to
deliver the magnetic targeted medication. However, using an external magnetic eld
for a prolonged duration is difcult and expensive. This issue may be resolved by
implanting a magnet internally to produce the magnetic eld, a technique that is
reported to successfully deliver medications to deep tissues (Ge etal. 2017).
430
S. H. Almurisi et al.
15.2.3 Ultrasound-Triggered Drug Delivery
Ultrasound (US) waves refer to mechanical waves with frequencies ranging from
20kHz to 30MHz and are employed for both diagnostic and treatment. Since the US
waves don’t ionize, they are a type of noninvasive radiation that delivers energy to
biological tissue with a small chance of negative effects (Ahmadi etal. 2020). The
various ways that the drug delivery system and ultrasonic waves interact encourage
uptake and specicity in successful targeted drug delivery (Xia etal. 2016). Three
distinct ways that improve invivo medication distribution when administered by
ultrasonic-responsible carriers: cell membrane permeabilization, vascular permeability expansion, and cellular endocytic uptake promotion (Fan etal. 2022).
Ultrasounds possess high spatial resolution and can target deep tissues to deliver
stimuli. The use of ultrasound in medicine is not foreign. Its use in imaging, stone
crushing, and thermal treatment has been reported (Kubota etal. 2021). The ultrasound functions by causing the particle to cavitation sonoporation, stable cavitation,
or inertial cavitation (Kooiman etal. 2020).
Microbubbles (MBs) are frequently employed as ultrasonic contrast agents due
to their high acoustic impedance mismatch with the surrounding tissue and their
size of 1–10 μm, which facilitates simple circulation through the vasculature
(Batchelor etal. 2020). There are several approaches to including therapeutics in
MBs, including therapeutic gas (Fix etal. 2015), direct drug attachment to the lipid
shell (Nesbitt etal. 2018), drug-lled liposome attachment (Malik etal. 2016), and
release of the therapeutics by raising the US intensity. The delivery of targeted ultrasound pulses triggers the MB to disintegrate through a series of mechanical effects,
starting with inertial cavitation to improve drug release and enhance cellular uptake
of drugs (Browning etal. 2021). However, these MBs can only produce contrastenhanced US imaging within the vasculature due to the limits of their large particle
size in the range of several micrometers and their limited extravasation from the
blood artery (Cui etal. 2019).
The nanobubbles (NBs), which are submicron bubbles typically 200–600nm in
diameter, are an appealing potential strategy to deliver drugs, showing increased
tumor accumulation and retention compared to MBs. The leaky vasculature provides an environment for increased permeation and retention, improving tumor biodistribution (Wu etal. 2019). The development of nanosized contrast agents with
the ability to effectively pass the leaky tumor vasculature and accumulate inside
tumors (the gaps range in tumor vasculature is 600 to 800nm) is crucial for anticancer drug delivery (Blanco etal. 2015). Also, the NB shells’ surfaces can be functionalized to improve their stealth and molecular targeting capabilities. For instance,
PEGylation could prolong the half-life of therapeutic agents in circulation and
enable better targeting of the lesion tissues (Jin etal. 2020).
15 Stimuli-Responsive PEGylated Nanocarriers
431
15.2.4 Light-Triggered Drug Delivery
Targeted drug delivery via the application of external light is an approach that promotes precise spatial resolution and temporal for the delivery of various physiologically active compounds, such as genetic material, proteins, and drug molecules. The
nanocarriers can accumulate in the target cells and tissues, after which controlled
light application irradiates the targeted diseased feature while leaving healthy tissues unaffected (Zhao etal. 2019).
Light responsiveness can be activated by a variety of wavelengths, including
ultraviolet (UV, 200–400 nm), Vis (400–750 nm), or near-infrared (NIR,
750–2000nm) light. UV and Vis light (short-wavelength light) are applied to attack
photolabile moieties and trigger light-sensitive agents. However, light has poor penetration and reach due to its short wavelength, limiting its application in deep tissue
targets for therapy. An additional concern is the risk of triggering cancer when tissues are exposed to these short wavelengths over extended time durations (Tao etal.
2020). NIR light, in contrast, is better for biological applications due to its higher
penetration into deep tissues, better safety prole, and lower risk of signal interference (Karimi etal. 2017).
Many different types of nanomaterials are currently being used to create NIRresponsive delivery systems, including semiconductor nanomaterials (such as copper suldes and bismuth suldes), Au-based nanomaterials (such as Au NPs and Au
nanorods (NRs)), carbon nanomaterials (such as GOs and carbon nanodots), and
upconverting nanoparticles (UCNPs) (Karimi etal. 2017). These materials are used
to fabricate NIR-activated nanoparticles due to their maximum optical absorbance
specic to NIR wavelengths. Other than nanomaterials, outstanding NIR-responsive
substances include conjugated polyelectrolytes and dye molecules ICG and IR780
that absorb light in the NIR region, resulting in an electron excitation and release of
heat energy (Yan etal. 2016). These substances transform and produce heat and/or
reactive oxygen species (ROS) with absorbed light, which then disrupts the nanoparticles to cause the site-specic release (Mohammed etal. 2019).
The matrices of thermosensitive hydrogels injections were typically incorporated with nanosized photothermal agents to facilitate change from light to heat and
initiate the release of drugs on-demand by inducing phase transition from the gel to
sol phase in traditional NIR light-responsive hydrogels (Qiu etal. 2018). The incorporated nanoscale NIR-absorbing components in some of these hydrogels may
leach out, degrading the photothermal action and lowering the efcacy of medication delivery (Wu etal. 2018b). To achieve the desired outcomes from extended
time in circulation and enable continuous treatment with just one administration of
the hydrogel, the poly(ethylene glycol) chains incorporate hydrogel formulations so
that their constituent parts can take up light in the NIR-II region, allowing for selfconversion of light into heat (Ruan etal. 2019).
432
S. H. Almurisi et al.
15.2.5 Electroresponsive Systems
The electric elds, whether endogenous or exogenous, can be applied in several
therapeutic methods (Kolosnjaj-Tabi etal. 2019). The type of stimuli-responsive
materials determines what triggers are required to stimulate the release of drugs,
whether extrinsic (external pulses) or intrinsic (changes in charge at the tissue
microenvironment level). The release of drugs from their carriers is triggered by
electric elds, one of the many applications. Systems that respond to electric elds,
such as electroresponsive drug delivery nanosystems, allow for targeted drug release
via spatial and temporal control (Uppalapati etal. 2016). Thus, the external application of a low-intensity electric eld enables on-demand sustained or pulsed delivery
of the active ingredient. Also, higher-intensity exogenous electric elds have been
shown to directly affect cellular membrane permeability, stimulate medication
delivery, and act as a tool for treatment to promote/improve (wound) healing and
restore tissue integrity (Kolosnjaj-Tabi etal. 2019).
Electroresponsive systems could be administered as (thin) lms or nanoparticles
and employed as implants in the body or drug carriers. These devices might be
implanted or injected, and upon electrical stimulation, they would (ideally) electrically activate surrounding tissue and cells over long periods (Raj et al. 2023).
Concurrently, organic “conductive” polymers (CPs) with the ability to carry and
allow the ow of electric charge have been developed (Lamprou 2023). The electronic structure of CPs, which alternates single and double bonds across its repeating structure, primarily determines their conductivity. Radical cations/anions
(polarons) or dications/dianions (bipolarons) are made more accessible to form during the doping process, and counter-ions from the solution enter the polymeric
material to balance the charge (Grancarić etal. 2018).
The CPs combine metallic and polymeric features, such as optical and electrical
abilities, that can respond to electrical and electrochemical triggers to release the
drug payload (Gupta 2022). Some examples of currently developed CPs with the
highest potential for therapeutic applications are polypyrrole, polythiophene, polyaniline, and poly (3, 4-ethylenedioxythiophene) (Paramshetti etal. 2023). However,
researchers are facing challenges in applying CPs for treatment due to poor biocompatibility, processability, and mechanical stability. This has prompted a study into
integrating CP and non-CP materials via chemical modication to produce composites with combined properties of the CP and non-CP materials that exhibit superior
drug delivery functionalities for biomedical applications. The conductivity of metals and exibility of polymers are combined in these materials (Paramshetti
etal. 2023).
The hydrogel is a polymer with hydrophilic, absorbing, and swelling capability
for holding large amounts of liquid in its structure. Water-soluble polymers crosslinked to produce the 3D network structure include synthetic materials PEG, polyvinyl alcohol (PVA), polymethacrylate-2-hydroxyethyl ester (PHEMA), and natural
biomaterials such as chitosan, starch, and cellulose (Rinoldi etal. 2021). The addition of an electric eld-responsive element to hydrogels results in hydrogels with
the added ability to produce mechanical energy from electricity, potentiating its
15 Stimuli-Responsive PEGylated Nanocarriers
433
application as a sensor, biomechanic agent, sound dampener, energy transductor,
chemical separator, drug delivery carrier, and tissue engineering component (Liu
etal. 2021).
15.3 Internal Stimuli-Responsive Systems
The advantage of using polymer nanoparticles for drug delivery lies in their ability
to safely and stably carry the drug load to the targeted cells/tissue. To provide a
therapeutic intervention effectively, there are numerous biological obstacles to overcome. These difculties include the capacity to avoid immune detection, precisely
reach the desired cells and tissues, and carry the drugs to specic intracellular sites.
Applying stimuli-responsive nanoparticles is a crucial strategy for ensuring the successful carriage of a therapeutic payload to the target region. These nanoparticles
are designed with the ability to alter their physical characteristics when triggered by
certain internal factors (Deirram etal. 2019).
There are several advantages to using endogenous stimuli-sensitive drug delivery
systems over conventional drug delivery systems, the most important being its
capacity to react to particular physiological signals within the body, including
enzyme action, pH levels, and redox (Abasian etal. 2021). The endogenous stimuliresponsive systems overcame the nonspecicity and toxicity linked to conventional
medicine delivery techniques (Sethuraman etal. 2021). These endogenous stimuliresponsive systems are designed to be sensitive to biological signals that start the
transport of medications by inuencing the tissues in the microenvironment, upregulating certain enzymes, interacting with antibodies and antigens, and recognizing
host-guest moieties in a particular state (Raza etal. 2019). The difference between
pathological and healthy, normal tissue has contributed to the development of endostimuli-responsive nanocarriers for the transportation and precise targeting of
therapeutic drugs (Das et al. 2020). Endogenous stimuli-responsive systems are
gaining high interest in nanotechnology research because they offer the potential to
develop multifunctional nanoplatforms for drug administration.
15.3.1 pH-Responsive Systems
The pH-triggered nanosystems take advantage of the distinct pH levels in healthy
and diseased tissue to precisely deliver drugs to the local site for more effective
treatment outcomes. This makes it feasible to regulate the delivery of medications
to target organs, whether the liver or the pancreas, and intracellular compartments,
including endosomes and lysosomes. The controlled release of drugs is linked to
microenvironment indices present in disease, as is the case in infection or cancer
(Goyal etal. 2019; Canaparo etal. 2019). For instance, tumor cells and their intracellular spaces (endosomes and lysosomes) have a slightly acidic pH, whereas normal pH is generally neutral (7.0–7.4) (Chen etal. 2018).
434
S. H. Almurisi et al.
pH-responsive nanoparticles are designed to modify their surface chemistry or
mechanical structure, disassemble, or release their load. It is possible to regulate
drug release and cell absorption by adjusting the characteristics of nanoparticles.
Therefore, pH-responsive nanoparticle is an effective method for designing therapeutic delivery systems using polymers with ionizable moieties (polymers with
shifting charge), linkages susceptible to low/acidic pH, or crosslinkers that integrate
polymers with non-cleavable linkages to produce particles that are able to swell or
acid-labile linkages that disintegrate the nanoparticle when exposed to certain pH
(Deirram etal. 2019).
Polymers containing ionizable moieties can be protonated or deprotonated,
which changes the soluble properties of the nanoparticle in aqueous media. In contrast, acid-labile covalent connections in the polymer backbone are employed to
cleave polymers and cause their breakdown in acidic conditions (Abasian etal.
2021). Acid-labile polymers frequently exhibit a slower internal structural transition
than polymers with ionizable moieties, making them more suitable for drug- delivery
systems (Tang etal. 2018).
Polyacids and polybases are the main categories used in polymers with ionizable
moieties. Polyacids have acidic moieties, including carboxyl, phosphate, or boronic
groups linked to the polymeric backbone, that become negatively charged when
protons are released in an essential environment. In contrast, primary groups in
polybasic polymers, such as amines or pyridines in an acidic pH, become positively
charged (Huang etal. 2018). The ionization and deionization typically take place
between a pH range of 4 and 8 for polyacids such as polyacrylic acid and polymethacrylic acid, where protons are taken at a low pH and released at a neutral or higher
pH.In contrast, pH-responsive polymers from polybases such as methacrylic acid
and N, N-dimethyl aminoethyl methacrylate, which have amino groups on their side
chains, accept protons under acidic conditions as cations and then release them
under alkaline conditions to reduce their solubility (Ofridam etal. 2021).
In addition, natural polymers like pectin, chitosan, or alginate, which are abundant, biodegradable, and biocompatible, have demonstrated distinct morphological
alterations in response to environmental stimuli. Natural polymers often have high
molecular weights; therefore, the appearance of many charges changes the conformation and assembly of the polymer chains intrinsically and has the benet of being
chemistry-modiable, which enables the addition of new functions to the polymeric
backbone (Schoeller etal. 2022).
Several studies have been conducted using pH-sensitive systems. For instance, a
pH-sensitive polymeric-chitosan and hydroxypropyl methylcellulose crosslinked in
the presence of tripolyphosphate nanoparticles was developed for the delivery of
melatonin in breast cancer therapy (Jafari etal. 2021). Results show that melatonin
encapsulated in polymeric chitosan and hydroxypropyl methylcellulose nanoparticles was more targeted at cancer cells than free melatonin, suggesting that the
nanoparticles may effectively treat breast cancer.
Additionally, polymeric nanoparticles with acid-labile linkage have been extensively used in drug-delivery systems (Wu etal. 2018a). Imine, hydrazone, oxime,
amide, acetals, and orthoester are examples of pH-sensitive chemical bonds that can
15 Stimuli-Responsive PEGylated Nanocarriers
435
be embedded within drug carriers. By cleaving the dynamic chemical bonds, the
conguration of the carriers can be changed, allowing for the controlled release of
the loaded pharmaceuticals (Zhuo etal. 2020).
Hydrazones were extensively investigated for their simple preparation, moderate
stability, and favorable sensitivity among pH-sensitive linkages (Qi etal. 2018).
Also, acetal is one of the most common pH-sensitive linkages used (Patil etal.
2012). Acetal bonds can be created as a connection between the carrier and the drug
or can be found in the structure of the carrier. The internal structure of the carrier is
damaged following the hydrolysis of the acetal link in the acidic environment,
which results in the drug’s release (Saadat etal. 2021). Other acid labile linkages
such as orthoester, citraconic amide, and Schiff base bonds were reported. The
chemistry of pH-sensitive bonds typically determines the effectiveness of drug
delivery systems.
The highly targeted drugs can be applied to specic lesions by conjugating the
drug molecules to delivery carriers via pH-responsive linkers. The polymer-drug
conjugate is one of the pH-responsive drug delivery approaches with acid-sensitive
links between the drug molecule and polymer. In a previous study, DOX was conjugated to a biodegradable, nontoxic, and nonimmunogenic nanoconjugate using PEG
and pH-sensitive hydrazone linkage. These DOX-nanoconjugates were successfully
demonstrated to inhibit the growth of invasive breast carcinoma cell lines in invitro
studies and were shown to be stable under physiological conditions (Patil 2012).
15.3.2 Redox-Responsive Systems
The fundamental processes of life, such as metabolism and respiration, depend on
redox reactions. All parts of life that are mediated by or impacted by redox reactions
are then referred to as redox biology (Franco and Vargas 2018). The availability of
electrons is crucial for biological systems, particularly for the mitochondrial electron transport chain that provides energy to cells. The metabolic process produces
ROS, which are highly reactive due to their existence as free radicals, ions, and
molecules with a single unpaired electron (Mirhadi etal. 2020). ROS are elevated
when there is insufcient electron supply, and unbalanced oxygen levels (hypoxia
or hyperoxia) impede mitochondria from producing ATP (Kaur and New 2019).
Since ROS controls immunological function, autophagy, inammation, and
stress-related responses, it is produced in normal cells in a highly controlled manner. Free radicals are much more than unwanted side products that cause harm.
Various cell types, such as cancer-associated broblasts (CAFs), endothelial cells
(ECs), and inammatory cells, along with processes like angiogenesis and hypoxia,
contribute to the production of ROS (Mirhadi etal. 2020).
During immunological or inammatory reactions, inammatory cells, particularly macrophages and neutrophils, cause the formation of ROS; meanwhile, angiogenesis, which is crucial for tumor growth, development, and metastasis, serves as
another signicant source of ROS.Additionally, the activity of endogenous antioxidant enzymes, including thioredoxin, superoxide dismutases (SOD), and NADPH
436
S. H. Almurisi et al.
oxidase, may contribute to high ROS levels (Mirhadi etal. 2020). Cells have a buffer system to prevent oxidative damage, and a group of enzymes, including glutathione peroxidase (GPx) and catalase (CAT) are responsible for turning free radicals
into stable and less harmful compounds (Kumari etal. 2018; Mirhadi etal. 2020).
Cells experience oxidative stress when ROS production exceeds antioxidant
defenses that scavenge the ROS molecules. High ROS levels in the body have been
associated with various diseases such as diabetes, heart disease, obesity, neurological disease, inammation, and cancer (Quader and Van Guyse 2022).
The antioxidant glutathione (GSH) is produced in the body from glycine and
γ-glutamyl cysteine (γ-GCS) (Raj Rai etal. 2021). Many researchers are developing
innovative redox-sensitive strategies for cancer diagnosis and therapy using GSH’s
antioxidant property, which detoxies the elevated oxidative environment (Khan
etal. 2022). The scientists can formulate and synthesize nanoparticles with the ability to respond to chemical triggers in the intracellular environment from elevated
GSH accumulation representative of tumor pathophysiology.
To make drugs sensitive to ROS in tumor regions, the functional groups might be
included in drug delivery systems. Diselenide bonds, succinimide-sulde bonds,
and the most extensively studies disulde bonds are among the often utilized redoxsensitive chemical bonds (Fu etal. 2022). Glutathione readily breaks down disulde
bonds in the tumor microenvironment and transfers them to sulfhydryl groups
(thiol), which causes the carrier to degrade. ROS thenxidises thiol groups to form
sulfenic acid, sulnic acid, and sulfonic acid (Gao and Dong 2018). Due to the
disulde bonds’ intrinsic instability under many conditions, they could be considered as a great linker in a nanoparticle drug delivery system (Fu etal. 2022). For the
prototype cancer drug paclitaxel, redox-sensitive poly(ethylene glycol) (PEG)based prodrugs, chitosan (CS)-based micellar systems, or polyethyleneimine (PEI)based amphiphilic micelles with disulde bonds as redox-responsive linkages have
all been successfully developed (Xu etal. 2019). The disulde linkage is embedded
in the nanoparticle structure and is triggered by changes in glutathione (GSH) concentrations, causing drug release (Gong etal. 2018).
Due to the attractive outcomes of disulde bonds, selenium (Se) has been studied
for its reactivity to reduction and high sensitivity to small amounts of oxidizing
agents. Improved redox-responsive strategies could potentially from the use of a
diselenide bond rather than the disulde bond is foreseen due to the bond energies
of the C-Se and Se-Se bond being less than compared to S-S bonds (Behroozi etal.
2018; Mirhadi etal. 2020). The redox sensitivity of the synthesized poly(ethylene
oxide)b-poly(furfuryl methacrylate) using diselenide (Se-Se) and disulde (S-S)
redox-responsive core-crosslinked (CCL) micelles was studied. The particles prepared utilizing diselenide bonds were highly sensitive compared to disulde bonds
(Yadav etal. 2023). Moreover, Se partakes in many different kinds of physiological
processes, including gene transcription, cell cycle, thyroid function, immunity, and
antitumor activities (Behroozi etal. 2018).