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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5373_Библиотеки_им_академика_М_И_Перельмана.pdf
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15.3.3 Enzyme-Responsive Systems
Many biological reactions use enzymes as catalysts, and certain enzymes are dysregulated and elevated in pathological conditions, which are considered common
features of several diseases, making them a potential biological trigger for treatments. Their incorporation into the design of targeted delivery is promising, as
enzymes are highly specic for their substrate, allowing for accurate, intricate, biologically similar chemical reactions (Quader and Van Guyse 2022). Hydrolases play
signicant roles in breaking down numerous biomolecules, including sugars, lipids,
proteins, DNA, RNA, and many more. The main hydrolase enzymes include protease, which hydrolyzes peptides; lipase, which hydrolyzes fat; glycosidase, which
hydrolyzes complex sugar; esterase, which hydrolyzes ester; and elastase, which
hydrolyzes elastin.
Numerous disorders, such as cancer, inammation, atherosclerosis, Alzheimer’s
disease, and viral infections, have reported elevated levels of proteases (Smith etal.
2021). Polymeric nanoparticles can be modied with enzyme-labile links to trigger
the release of their cargo when certain enzymes are present and reectively cleaved
by overexpressed enzymes (Shahriari etal. 2019). Several hydrolytic enzymes,
including proteases, glycosidases, and lipases, as well as oxidoreductases like peroxidases, have been used in drug delivery because of their ability to cleave various
natural and synthetic polymers, including those containing particular amino acid
sequences and natural polysaccharides (Dou etal. 2020). The controlled release of
drugs from enzyme-sensitive systems occurs under enzyme catalysis (Abasian
etal. 2021).
Proteases can be grouped according to the peptide bond cleavage action and
essential amino acids at the active site: cysteine, threonine, serine, aspartate, glutamic acid, and matrix metalloproteinases (MMPs) (Dudani etal. 2018). Another
hydrolase, called an esterase, hydrolyzes ester bonds to produce acid and alcohol
molecules. Numerous cancer cells overexpress the esterase enzymes, which can be
used as triggers for delivering tumor-targeted drugs (Abbasi etal. 2023). Meanwhile,
glycosidases catalyze hydrolysis reactions in complex sugars, breaking the glycosidic linkage in these molecules. The overexpression of this enzyme in pancreatic
juice and saliva in diseased individuals is thought to be an enzymatic trigger for
polysaccharide-based drug delivery systems (Kapalatiya etal. 2022). Additionally,
oxidoreductase is vital in oxidative stress because of its signicance in oxidative
environments and its ability to detect glucose through the use of glucose oxidase
(GOx); this has enabled this enzyme to be applied Alzheimer’s and cancer treatments (Irshad etal. 2022).
Matrix metalloproteinases (MMP), hyaluronidases, and cathepsin are among the
enzymes that directly contribute to the development of atherosclerosis. The proteolytic enzyme degrades the extracellular matrix proteins such as gelatin, collagen,
brin, and elastin, while hyaluronidase is an enzyme family that can break down
hyaluronic acid (HA) specically and predominantly, it also plays a crucial part in
the tissue’s response to injury. Cathepsins are lysosomal cysteine proteases that
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could inactivate related enzymes, breakdown proteins, and increase atherosclerotic
inammation in response to microenvironment imbalance (Song etal. 2022).
Typically, enzyme-triggered drug-release nanocarriers have an enzyme-substrate
linker unit linking the nanocarrier and drug, which serves as the cleavage site for the
enzyme. The selection of an appropriate enzyme stimulus, informed by the disease
pathophysiology and the desired enzyme activity, is the rst design decision to be
made when creating an enzyme-sensitive system (Duan etal. 2020). The mechanism of action behind enzyme-responsive systems is the physical and chemical
modications that the system undergoes in response to enzyme exposure, resulting
in the release of drugs at the target site. Cleavage of the linker between the nanocarrier and the bioactive molecule via the nanocarrier shell or carrier degradation or
cleavage of the functional groups leads to structural changes in the system that
allow for the release of the drug (Kapalatiya etal. 2022) .
15.3.4 Self-Regulated Systems
Self-regulated nanodrug delivery systems comprise drug delivery platforms that can
detect changes in physiological indices and adjust their characteristics or performance accordingly due to these external or internal biological signals. The drug
delivery system can be designed for open-loop control or closed-loop (feedback). In
open-loop control, the drug delivery system is established by a control system that
governs drug release. In contrast, in closed-loop control, physiological data are
received and fed back to the controller, which modies the rate of drug release
(Wang etal. 2021).
Feedback indicates a system that continuously triggers itself whenever necessary, meaning that the outputs of the system are fed back into it as inputs. The
human body generates positive or negative feedback to maintain equilibrium (Arun
etal. 2021). Positive feedback describes a system’s output as enhancing the initial
stimulus; examples include births, lactation, blood clotting, etc. When the body uses
negative feedback, which is a typical form of feedback mechanism, the output of the
system will suppress the initial stimulus, as in the case of thermoregulation, blood
sugar regulation, osmoregulation, etc. Closed-loop drug delivery systems, often
referred to as feedback-regulated systems, are a more advanced version of modied
drug-releasing systems that respond to signals from the body to release drugs. Any
biochemical factor (pH, temperature, pressure, and ion concentration) created in the
body because of unexpected physiological conditions can serve as one of these
triggers.
Traditional drug delivery is limited by brief circulation in the system, repeated
administration, and adverse effects because of disorderly release, nonspecic biodistribution, rapid drug absorption, and the possibility that the drug release could
reach highly toxic levels. Using self-regulated systems, drug delivery can be triggered, stopped, raised, decreased, or maintained at desirable levels in the body since
the system will release the drug as long as it recognizes the abnormal biochemical
change. This means that the drug will be released as and when required, and the
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system may be constructed so that the ratio of drug concentration to stimulus intensity is proportionate (Sawalwade etal. 2020). Thus, conventional drug delivery systems have been developed into new, smart systems that respond to specic stimuli,
allowing the drug to bind to the target site and release the drug predictably over
prolonged periods with enhanced bioactivity.
The basic design of self-regulating drug delivery systems consists of a drug reservoir, a rate-control membrane, and a sensor that responds to the biochemical triggering agent. The drug reservoir is encapsulated within a semipermeable polymeric
membrane. The permeation of the triggering agent activates the system, and the
drug is released depending on the reversible competitive binding of the triggering
agent with the biosensor (Sawalwade etal. 2020). This sort of drug delivery is
appropriate for molecules such as DNA, siRNA, nucleotides, proteins, peptides, and
others that are specic in their action but are cytotoxic. Hence, uctuations in their
blood levels are undesirable. Recurring administration of these molecules can exacerbate their adverse effects and cytotoxicity, but closed-loop drug delivery can avoid
this (Sawalwade etal. 2020). For instance, insulin injections are frequently used to
treat diabetes. Even though regular insulin injections quickly lower blood sugar
levels, they also always induce injection pain and a decrease in patients’ quality
of life.
Therefore, an alternative diabetic treatment that controls drug release continuously and automatically and is directly triggered by glucose is needed. The usage of
glucose-sensitive materials, a type of “intelligent” polymer, has increased in selfregulating systems. These materials continually and automatically regulate insulin
release, which is triggered by a raised blood glucose level. Drug delivery devices
that respond to glucose levels can be helpful in treating diabetes and replacing
repeated insulin injections by combining drug administration in response to glucose
with minimum patient involvement and enhanced diabetic quality of life (Wang
etal. 2019).
Recently, formulations have been developed that modify insulin release rates
according to variations inlocal glucose levels. For instance, polymeric nanoparticles with the ability to alter their insulin release proles have been developed using
acid-degradable, acetylated-dextran polymers; nanoparticles made with high cyclic
acetal content dextran (71% of residues) release insulin more rapidly than those
produced from high acyclic acetal content dextran (94% of residues). The potential
of this delivery system to release insulin in response to glucose following a
therapeutic- specic prole represents a signicant step forward in targeted insulin
delivery (Volpatti etal. 2019).
15.4 Dual andMultiresponsive Systems
Besides single-responsive systems, dual or multistimuli-responsive systems are
gaining interest in targeting different sites and disease conditions. Dual or multiple
stimuli-responsive drug-delivery systems were rst developed for targeted cancer
treatment and respond to a combination of internal and external biological triggers
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for drug release (Zhao etal. 2021). Compared to a single responsive system, dual
and/or multistimuli systems use various active triggers systematically incorporated
into one nanoplatform, resulting in a multifaceted approach that has superior performance to simple nanosystems in facing physiological/pathological barriers. Dual/
multiresponsive nanosystems respond to the stimuli simultaneously or subsequently
to achieve targeted drug delivery (Zhao etal. 2021). Based on the specic targeting
site and the response needed, a combination of exogenous triggers that use pH,
redox potential, temperature, presence of enzymes, etc., can be considered triggers
for dual or multiresponsive systems.
15.4.1 Temperature andpH Dual Stimuli-Responsive Systems
Temperature and pH-responsive polymers have been studied vastly in dual stimuli
systems triggered by more precise, controlled, and targeted indices to stimulate the
polymer responses. The trigger system is formulated by conjugating a pH- responsive
polymer to a thermosensitive polymer. Several polymers fullling these criteria
have been developed in the last 10years for cancer treatment applications due to the
increased temperature and acidic pH found in the tumor microenvironment when
compared to healthy tissues (Pham etal. 2020b; Zhao etal. 2021; Zifar etal. 2023).
The tumor cells’ abnormal characteristics, including fast metabolism and abnormal
proliferation of cells, cause accumulation of lactic acid, resulting in an acidic pH
(pH5.7–6.9) in the cells and microenvironment (Pham etal. 2020a, b).
The LCST is an essential characteristic of thermoresponsive polymers. At higher
LCSTs, the bonds interacting between polymer and drug molecule weaken, increasing the hydrophobic interactions present in the molecule and causing the polymer to
dehydrate and shrink. Poly (N-isopropyl acrylamide) (pNIPAAm) has been widely
studied because of its LCST of approximately 32°C; above this LCST temperature,
its gel structure will collapse (Ghalehkhondabi etal. 2023; Pham etal. 2020b; Reza
Soltani etal. 2023; Zhao etal. 2021). This applies to be used at body temperature
(37°C), where it will shrink. The LCST transition changes the polymer state from
water-soluble to water-insoluble. The pH-responsive polymers commonly use weak
acids, acrylic acids (AAs), poly(2-(diisopropylamine)) ethyl methacrylate (PDPA),
and chitosan in their formulation (Zhao etal. 2021). Once both polymers are mixed,
a dual responsiveness system in the form of micelles or nanoparticles will be
created.
In the research of Reza Soltani etal., Molybdenum disulde (MoS2) nanosheets
were mixed with pH and temperature-responsive monomers methyl methacrylate
(MMA) and N-isopropyl acrylamide (pNIPAm) to allow controlled release and
improved DOX delivery into breast tumor cells. The MoS2@pNIPAM-MMA/GLN
is a dual-triggered system, with the two-dimensional (2D) MoS2 acting as a carrier
for DOX loading (Reza Soltani etal. 2023). Characterization of the system in blood
model uid indicated slow drug release at pH7.4, 37°C, whereas 98% of the drug
was released at pH5.6, 50°C after 6h, an improvement in controlled DOX delivery
across the tumor cells under certain pH and temperature (Reza Soltani etal. 2023).
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Another report has also elaborated the fabrication and characterization of a
potential, dual-responsive nanosystem consisting of pNIPAm-PAA spheres for controlled release of DOX in breast cancer treatment (Ghalehkhondabi etal. 2023). The
poly(acrylic acid) (PAA) carriers were fabricated using polymerization via the precipitation method, followed by emulsion polymerization to add a thermoresponsive
pNIPAm coating on the outside of the carrier spheres. The nanosphere cores were
loaded with DOX as a model drug. The resulting nanospheres showed a pH- and
temperature-responsive drug release prole in the release medium, with slight leaking at pH7, and 37.0°C, which improved signicantly in more acidic environments
(pH ~5.5), indicating the potential for drug release at the tumor site. The nanosphere
release observed was approximately 2.3-fold higher than under neutral pH and temperature (Ghalehkhondabi etal. 2023). Lower temperatures decreased drug release
proles in both acidic and neutral pH.
Temperature-pH dual stimuli microcapsules system was also studied to improve
systems for the controlled release of drugs. In a study by Chen etal. (2014), particles encapsulating Nile Red (NR) and uorescent green (OG) dyes were prepared
using temperature-sensitive pNIPAm particles. The authors reported signicant pHand temperature differences in the dye release. At low pH conditions, the microcapsule shell swelled and released the OG, but the NR was not released from the
microparticles because of the electrostatic repulsion between the positively charged
polymer chains of the shell. OG release was in response to pH change, but not
NR.Variations in pH stimulus only triggered the release of OG but did not affect the
NR.However, when the microcapsules were exposed to increasing temperature, it
was noticed that the NR was released, but the OG was unaffected (Chen etal. 2020).
15.4.2 pH andRedox Potential Dual-Stimuli Responsive Systems
The redox-responsive DDs is a great system as well for targeting potential tumor
cells; however, there are some challenges faced by this system, such as undesirable
drug release behavior at non-targeted tissues with unresolved toxicities issues and
unsatisfactory dose of chemotherapeutic agents reaching the targeted site (Jia etal.
2021; Pham etal. 2020b; Zifar etal. 2023). Therefore, modication of the initial
redox system with the addition of pH-/ROS-sensitive groups and enzyme materials
may provide great potential in addressing the challenges mentioned above. In this
case, the pH-redox system is still predominant compared to the others. The synergistic actions from this dual system can help increase the drug release rate at a
condition of low pH and high redox potential (Jia etal. 2021).
Dong etal. produced an oxidation-pH responsive hydrogel b PEG-b-P(METMA)
with pendent thioether activity by performing reversible addition-fragmentation
chain transfer polymerization of a tert-butyloxycarbonyl (Boc)-l-methionine-(2methacryloylethyl)ester (Boc-METMA) monomer using a poly(ethylene glycol)
(PEG)-based chain transfer agent. The b PEG-b-P(METMA) had self-assembly
properties, forming micelles at pH over 6.0, and was hydrophilic at pH under 6.0,
due to the protonable amine groups present in its structure. Curcumin (CUR) loaded
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into the micelles showed a pH-dependent release prole (Dong etal. 2020). In
H2O2, swelling of the micelles was observed, followed by disintegration to release
the drug. H2O2 triggered oxidation of the thioether to sulfoxide, changing the micelle
solubility prole. The pH-dependent release and the H2O2 responsive behavior
showed that PEG-b-P(METMA) micelles had exciting potential for delivering
drugs that respond to ROS (Dong etal. 2020).
Ren et al. studied biocompatible, charged pH/redox dual-stimulus response
nanoparticles using poly-γ-glutamic acid (γ-PGA), cysteine (Cys), and chitosan
(CS) for the controlled release of DOX.The triggers acted on electrostatic interactions and amide bonds in the γ-PGA-CS particles crosslinked in situ using the disulde bonds in cystine (Cys). The resulting γ-PGA-S-S-CS-DOX nanoparticles
showed signicantly higher DOX release in acidic and redox environments, triggers
that are present in the tumor cell microenvironment for the release of DOX (Ren
etal. 2019). Similarly, a pH/redox potential responsive dual stimuli system was
developed by Ding etal. using polyacrylic acid (PAA-pH-responsive) and tocopherol succinate (TOS). The self-assembly constructed vesicle system consists of
amphiphilic PAA-cystamine (cys)-TOS in the anticancer methotrexate drug aqueous solution. The dual stimuli polymers showed increased release of the drug in
response to pH and GSH compared to pH alone, as GSH acts on the disulde bond
of cystamine. In contrast, pH acts on the amide bonds in PAA-cys-TOS to cause the
vesicles to disintegrate, resulting in faster drug release (Ding etal. 2020).
15.4.3 Multistimuli Responsive Systems
Nanocarriers applying multistimuli responsive systems observe drug release in predetermined internal or external triggers as illustrated in Fig.15.2 (Fu etal. 2018).
The drug delivery systems responsive to stimuli were developed for targeted
cancer treatment and respond to various combinations of internal and external stimuli. Multiple stimuli-responsive drug-delivery systems (MSR-DDSs) can be
designed with the advantages of increased drug encapsulation efciency, increased
time in circulation, improved stability, ability to recognize receptors, and drug
release via controlled degradation at the target site (Chen etal. 2020; Jia etal. 2021).
A PAA-co-spiropyran (SP) methacrylate nanogel crosslinked by N,Nbis(acryloyl)cystamine containing disulde was developed by Chen etal. with light,
pH, and redox-sensitive properties. The nanogel was loaded with DOX-HCl as a
model drug via electrostatic interaction with AA.The nanogel response to UV light
irradiation and low pH, when the hydrophobic SP transformed to the hydrophilic
merocyanine (MC), resulted in swelling (Chen etal. 2017). The MC was able to
emit an intense green light upon uptake in the cancer cell’s nucleus via endocytosis,
facilitating cell imaging. Furthermore, the nanogel was also disrupted in the presence of a reducing agent, which reacts with the disulde crosslinkers in the nanogel,
resulting in oxidative breakage. The light activated the release of DOX-HCl, pH,
and Dithiothreitol (DTT) reducing agent. In vitro assessments for cytotoxicity
15 Stimuli-Responsive PEGylated Nanocarriers
Fig. 15.2 Illustration of multistimuli-responsive systems
443
showed that the nanogel encapsulating DOX was able to cause death in the cancer
cells, an observation enhanced with UV light exposure (Chen etal. 2017).
Two different polymers were synthesized for sensitivity to pH, temperature, and
redox to allow drug release under desired pH5, 40°C, and GSH≥10mM [(Poddar
et al. 2020). The synthesized polymers were 2-(2-((4-(hexyloxy)benzyloxy)carbonyl)ethylthio)ethyl acrylate (HBCEEA), and N-isopropyl acrylamide (NIPA) and
poly(ethylene glycol methyl ether acrylate) (PEGMA) copolymer, which are sensitive to pH, and temperature and redox potential, respectively. Combined, these two
polymers result in polymer poly[HBCEEM-b-(NIPA-r-PEGMA)] (PHNP) with
sensitivity to pH, temperature, and redox potential. Using multistimuli increases the
drug release rate from the polymer when compared to dual-responsive stimuli systems (Poddar etal. 2020).
In some studies, dimers such as Au-FexOy were used to fabricate advanced
inorganic materials termed ‘‘heterostructures” (HSs). These HSs are produced
using more than two inorganic domains to combine the functional moieties of NPs
with various drugs onto the carrier, resulting in a structure with apparent geometric features (Jia etal. 2021). Kakwere etal. prepared the smart inorganic HSs that
responded excellently to magnetic elds with heating. The pH- and thermoresponsive polymers were combined with Au-FexOy-HS moieties. The iron oxides
present in the Au were used as magnetic resonance imaging (MRI) agents and
thermal media for magnetism-induced hyperthermia or heat triggers (Kakwere
etal. 2018).
Meanwhile, the Au-molecules allow for heat release of the FexOy domain
under an AMF.The heat-sensitive polymer pNIPAm was linked to the Au-domain
via a gold mercaptan bond to allow Nile blue dye to be loaded. Finally, the
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surface of the FexOy was attached with a pH-sensitive polymer, PDMAEA, to
deliver non-green uorescent protein-small interfering RNA (GFP-siRNA)
(Kakwere etal. 2018). From the observation, HSs respond to low pH levels in the
tumor microenvironment, triggering the PDMAEA to undergo hydrolysis to
change the potential from positive to negative, releasing siRNA.It was also noted
that at a lower temperature than the (LCST; 43°C), pNIPAm in HSs dissolve in
water and change its conformation to a globule to release the content while
increasing the temperature (above LCST) by AMF (Kakwere etal. 2018; Ruiz
etal. 2022; Zhao etal. 2021).
S. H. Almurisi et al.
15.5 Theranostic Applications ofStimuli-Responsive
PEGylated Nanocarriers
Theranostics refers to the application of a combination of therapeutic and diagnostic
approaches to detect and treat diseases simultaneously or sequentially. The combination of drugs and techniques in this approach has seen major focus in cancer
diagnosis and treatment. One such approach is the use of stimuli-sensitive PEGylated
nanocarriers. The PEGylation technique involves the conjugation of PEG, the
water-soluble polymer chains to any therapeutic molecule (Cheng et al. 2014;
Mishra etal. 2016). The FDA has approved PEG as a safe, non-toxic, and poorly
immunogenic material with poor uptake by the reticuloendothelial system (RES),
allowing for longer drug circulation in the blood and better targeting due to enhanced
permeability and retention (EPR) (Wang etal. 2016).
Further, the addition of an intelligent polymer in the PEGylated prodrugs
increased the response of the nanocarrier to the tumor physiological microenvironment invivo. It developed a novel system for site-specic targeted drug delivery.
The thermoresponsive stimuli systems using smart materials are the most preferred
systems to be studied for pharmaceutical and biomedical applications (Mishra
etal. 2016).
A thermoresponsive PEGylated polyaspartamide derivative (mPEG-PAAHP)
containing pendant phenyl moieties was developed with up to 99% paclitaxel (PTX)
drug loading efciency. The formulated mPEG-PAAHP NPs also had evident temperature responsiveness at 25°C and anticancer activity against Hela cells, suggesting that temperature-responsive mPEG-PAAHP had good potential as a carrier for
hydrophobic anticancer drugs (Zhang and Jiang 2019).
Alamoudi etal. recently reported a noninvasive thermoresponsive drug delivery
strategy using a PEGylated liposome bubble carrier loaded with ammonium bicarbonate (ABC) salt. The authors also report the characterization of ABC–siRNA
thermoresponsive lipoplexes to effectively deliver Bcl2-siRNA and/ or MRP1siRNA to small carcinoma lung cancer cells via endosomal escape. Upon temperature elevation, the ABC load was degraded to produce water, ammonia, and carbon
dioxide, creating a temporary lesion at the membrane of the nanocarrier and releasing the loaded drug (Chen etal. 2014). It was reported that the cancer cells took up
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the siRNA-liposomes in 5minutes, followed by release of the siRNAs in the cytoplasm for successful gene silencing (Alamoudi etal. 2017; Chen etal. 2014).
A recently developed PEGylation polyphenol–cisplatin complexation-based
core-shell structured nano-prodrug (PEG-GAx/Pt) has been studied using pH and
ROS-responsive targeted system (Dong et al. 2022). First, the PEG-GAx/Pt,
methoxyl-PEG is terminated with one (PEG-GA) or two (PEG-GA2) gallic acid
moieties and was complexed with cisplatin (CDDP) into homogeneous NPs. The
drug release of the Pt invitro was studied at pH5.0 and pH7.4, respectively. The
results indicate that at pH5.0, in the span of 48hours, the PEG-GA/Pt and PEG-GA2/
Pt NPs had released 47% to 59% of Pt. These values were reduced to 20% less in
both PEG-GA/Pt and PEG-GA2/Pt NPs at pH7.4. Under acidic pH, Pt release acted
on the polyphenols to weaken the bonds between them and Pt (II). To promote the
ROS-responsive, H2O2 (reducing agent) was added, and an oxidation reaction with
the galloyl group promote the release of the Pt (Dong etal. 2022). Therefore, the
researchers suggested that PEG-GAx/Pt NPs stayed longer in the circulatory system
and presented localized accumulation at the tumor site, thus lowering its toxicity
prole and improving its action on the tumor.
In another study, Song et al. also fabricated pH-sensitive PEGylated DOX
micelles with self-assembly ability in aqueous solutions via esterication and Schiff
base reactions. The NPs had high drug encapsulation efciencies and were highly
sensitive to pH for controlled drug release. In MCF-7 cancer cells, the micelles
showed fast prodrug internalization with good antitumor activity (Song etal. 2021).
Under normal physiological pH, the bridged Schiff bases maintained the structure
of the nanoparticle but were able to disassemble in more acidic environments.
Furthermore, cell viability assays indicated that PEG-Schiff-DOX NPs were more
potent against human breast cancer cells (MCF-7) when compared to free
DOX. Further studies using the nanoparticle revealed a new DOX-based PEGSchiff- DOX polymer with programmed DOX release behavior; the new polymer
has the potential for higher drug loading, release over longer durations, and increased
bioactivity (Song etal. 2021).
15.6 Clinical Status, Challenges, andOutlook
Polymeric nanocarriers have received interest from researchers in recent years due
to their function as carriers for various molecules, including bioactive drugs, proteins, genes, and nucleic acids, for effective use in therapeutic and pharmacological
applications (Bilal etal. 2021). The therapeutic nucleic acids cargo may be intercepted and/or destroyed before it reaches the target by the various physiological
barriers in the blood and tissue via opsonization, endocytosis by the mononuclear
phagocytic system, tissue pressure, endosomal escape, and intracellular transmission (Yu etal. 2021). Through years of study of nanomaterials, strategies to overcome these challenges have been developed. Therefore, acid- or enzyme-separable
PEGylation is used to achieve surface charge shielding to increase steric stability.
PEGylation is attaching PEG polymer chains, either covalently or noncovalently, to
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molecules and macrostructures (Osman etal. 2018). Interestingly, these polymeric
nanocarriers can be designed and fabricated to respond to certain stimuli or triggers
based on the mechanism of release; this includes endogenous or exogenous factors
to ensure the drugs are delivered at the target site and following a controlled release
pattern. Examples of triggers include enzymes, temperature, redox values, pH, glucose levels, or oxygen levels intracellularly, and light, ultrasound waves, magnetic
elds, or light for outside triggers (Das etal. 2020).
Epirubicin-loaded polymeric micelles (NC6300) have begun phase I and II
investigations (NCT03168061) to treat hepatocellular cancer in clinical trials as pHstimulated nanoparticles (Das etal. 2020). The micelles are pH-responsive; in the
patient, variables such as tumor pH or reducing agents present in the circulatory
system have made them challenging to manage (Kamaly etal. 2016).
Therefore, most clinical trials are exogenous stimuli-responsive nanosystems
(Abu-Thabit and Makhlouf 2018). Two magnetically sensitive iron-based nanocarriers, iron oxide magnetite (Phase IV, NCT00920023) and DOX-loaded iron and
carbon (Phase I/II, NCT00041808), are currently undergoing clinical trials to treat
cancer. Additionally, the following three clinical studies used the thermally sensitive
DOX-incorporated liposomes: individuals suffering from recurring regional breast
cancer are being studied in phases I and II to determine the safety of the treatment,
including highest tolerated dose, pharmacokinetics, and effects of hyperthermia
(NCT00826085); phase III of the ThermoDox with radiofrequency ablation for
hepatocellular carcinoma treatment has become complete (NCT00617981). Also,
targeted antibody-drug conjugate in a clinical trial for Trastuzumab Emtansine
alongside Docetaxel and possibly Pertuzumab in patients with Metastatic breast
cancer (Phase I/II, NCT00934856).
The design of stimuli-responsive nanocarriers still faces certain challenges.
Although there has been progress, creating stable nanocarriers in a healthy medium
is still difcult. The problem of overdesigning nanocarriers with various functionalities in one molecule complicates their ability to be used in clinical trials (Kaushik
etal. 2022). Additionally, the clinical translation of nanotherapeutics depends on
their large-scale, highly repeatable manufacture; many nanotherapeutics cannot
reach the market due to their intricacy (Zhang etal. 2020).
More and more, researchers are focusing their attention on developing methods
for early disease diagnosis and treatment using nanotechnology. Strategies for
improved targeted drug delivery and diagnostics with high efcacy are explored to
achieve this. The main objectives of such research are to shed insight into methods
that can enhance targeted drug administration and imaging while preserving efcacy, and extensive research has been done. The engineered nanocarriers have
helped overcome some of the problems associated with ‘free’ drug delivery (limited
bioavailability, drug resistance, and drug toxicity), such as PEGylated nanosystems
functionalized with biologically active moieties (Tapasya etal. 2022).