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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5894_Библиотеки_им_академика_М_И_Перельмана.pdf
7 PEGylated Nanocarrier asaPromising Tool forSite-Specic Delivery ofTherapeutics
217
transport in the body, is suitable for use in these formulations due to its high capacity for loading nucleotides, biodegradability, non-toxicity, and consistent production procedure. Additionally, albumin is employed in gene therapy. Targeted drug
delivery approaches to the tumor can enhance anticancer efcacy and improve the
safety prole by sparing healthy tissues.
Recently, tumor-targeted monoclonal antibodies (mAbs) such as cetuximab,
trastuzumab, and anti-CD3 mAb as well as other targeted ligands (including folate,
RGD, and apolipoproteins), have been bound to the surfaces of albumin nanoparticles, further functionalizing them, enhancing drug uptake in tumor cells (Altintas
etal. 2013). The epidermal growth factor receptor (EGFR) is highly overexpressed
on the surface of tumor cells. Altintas etal. developed a glutaraldehyde crosslinked
albumin core that has a surface modied with bifunctional PEG 3500 and the single
variable domain of antibody-(Ega1) against the epidermal growth factor receptors.
The multikinase inhibitors 17,864 have been loaded into the core of the nanoparticles and are retained into the particles via Lx-based platinum coordinal linkagewhich couples the drug due to methionine residue of albumin and released in a
reductive environment of the cytosol, where the 17,864 is released from the platinum linker. Seventeen thousand eight hundred sixty four is an analogue of sunitinib.
Multikinase inhibitors inhibit the activity of several receptor tyrosine kinases by
competitive inhibition with ATP, and are thus able to intervene in proliferation and
survival of tumor cells and angiogenesis. Multikinase inhibitors inhibit the activity
of several receptor tyrosine kinases by competitive inhibition with ATP, and thus are
able to intervene in proliferation and survival of tumor cells and angiogenesis.
A study reveals that in comparison to PEGylated nanoparticles, nanoparticles
modied by EGa1-PEG demonstrated a 40-fold higher afnity for EGFRoverexpressing cancer cells. By clathrin-mediated endocytosis, the nanoparticles
loaded with 17,864-Lx were taken up by the tumor cells followed by lysosomal
degradation. EGa1-directed nanoparticles, when administered intracellularly, successfully release the kinase inhibitor and reduce tumor cell growth; however, no
anti-tumor effect was observed on 14C cells upon administration of the non-targeted
formulation (Altintas etal. 2013)
The utilization of monoclonal antibodies (mAbs) and transferrin is widespread
as targeting ligands for actively targeted nanomedicine formulations. In the family
of epidermal growth factor receptors, the human epidermal growth factor receptor 2
(HER2) is overexpressed in the stomach, ovary, lung, and breast cancers (Tai etal.
2010). It comprises a tyrosine kinase domain inside the cell as well as an external
ligand-binding domain. It might be argued that HER2 is an ideal marker for precise
delivery to tumor cells because it is an accessible cell surface receptor that is overexpressed in both original tumors and metastatic locations. The anti-HER2 monoclonal antibody 1F2 recognizes the extracellular domain of HER2 exclusively.
Kouchakzadeh etal. (2013) formulated a PEGylated human serum albumin (HSA)
nanoparticle that is linked to a thiolated 1F2 mAb and allows for the incorporation
of many drugs and nucleotides. For 1F2-modied nanoparticles, PEGylation can
produce the maximum cellular absorption.
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S. Acharya et al.
According to different studies, brain endothelial cells with expressed transferrin
receptors mediate the endocytosis of transferrin by the cells. Most polar nucleosides, such as azidothymidine, an HIV-1 chemotherapeutic drug, do not easily cross
the blood-brain barrier. Mishra et al. (2006), formulated transferrin-anchored
PEGylated albumin nanoparticles with azidothymidine loading (Tf-PEG-Nps)
(Fig.7.12f). By employing PEG to modify the surface, surface-active RES interception and sequestration of nanoparticles might be prevented.
7.6.7 PEGylated Dextran forTargeted Drug Delivery
Dextran, a polymer composed of glucose residues primarily connected by 1,6bonds, serves as a drug transporter. Nevertheless, there are specic challenges associated with dextran such as high molecular weight dextran that has been implicated
in immunogenicity. The dextran molecule grafted with short PEG residues serves as
a better approach than long-chain dextran as a carrier system as shown in Fig.7.12g.
After attaching several PEG residues, the dextran core may still include free reactive
groups that are ideal for the attaching or single-point modication of a variety of
medicines, such as proteins and peptides, to produce their long-circulating forms.
Lukyanov etal. synthesized PEGylated dextran and from the biodistribution studies, it was reported that Dextran’s liver absorption is reduced and its circulation
half-life is markedly extended by PEG alteration. The amount of PEG residues
added determines the extension of the circulation time. Further, it was concluded
that the remaining reactive groups, such as amino groups, in the PEGylated dextrans, make them ideal long-circulating transporters for therapeutic as well as diagnostic substances (Lukyanov etal. 2004).
In another study, Naeye etal. synthesized PEGylated dextran nanogel for the
delivery of siRNA.It was concluded from the study that PEGylated nanogels were
readily absorbed by HuH-7 human hematoma cells and A431 human epithelial carcinoma cells. In addition, siRNA-loaded PEGylated nanogels signicantly reduced
enhanced green uorescent protein (EGFP) levels in a human hepatoma cell line
(HuH-7_EGFP) while being non-toxic to the cells (Naeye etal. 2010).
7.6.8 PEGylated Carbon Nanotube forTargeted Drug Delivery
Carbon nanotubes (CNTs) (Fig.7.12h) have acquired a lot of attention in the biomedical eld since they were discovered by Sumio Iijima in 1991 because of their
peculiar framework and characteristics which include high aspect ratios, sizable
surface areas, rich surface chemical functionalities, and size stability on the nanoscale (Son etal. 2016). A single graphene sheet can be utilized to create singlewalled carbon nanotubes (SWNTs), while multiple graphene sheets can be utilized
to create multi-walled carbon nanotubes (MWNTs) (Elhissi etal. 2012).
Additionally, studies have reported that non-spherical nanocarriers (such as
CNTs) are preserved in the lymph nodes for a sustained duration as compared to the
7 PEGylated Nanocarrier asaPromising Tool forSite-Specic Delivery ofTherapeutics
219
globular nanocarriers (e.g., liposome) (Bottini etal. 2011; Elhissi etal. 2012). The
tiny nanoneedle mechanism allows for easy passage of functionalized CNTs
(f-CNTs) across the plasma membrane with the help of an energy-dependent,
endosome- mediated manner. This is because CNTs can be attached with large targeting moieties to offer sustained/controlled release behavior with cellular targeting.
It is a proven technique for treating cancer by stimulating apoptosis in cancer
cells with the help of mitochondrial targeting. Many cancer cells develop antiapoptotic properties by upregulating anti-apoptotic proteins, such as B-cell lymphoma- 2 (Bcl-2), Bcl-XL, and myeloid cell leukemia-1 (Mcl-1), which prolongs
their continuity. Bcl-2 proteins have been a potential therapeutic target for the development of methods to eradicate cancer cells. Due to their favorable pharmacokinetic, safety, and superior cellular internalization proles, PEGylated Carbon
Nanotubes (CNTs) have been used as a promising platform for delivering a variety
of drugs, including small molecules and biomacromolecules. These anti-apoptotic
proteins are susceptible to being inhibited by some small molecules like ABT737.
Kim etal. (2017a, b) created a non-covalently bonded PEG-coated carbon nanotube-
ABT737 nanodrug that enhances mitochondrial targeting and boosts the effectiveness of therapy against lung cancer. Apoptosis was brought on by the
PEG-CNT-ABT737 nanodrug which was built up in the mitochondria of A549 nonsmall cell lung cancer cells. The proposed mechanism was abruption of mitochondrial membrane potential (MMP), lowering the expression of Bcl-2, and production
of intracellular ROS generation resulting in enhanced efcacy against lung cancer.
In another study by Mehra and Jain (2015), it was reported that the nuclear hormone receptor superfamily’s estrogen receptors (ERs) are overexpressed in malignant cells. After connecting specically to each receptor by endocytosis or a tiny
nanoneedle mechanism, MWCNTs tethering (Estrogen) likely distributes doxorubicin (DOX) more effectively into the malignant cells. Due to the upregulation of
estrogen receptors (ERs) on human breast MCF-7 cells, estrone-anchored nanotube
formulation was more readily absorbed than free DOX. Similarly, the elevated
cancer- targeting propensity of the estrone-anchored MWCNTs formulations was
also validated by the pharmacokinetic and boosted anti-tumor actions.
7.6.9 PEGylated Quantum Dots forTargeted Drug Delivery
The utility of quantum dots (QDs) (Fig.7.12i) for biological applications is predicated on stably dispersing the particles in aqueous media. Their hydrophobicity and
toxicity, however, limit their application in bioimaging (Xiao etal. 2014). To overcome this challenge, the surface of the QDs can be appropriately modied or they
can be encapsulated in a suitable polymer. Hydrophobic drugs have been routinely
delivered using PEG as it is not only highly soluble in organic solvents but is also
biodegradable and biocompatible. Targeted drug delivery has been explored to treat
inammatory bowel disease. However, due to the lack of specic receptors, this
strategy has resulted in suboptimal efcacy as well as intolerable toxicity. Epithelial
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S. Acharya et al.
cells and inltrating immune cells in the colon have been reported to over-express
CD98 upon inammation.
Xiao etal. (2014), developed nanoparticles loaded with CD98 Fab′-conjugated
quantum dots (Fab′-NPs). CD98 antibodies were digested and reduced to generate
Fab′–SH. Next NPs were coated with a hetero-bifunctional cross-linker (MAL-
PEG- NHS), yielding maleimide-functionalized PEG-NPs (MAL-PEGNPs). Finally,
MAL-PEG-NPs were reacted with Fab′–SH to obtain the nal NPs (Fab0-NPs). In
vitro experiments revealed that the internalization of Fab′-NPs into cells occurred
via CD98-mediated endocytosis. The study also demonstrated superior cellular
uptake efciency.
Black phosphorus quantum dots (BPQDs) have been recently discovered and
they offer promising biomedical applications. Moreover, phosphorus, which constitutes roughly 1% of human body weight, is not only an essential macronutrient but
is also known for its biocompatibility. A nanoplatform based on BPQDs has been
designed for targeted tumor therapy. Wang etal. (2020), developed a novel FA (folic
acid)-PEG@BPQD@DOX formulation for targeting the folate receptor (FR) in
293T mouse xenograft. Briey, reactive oxygen and heat were produced in the
BPQD upon laser irradiation, which further resulted in cell damage. Meanwhile, an
increase in temperature led to drug release from the nanocomposite. Therefore, an
excellent tumoricidal effect was demonstrated by this BP-based drug delivery system that combined chemotherapy, targeted synergistic photodynamic therapy
(PDT), and photothermal therapy (PTT).
7.6.10 PEGylated Chitosan forTargeted Drug Delivery
Among all other polymeric nanoparticles, chitosan-based nanoparticles are the most
effective, economical, and eco-friendly. Chitosan nanoparticles (ChNPs) (Fig.7.12j)
have attracted immense attention for biomedical applications due to their cationic
characteristics, electrostatic interactions, biodegradability, and biocompatibility. A
biological macromolecule called chitosan has a variety of bioremediation, anticancer, and drug carrier capabilities. Numerous studies have shown that ChNPs are a
potential targeted medication delivery mechanism for the treatment of cancer. Many
growth factors or growth factor receptors, including the vascular endothelial growth
factor (VEGF) family, the epidermal growth factor (EGF) receptor family, and the
transferrin receptor are overexpressed on the surface of tumor cells in cancer
(Herdiana etal. 2021).
Chitosan nanoparticles (NPs) were modied at the surface with PEG to provide
stealth character and transferrin (Tf) for the active targeting function by transferrin
receptor-mediated endocytosis to promote drug delivery to cancer cells. It was discovered that cancer cells took up NP-PEG-Tf more readily than non-targeted cells.
Recent developments in monoclonal antibodies for targeted drug delivery represent a signicant advancement in the biomedical profession, particularly in the
treatment of breast cancer (Nag etal. 2016). To improve longer blood circulation
times, higher solubility rates, better RES escape capabilities, and less antigenicity,
7 PEGylated Nanocarrier asaPromising Tool forSite-Specic Delivery ofTherapeutics
221
doxorubicin-loaded chitosan nanoparticles were treated with polyethylene glycol.
Additionally, labeling these nano-systems with breast cancer-specic monoclonal
antibodies (mAbs) like anti-human mammaglobin (Anti-hMAM) and anti-human
epidermal growth factor (Anti-HER2) has been a promising method to increase the
specicity and sensitivity levels of the developed CSNPs system, potentially
improving the survival rate and quality of life of breast cancer patients (Helmi
etal. 2021).
7.7 Site Specific Delivery ofTherapeutics
Site-specic drug delivery is the specialized form of drug delivery in which the drug
is targeted to the desired target site in optimum therapeutic concentrations at a predened rate. This avoids potential off-target adverse effects ranging from acute to
chronic effects followed by coma and death. Site-specic delivery of the drug can
be achieved through some of the following approaches:
1. Utilizing a carrier moiety in which the drug can be loaded, this can be done to
safeguard the drug in other parts of the body.
2. Ligand-mediated targeting for release of the active drug only at the desired site.
3. The drug can be chemically or physically modied for targeted release, e.g.,
Prodrug approach (Hassanzadeh 2021).
The site-specic delivery of the drugs can be accomplished by using the
PEGylation strategy for various disorders as follows.
7.7.1 Brain Disorders
In the ght against deadly brain diseases, targeted drug delivery via the blood-brain
barrier (BBB) is a challenging task. The main obstacles include rapid blood ow,
RES absorption, and nanocarrier excretion. PEGylation has proven to be benecial
for the targeted delivery of drugs to the brain. It is generally known that PEGylation
can lengthen the period that nanocarriers remain in the bloodstream by preventing
RES uptake, which is essential for enhancing the uptake of nanocarriers into the
brain. For the targeted delivery of molecules that bind to the brain, PEGylation also
serves as a linker. This carrier system is used to deliver proteins, peptides, and drugs
of high molecular weight to the brain (Gajbhiye etal. 2020).
PEGylated dendrimers are also employed for targeted brain delivery. Santos and
coauthors used various generations of cationic poly(amido amine) (PAMAM)
linked with PEG for the treatment of stroke. BBB model’s integrity was maintained
invitro, and rat primary astrocytes or bEnd.3 (bEnd.3 is a mouse brain cell line
derived from BALB/c mice) cells were not negatively affected by PEGylated dendrimers, and no cytotoxicity was observed. After 24h of injection, PEGylated dendrimers were found in the ischemic cortex neurons of animals suffering from focal
brain ischemia, demonstrating their ability to serve as a delivery method during
stroke (Santos etal. 2018).
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S. Acharya et al.
Further Zhang et al. reported that DOX-loaded (Arginyl-glycyl-aspartic acidpeptide) RGD-PEG PAMAM dendrimer can target integrin receptors that are overexpressed in brain cancer (glioma). When tested on C6 glioma cells, it was found
that the dendrimers were more effective than non-targeted PEGylated
PAMAM. RGD-PEG-PAMAM accumulated in the tumor more signicantly in
mice with C6 brain tumors than in mice with unmodied dendrimers or free medicines. Also, the survival rate in mice treated with the modied formulation (RGDPEG- PANAM) was signicantly higher than the other groups (Zhang etal. 2011).
7.7.2 Pulmonary Disorders
Inhalation-based drug delivery systems using nanocarriers have become the subject
of in-depth research. These drug delivery technologies offer strong, adaptable tools
for specically targeting and treating pulmonary disorders.
Kolte etal. prepared PEGylated nanoparticles of poly(lactic-co-glycolic acid)
(PLGA) and cationic polymer polyethyleneimine (PEI) for delivering
pDNA.PEGylation of nanoparticles resulted in decreased toxicity and improved
cellular absorption and pDNA expression. It further enhanced the mucus barrier
penetration of nanoparticles while preventing pulmonary macrophage absorption.
In the next step, PEGylated composite NPs were lyophilized into a dry powder
inhaler (DPI) and combined with lactose carrier particles. This increased the aerosolization characteristics and lung deposition with no alteration in the pDNA bioactivity. Thus it can be concluded from the study that local administration of pDNA to
pulmonary tissue for efcient treatment of fatal lung illnesses may be made possible
through this integrated method (Kolte etal. 2017).
Kim etal. studied the enhanced anti-cancer activity of PEGylated erlotinib for
the treatment of non-small cell lung cancer. The formulation showed signicant
cytotoxicity in HCC-827 and NCI-H358 and also exhibited a better remission of
tumor, indicating a strong therapeutic efcacy. In comparison to the control and free
erlotinib groups, mice treated with the PEGylated nano formulation showed tumor
reduction by ve and twofolds, respectively. Based on these ndings, it can be concluded that the prepared formulation offers a promising drug delivery strategy for
the treatment of lung cancer (Kim etal. 2017a, b).
7.7.3 Cancer
The PEGylation approach can be employed in the formulations meant for tumor
suppression. The extent of PEG coating required for tumor accumulation has been
clearly stated by Mozar and Chowdhury. Low-density PEGylation creates a “mushroom state” (Fig.7.13), that is susceptible to increased opsonization (engulfment of
any foreign material, xenobiotics, or biomolecules by opsonin proteins) and cellular
absorption and can eventually demonstrate higher tumor accumulation and enhanced
intra-tumor drug effectiveness. However, a denser PEG results in less opsonization
7 PEGylated Nanocarrier asaPromising Tool forSite-Specic Delivery ofTherapeutics
Fig. 7.13 Formation of low-density “mushroom state” by PEG moiety
223
and cellular uptake ultimately resulting in less intratumor accumulation (Mozar and
Chowdhury 2018).
In one study, Guo et al. reported the effectiveness of 2,3-dimethylmaleicanhydride- poly(ethylene glycol)-ε-poly--lysine-doxorubicin/lapatinib polymeric
(DMMA-P-DOX/LAP) nanoformulation against breast cancer. After being released
from DMMA-P-DOX/LAP, the DOX and LAP signicantly reduced the tumor in
the MCF-7 (breast cancer cell line) model, and the penetration of active drugs inside
the tumor tissues was effectively enhanced (Guo etal. 2020). Xin etal. synthesized
paclitaxel (PTX) loaded methoxy poly(ethylene glycol)-poly(ɛ-caprolactone)
(MPEG-PTMC) nanoparticles and investigated for their potential anticancer properties against glioblastoma multiform. The concentration of PEGylated nanoparticles was signicantly increased in the brain tissues after 12h of administration. The
survival rate in the animals treated with MPEG-PTMC was higher than in the other
groups (Xin etal. 2010).
Lee etal. studied the effect of albumin-based PEGylated nanoparticles loaded
with PTX (HSA-PEG/PTX) on breast cancer. The spherical HSA-PEG/PTX
nanoparticles have shown effective cellular delivery and resulted in cytotoxicity in
multiple breast cancer cells. The HSA-PEG-based nanoparticles have further demonstrated sustained systemic circulation over 96 h and improved intra-tumoral
retention in a mice model of breast cancer, leading to a noteworthy anticancer effect
along with an extended lifespan of the animals (Lee etal. 2018).
7.7.4 Inflammatory Disorders
Inammation is the rst response of the body’s immune system, and excessive or
persistent inammation causes chronic inammatory diseases such as rheumatoid
arthritis and inammatory bowel disease (Cao etal. 2015). Activated macrophages
greatly inuence in initiation, maintenance, and pathogenesis of this disease by producing several pro-inammatory cytokines. Suppression of pro-inammatory cytokines and mediators from activated macrophages has been investigated as a key
strategy for the treatment of inammatory diseases. There are many Diseasemodifying anti-rheumatic drugs (DMARDS), which are being used for treatment.
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S. Acharya et al.
However, lack of efcacy and drug-related adverse effects are important reasons for
the discontinuation of treatment in patients with inammatory diseases. The development of new biological therapies seeks to address these problems by specically
targeting the pathogenic mechanisms of disease (Mcdonnell etal. 2013).
Folate (FA) receptors are highly overexpressed on these activated macrophages
but are limited in normal tissues. FA conjugate was considered a therapeutic target
drug for the population of pathologic cells (Pirmardvand Chegini et al. 2018).
Chandrasekar etal. (2007) synthesized folate targeted PEG conjugates of anionic
poly(amidoamine) (PAMAM) generation 3.5 dendrimer (G3.5 PAMAM) loaded
with indomethacin as a targeted drug delivery system to treat inammation. The
conjugates revealed that approximately 7, 11, and 20 folate-PEG moieties were
attached to each molecule of G3.5 PAMAM dendrimer. Drug loading was signicantly increased in the folate PEG conjugates when compared with the nonconjugated dendrimer. The folate-PEG conjugates had shown reduced uptake by RES
organs and in particular, the exposure to stomach was nearly one-tenth of the nonconjugated dendrimer, indicating the limited gastric-related side effects.
7.7.5 Bone Disorders
Osteoarthritis (OA) is a chronic and irreversible degenerative disease characterized
by synovial inammation and cartilage destruction (Xiong etal. 2021). Although
many clinical therapeutics like nonsteroidal anti-inammatory drugs (NSAIDs),
glucocorticoids (GCs), and other drug treatments are effective strategies for OA,
there are still some shortcomings that need to be overcome such as frequent injection, gastrointestinal, and cardiovascular risks, and potential overdose. Formononetin
(FMN) is a phytoestrogen puried from natural herbal plants (e.g., Astragalus mem-
branaceus, Trifolium pretense). It was reported to have pharmacological effects
including anti-inammatory capacity by suppressing IL-6 and TNF-α in neuroinammatory rats and effectively antagonized proteoglycan loss by decreasing the
expression of Matrix metalloprotease (MMP)-3, MMP-13, and attenuating oxidative stress. However, the bioavailability of FMN is low because it has poor water
solubility and can hardly penetrate through the dense matrix of cartilage. Besides,
with no specic targeting, FMN may be rapidly cleared in the joint. Sometimes, the
retention time after intra-articular (IA) injection is short and repeated articular
injection is inevitable. Thus, it is imperative to increase the water solubility and
cartilage-targeting effect of FMN to improve its pharmacological effects (Xiong
etal. 2021).
Polymer-drug conjugates (PDCs) are uniform-sized nanoparticles formed by
linking hydrophilic polymers with drugs. It is one of the effective strategies in drug
synthesis to enhance drug solubility and efcacy. Polyethylene glycol (PEG) with
negligible toxicity and immunogenicity has been widely applied in PDCs, and it has
increased drug solubility and improved cell growth (Xiong etal. 2021).
For cartilage-targeting, peptide-mediated (e.g., chondrocyte-afnity peptide
CAP, anti-inammatory peptide KAFAK, and RGD-modied) delivery systems
7 PEGylated Nanocarrier asaPromising Tool forSite-Specic Delivery ofTherapeutics
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have been used for modication of free drug molecules. Xiong etal. (2021) synthesized a nanosized amphiphilic polymer-drug conjugate (PEG-CollBP-FMN,
PCFMN) for OA therapy, which was prepared by PEGylation of FMN followed by
coupling with cartilage-targeting peptide (CollBP) to increase the bioavailability of
FMN. PCFMN showed higher drug solubilization than unmodied FMN after
PEGylation, demonstrating the effectiveness of PEGylation. PEGylation can
enhance the pharmacokinetic properties of drugs. With excellent hydrophilic ability,
PEG chains grafted on nanoparticles generate a sufciently thick hydrated cloud
that strongly prevents NPs from aggregation. As evidenced by the cellular uptake
analysis, the CollB-peptide conjunction endowed PCFMN with a high cell penetration efciency. Thus, PCFMN, a cartilage-targeting, and PEGylated nanodrug, had
a more remarkable effect on down-regulating MMP-13 preventing cartilage degradation, and improving solubility. This contributed to enhanced anti-arthritic effects
both invitro and invivo indicating that a targeted nano-drug design is a promising
therapeutic strategy for OA (Xiong etal. 2021).
7.7.6 Blood Disorders
Hemophilia A and B involve a decrease in coagulation factors such as factor VII
which results in prolonged bleeding. The PEGylation approach helps to prolong the
half-life of drug or drug-loaded carriers in the blood. The brand name drug
“Esperoct” includes factor VIII in glyco-PEGylated form for the treatment of hemophilia A. This was found to increase the drug’s half-life by 1.6 times (Zhou
etal. 2015).
Apart from that, PEGylated nanocarriers nd applications in leukemia. Here
PLGA is modied with mPEG for modulating its hydrophilicity as well as to render
the nanoparticles with stealth properties to evade the RES and prolong systemic
circulation. These biodegradable and biocompatible nanoparticles have been extensively studied for applications in controlled release. Following intravenous administration, the residence time for PLGA-mPEG nanoparticles was reported to be
signicantly longer than that for PLGA nanoparticles which were rapidly cleared
from circulation. This has been attributed to the steric barrier provided by PEG
which minimizes the opsonization of the particles.
7.8 Stimuli-Sensitive Nanocarriers
To improve drug delivery specicity, efcacy, and biological activity, stimulisensitive nanoparticles have been logically conceived and designed based on tissue
pathology, tumor microenvironment, and intracellular compartments. Overall, the
stimuli that the nanocarriers can respond to are the following: internal stimuli such
as redox potential, pH, hypoxia, H2O2, ATP, and specic enzymes; external stimuli
can include thermal, magnetic and electric eld, ultrasound, and light (Fig.7.14).
The stimuli-sensitive functions make it easier to release drugs on demand or under
226
Fig. 7.14 Various stimuli responsive strategies
S. Acharya et al.
control, promote site-specic accumulation, activate drugs or probes, expose
ligands, activate nanoparticles, convert charges, signal in particular locations, detect
unique pathological factors or molecules, and thus widely used as theragnostic
agents. Furthermore, external forces, or stimuli, may also be able to alert nanocarriers to changes in their biological performance. For instance, an external magnetic
eld may enhance the tumor’s magnetic nanocarrier accumulation to rise.
Additionally, the stimuli might be used to activate specic prodrug-formulated
nanocarriers biologically in sick areas or cells to provide precision therapy
(Mi 2020).
7.8.1 External-Responsive Nanocarriers
7.8.1.1 Ultrasound-Responsive PEGylated Nanocarriers
Researchers have developed PLGA-PEG nanoparticles as suitable vehicles for the
efcient delivery of miRNAs using ultrasound and microbubble approaches. This
type of delivery system was specically used for the delivery of plasmid vectors
expressing a specic promotor called survivin on their surface, for the treatment of
cancer. This novel approach overcomes the limitations associated with miRNA
delivery into the body. Researchers have developed a formulation, which upon
administration into the body, followed by the ultrasound treatment of particular frequency, releases miRNA for anti-cancer therapy (Devulapally etal. 2018). There are
many challenges associated with systemic delivery of siRNA and the most troublesome challenge is the rapid degradation of naked siRNAs. siRNAs, when administered as complex formulation, suffer from aggregation issues thereby getting
engulfed by the macrophages in the body.
To combat these issues, scientists have invented “SiPlex,” a complex of siRNA
and liposomes. The most effective means of delivery of SiPlex is by coupling it with
PEG moiety and administering it as a microbubble formulation. Ultrasound
radiation- triggered release of these microbubbles was signicantly higher than the