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7 PEGylated Nanocarrier asaPromising Tool forSite-Specic Delivery ofTherapeutics
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unaltered PEG-siPlexes. This SiPlex enters the cells on exposure to ultrasound and
entry is more efcient than the formulations without PEG moiety. Also, the developed PEG-siPlexes showed greater efcacy in gene silencing, as compared to
unmodied drugs. One more advantage of this system is that it only releases the
siRNA in the presence of ultrasound, so the time and space for the release of siRNA
in the body can be precisely controlled with this approach (Vandenbroucke
etal. 2008).
7.8.1.2 Thermal-Responsive PEGylated Nanocarriers
Researchers have explored the PEGylation approach for inducing photothermal
damage to tumor cells when exposed to light, known as photothermal therapy.
Various nanomaterials including nanostructures, carbon nanotubes, and nanographene have been investigated for the delivery of anti-cancer agents by using the
photothermal approach. The PEG-modied nanocarriers possess very strong optical
absorption properties when they are subjected to NIR radiation of frequency in the
NIR window. Specically, an NIR laser of 808nm and a power density of 1W/cm2
was applied and it resulted in a rapid increase in the temperature in a concentrationdependent manner. This makes for an efcient stimuli-responsive approach to the
delivery of anti-cancer medications (Farani etal. 2020).
Doxorubicin suffers from a change in the crystallization state at various temperatures. Doxil®, a stealth liposomal formulation of doxorubicin, was studied for this
thermal effect. Various crystalline states of the drug can be easily conrmed by differential scanning calorimetry (DSC). To study the effect of temperature on
Doxorubicin, scientists have studied the Doxil® formulation in comparison with
unloaded liposomes. Techniques like microcalorimetry provide information about
the changes in thermal behavior of the drug under different heating programmed in
an orderly fashion.
For this study, PEGylated Doxorubicin liposomes were prepared and upon application of heat for a prolonged period of time (2h at 80°C), irreversible thermal
behavior of the drug was analyzed. This indicates the leakage of the drug from the
formulation on prolonged heat treatment (Perinelli etal. 2017). Researchers have
developed PEGylated NGO (Nanosized Graphene Oxide), by a one-step green
reduction reaction. This PEGylated NGO is useful in photothermally controllable
drug delivery systems. This formulation, upon laser irradiation with an 808nm
laser, shows a 14-fold increase in drug release. This PEGylated NGO was found to
show decreased cell viability, loss of mitochondrial membrane potential, and suppression of tumor cell growth. Its effect on the induction of apoptosis has been
studied in various animal tumor models. PEGylation of NGOs has also increased
their stability on prolonged storage (Chen etal. 2014).
7.8.1.3 Magnetic Responsive PEGylated Nanocarriers
Scientists have developed a Doxorubicin formulation for anti-cancer applications
by formulating it with PEG-coated superparamagnetic iron oxide nanoparticles
(SPIONs) for improved drug delivery to cancer cells. SPIONs are magnetic-active
materials, popularly used in many magnetic-responsive drug delivery systems as
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S. Acharya et al.
they get activated upon the application of a magnetic eld. In this study, nanoparticles were loaded with the drug, using a pre-formed DOX-Fe2+ complex, reversible
at lower tumorous pH. Doxorubicin-loaded nanoparticles were found to have a
hydrodynamic size around 60nm and a zeta potential of zero at the physiological
pH.These parameters favored increased stability as well as decreased elimination.
At physiological pH, when compared with the plain drug administration, the liposomes show 60% drug release. The in vitro cytotoxicity of the formulation on
MCF-7 breast cancer cells was equivalent to that of free DOX solution. DOX was
reversibly bound to the SPION surface and PEGylation inuenced the release and
stability of the liposomal formulation (Gautier etal. 2012).
PEGylated liposomes were also studied by the Vannier group, wherein, they
developed citrated SPIONS (Superparamagnetic iron oxide nanoparticles), i.e.,
C-SPIONS and the side effects were studied after PEG coating. The cardiotoxicity
and hepatotoxicity were observed when the liposomes were coated with PEG moiety. The negative charges of the citrate group prevent liposomal aggregation and
enhance the stability of the formulation. The stealth nature imparted by the PEG
moiety shows improved release characteristics under the application of a magnetic
eld as well as improved stability properties. PEGylated C-SPIONS were also
found to show enhanced doxorubicin efcacy and delivery.
Dual pH/magnetic responsive PEGylated Fe3O4 DOX nanoparticles have been
developed to overcome limitations of the drug such as non-selective distribution and
side effects. Citrate-coated nanoparticles were prepared and then functionalized
with the PEG moiety to obtain PEGylated nanoparticles. The nanoparticles were
roughly spherical in shape and showed strong magnetism as compared to the neat
DOX nanoparticles. They also showed high drug loading capacity, pH, and magnetic eld-responsive drug release (Ji etal. 2018).
7.8.2 Internal-Responsive Nanocarriers
7.8.2.1 pH-Responsive Systems
Solid tumors have a unique microenvironment that is characterized by several factors such as elevated temperatures, elevated expression of certain enzymes, a redox
potential biased toward reduction, and acidic pH, usually around 6.5. The low extracellular pH of solid tumors is due to their preference for anaerobic respiration. To
deliver drugs to tumors, pH-responsive NPs have been extensively researched.
Changes in pH trigger drug release in these NPs. This can be achieved by the incorporation of protonatable groups or the formation of acid-labile bonds. pH- responsive
NPs have been designed using protonatable/ionizable groups. Acidic pH results in
charge reversal or protonation of the incorporated functional groups which disturbs
the nanocarrier’s hydrophilic-hydrophobic equilibrium. This imbalance disassembles the NP structure subsequently releasing the encapsulated cargo. Some of the
commonly used ionizable groups include amino, sulfonate, imidazolyl, and carboxyl groups. Drug is released from these NPs through mechanisms that depend on
7 PEGylated Nanocarrier asaPromising Tool forSite-Specic Delivery ofTherapeutics
Fig. 7.15 The pH-responsive PEGMnCaP nanocarriers with contrast amplication ability have
been developed for MR imaging of tumor malignancy. (a) The composition and characterization
of Mn2+-doped PEGMnCaP. (b) PEGMnCaP specically enhanced the contrast in C26 tumors for
three-dimensional (3D) MR imaging. (Adapted with permission from Mi 2020 under CC BY 4.0
DEED Attribution 4.0 International (https://creativecommons.org/licenses/by/4.0/))
229
the acid dissociation constant (pKa) of the introduced functional group such as
aggregation, precipitation, or dissociation (Alsawaftah etal. 2022).
In order to effectively deliver anticancer drugs, one study proposes the formulation of pH-responsive PEGylated palladium nanoparticles (PdNP) as a drug nanocarrier system. To synthesize the nanocarrier, doxorubicin (DOX) had to be
conjugated via hydrazone interaction to the surface of PEGylated PdNPs. It was
shown that HeLa cancer cells took up the NPs preferentially. Studies on invitro
apoptosis have demonstrated that PEGylated PdNPs loaded with DOX induce cell
death. In addition to their low toxicity, the unloaded PEGylated PdNPs were biocompatible. NPs loaded with DOX showed a strong tumoricidal effect in HeLa
tumor xenograft models (Shanthi etal. 2015). pH-responsive PEGylated nanocarriers have also been utilized in MR imaging. Mi etal. have developed Mn2+-doped,
polymer hybrid calcium phosphate (CaP) nanocarriers (PEGMnCaP). This platform
nds application in MR-based tumor imaging as it is endowed with intratumoral
pH-triggered contrast amplication. High relaxivities can be obtained upon binding
of Mn2+ with surrounding proteins This enables specic and sensitive amplication
of contrast in tumors resulting in accurate 2D and 3D MR imaging (Fig. 7.15)
(Mi 2020).
7.8.2.2 Redox-Responsive Systems
Redox-responsive delivery systems with disulde bonds have been well studied by
many researchers. Disulde bonds can be easily broken down by reducing glutathione into sulfhydryl groups, which causes the degradation of carriers and facilitates
the release of cargo. The disulde bond can be cleaved by the tumoral intracellular
glutathione (GSH, 2–10mM), a strong biological reducing agent while remaining
stable in a predominantly oxidizing extracellular space, where GSH concentration
is much lower, 2–20μM (Chi etal. 2017). Since cancer cells have four times the
amount of GSH compared to normal cells, GSH is utilized to create redox- responsive
nano preparations.
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S. Acharya et al.
For instance, Chi etal. (2017) synthesized a novel liposome that was loaded with
doxorubicin (DOX) and showed cytoplasmic drug release that was triggered by
GSH due to disulde linker reduction, PEG de-protection, and liposome membrane
destabilization. Chol-SSmPEG/HA is a sheddable PEG conjugated with cholesterol
through a disulde (eSSe) bond. PEGylation prolongs invivo circulation by preventing the reticuloendothelial system’s (RES) quick clearance. By taking advantage of ligand-receptor interaction, hyaluronic acid (HA) has emerged as a desirable
ligand for intracellular delivery to tumors overexpressing CD44, and it has been
demonstrated to improve anticancer efcacy. Once inside the cells, PEG detachment would cause DOX to be released in response to intracellular GSH.
With many studies on the redox-responsiveness of disulde bonds going on, diselenide bonds are attracting much attention as well. Diselenide bonds have similar
reduction sensitivity and redox-responsive ability as that of disulde bonds. As the
Se–Se bond and C–Se bond have lower bond energy than the of S–S bonds, a more
sensitive redox-responsive delivery system can be designed with the use of diselenide bonds in tumor therapy (Guo etal. 2018). Diselenide-rich amphiphilic diblock
copolymers were fabricated to encapsulate two antitumor drugs with synergistic
therapeutic effects, Camptothecin (CPT) and Doxorubicin (DOX), then visible
light-induced dynamic exchange of diselenide bonds in the hydrophobic core promoted the formation of core crosslinking micelles, CPT/DOX-CCM.Upon intravenous administration, hand-in-hand release of CPT and DOX was accelerated
signicantly in tumor’s redox microenvironments.
7.8.2.3 Enzyme-Responsive Systems
Enzyme-responsive drug delivery systems (DDS) are designed to respond to the
biocatalytic activity of enzymes, resulting in macroscopic changes in their physicochemical characteristics. The development of these responsive elements for DDS
largely depends on the regulation and/or dysregulation of enzymes within the intracellular environment and their involvement in various biological and metabolic processes (Raza etal. 2019).
Certain enzymes that are overexpressed are associated with the pathophysiology
of many diseases. Enzyme-cleavable peptides can be used to create enzyme-driven
nanocapsule deshielding, allowing the drug to be released selectively into cancerous
tissues or tumor cells. Although most nanocapsules cannot be used for intracellular
drug release, enzyme-responsive delivery systems have been designed specically
for cancer treatment. Such targeted delivery approaches can offer superior tumor
inhibition and minimize toxicity in normal tissues. As enzymes are secreted at a
specic time and location, their structural characteristics provide excellent substrate
specicity (Zhang etal. 2017). Enzyme-triggered nanocarriers (NCs) can be created
by modifying their surface, which react catalytically with enzymes overexpressed in
the extracellular environment of cancer cells (Kaushik etal. 2022).
Among the most useful enzymes for developing innovative drug delivery systems (DDS) are proteases, which are commonly elevated in infectious disorders like
cancer. Glycylphenylalanylleucylglycine (GFLG) is an oligopeptide that has been
incorporated in multiple drug delivery systems as an enzyme-sensitive spacer. It is
7 PEGylated Nanocarrier asaPromising Tool forSite-Specic Delivery ofTherapeutics
Fig. 7.16 (a) Schematic representation of the preparation of lysine peptide dendrimer-GFLG-
gemcitabine conjugate (dendrimer-GEM) and (b) tumor uptake of the conjugated nanoparticles is
mediated by the EPR effect and enzyme-responsive drug release
231
preferentially cleaved by the lysosomal cysteine protease cathepsin B, which is
highly expressed in most tumor cells, including breast cancer cells.
In response to this, Zhang etal. (2017), developed an efcient nanoscale chemotherapeutic prodrug, a PEGylated lysine peptide dendrimer-gemcitabine conjugate
(Dendrimer-GEM) based nanoparticle that is responsive to the enzyme cathepsin
B.The dendrimer and gemcitabine (GEM) are conjugated through a highly effective
click reaction using GFLG tetrapeptide. The resulting nanoparticles release the drug
signicantly faster in the tumor microenvironment in response to higher cathepsin
B concentration (Fig.7.16).
7.8.2.4 Hypoxia-Responsive Systems
Solid tumors often suffer from hypoxia, a condition characterized by low oxygen
pressure due to irregular blood ow and high interstitial uid pressures. Hypoxic
regions in tumors can contribute to disease progression, resistance to chemotherapy
and radiotherapy, and relapse. Unfortunately, drug carriers often cannot penetrate
these hypoxic niches, making it challenging to treat tumors in areas such as the
breast, pancreas, cervix, rectum, head, and neck. Among other causes, resistance to
therapy is often induced by poor drug delivery to the hypoxic regions.
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S. Acharya et al.
To address this challenge, hypoxia imaging agents and hypoxia-activated anticancer prodrugs have been developed. In a study, researchers have developed a
nanocarrier PEG-azobenzene-PEI-DOPE (PAPD)that allows for hypoxia-induced
siRNA uptake as well as gene silencing. This nanocarrier comprises polyethylene
glycol 2000, azobenzene, polyethyleneimine (PEI) (1.8kDa), and 1,2-dioleyl-sn-
glycero-3-phosphoethanolamine (DOPE) units. Azobenzene acts as a hypoxiaresponsive linker and undergoes a reduction in the tumor microenvironment of the
hypoxic niches. Researchers utilized azobenzene as a hypoxia-responsive bioreductive linker for hypoxia-targeted delivery of siRNA from PEGylated nano preparations upon PEG removal/cleavage. siRNA delivery was evaluated by linking the
azobenzene unit to PEG2000 at one end. The other end was conjugated to PEI
(1.8kDa)-DOPE to obtain PAPD.PEG2000 was incorporated due to its hydrophilicity and to stabilize the nanocarrier during systemic circulation (Kulkarni
etal. 2018).
7.8.3 Multimodal Responsive Nanocarriers
In multimodal responsive drug delivery, nanocarriers have been developed that
respond to more than one stimulus, such as changes in intracellular pH and GSH,
which help improve the drug delivery. Platinum drug delivery nanocarriers have
been developed to react to intracellular GSH and low pH.While GSH induces separation, controlled drug release is triggered by the low pH. Several responsive
nanoparticles have shown great potential in achieving prolonged systemic circulation, enhanced tumor uptake and penetration, cellular internalization as well as
endosomal escape. For instance, nanocarriers can disassemble at the acidic pH in
the tumor microenvironment. GSH then activates the platinum prodrugs, promoting
penetration to treat pancreatic tumors that are known to have low permeability
(Mi 2020).
Scientists have successfully developed glucose-sensitive vesicles with immobilized glucose oxidase (GOD) using pH-sensitive polymers. The GOD catalyzes glucose to gluconic acid, which then alters the structure of the vesicles and releases
their contents. Researchers have extensively studied GOD-immobilized polymer
vesicles, particularly Gu and colleagues. They employed pH-sensitive diblock polymers, including PEG and ketal-modied polyserine (PEG-poly(Ser-Ketal)), to
encapsulate recombinant human insulin, GOD, and catalase (CAT) to prepare
glucose- sensitive vesicles (Fig.7.17).
Ketal, an acid-labile group, undergoes acidic hydrolysis when gluconic acid is
produced from glucose oxidization, leading to the formation of PEG-polyserine.
PEG-poly serine shows high aqueous solubility and it causes the dissociation of
vesicles which subsequently release insulin. To prolong the release of insulin following subcutaneous administration, vesicles were combined with a thermoresponsive and biodegradable polymer called Pluronic-127. This mixture was reported to
rapidly form a stable hydrogel with evenly dispersed nanovesicles. The
7 PEGylated Nanocarrier asaPromising Tool forSite-Specic Delivery ofTherapeutics
Fig. 7.17 Chemical structure of pH-sensitive copolymer PEG-poly(Ser-Ketal) and schematic representation of enzyme-based glucose-responsive nanovesicle
233
nanovesicles were found to be highly compatible with living tissue and effectively
regulated blood glucose levels in the normal range for up to 5days (Zhao et al.
2017a, b).
7.9 Conclusion
Nanocarriers are often PEGylated to achieve specialized drug delivery mechanisms
with improved target specicity, targeted delivery, regulated drug distribution, and
enhanced drug efcacy invivo. PEG has been incorporated into drug delivery systems to improve the pharmacokinetic prole of both macromolecular therapies and
particulate formulations. This increases the stability, and biocompatibility prole of
the nanoparticle along with increased capability to infuse into the biological membranes and decreases the toxicity of drugs. Out of the two main PEGylation
approaches, non-covalent modication is generally preferred because of the additional benets of the purication and prevention of drug loss. The PEGylated nanocarriers hence formed could be targeted to the desired body site by active (with the
help of specialized receptors) and passive (e.g., EPR effect in cancer) targeting
mechanisms. Several PEGylated targeted nanocarrier systems such as polymeric
nanocarriers, nanobers, quantum dots, liposomes, dendrimers, micelles, proteinbased nanoparticles, and metal-based nanoparticles are well explored for their benets over conventional drug delivery systems. These systems are employed mainly
for the treatment of pulmonary, brain, bone disorders, and gastrointestinal disorders,
and are widely explored in cancer.
234
S. Acharya et al.
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 elds, ultrasound, and light.
Acknowledgments The author, R.K.T, acknowledges the Department of Pharmaceuticals,
Ministry of Chemicals and Fertilizers, India, for supporting the drug discovery and formulation
research at NIPER Ahmedabad. R.K.T also acknowledges the Department of Science and
Technology, Government of India, for a Core Research Grant funding (File No. CRG/2021/005402)
and also acknowledges the Indian Council of Medical Research (ICMR), New Delhi, for the grant
File Id: 2021-14161 and grant File Id: IIRP-2023-4849/F1 for supporting research in RKT lab.
References
Abdelfattah A, Aboutaleb AE, Abdel-Aal ABM, Abdellatif AAH, Tawfeek HM, Abdel-Rahman
SI (2022) Design and optimization of PEGylated silver nanoparticles for efcient delivery of
doxorubicin to cancer cells. J Drug Deliv Sci Technol 71:103347
Agrahari V, Agrahari V (2018) Advances and applications of block-copolymer-based nanoformu-
lations. Drug Discov Today 23:1139–1151
Alsawaftah NM, Awad NS, Pitt WG, Husseini GA (2022) pH-responsive nanocarriers in cancer
therapy. Polymers (Basel) 14:936. https://doi.org/10.3390/polym14050936
Altintas I, Heukers R, van der Meel R, Lacombe M, Amidi M, van Bergen En Henegouwen PMP,
Hennink WE, Schiffelers RM, Kok RJ (2013) Nanobody-albumin nanoparticles (NANAPs) for
the delivery of a multikinase inhibitor 17864 to EGFR overexpressing tumor cells. J Control
Release 165(2):110–118
Andrianov AK (2023) Noncovalent PEGylation of protein and peptide therapeutics. Wiley
Interdiscip Rev Nanomed Nanobiotechnol 15:e1897
Belén LH, Rangel-Yagui CDO, Beltrán Lissabet JF, Effer B, Lee-Estevez M, Pessoa A, Castillo
RL, Farías JG (2019) From synthesis to characterization of site-selective PEGylated proteins.
Front Pharmacol 10:1450
Betancourt T, Byrne JD, Sunaryo N, Crowder SW, Kadapakkam M, Patel S etal (2009) PEGylation
strategies for active targeting of PLA/PLGA nanoparticles. J Biomed Mater Res Part A
91(1):263–276
Bottini M, Rosato N, Bottini N (2011) PEG-modied carbon nanotubes in biomedicine: current
status and challenges ahead. Biomacromolecules 12:3381. https://doi.org/10.1021/bm201020h
Cao J, Naeem M, Noh J-K, Lee EH, Yoo J-W (2015) Dexamethasone phosphate-loaded folate-
conjugated polymeric nanoparticles for selective delivery to activated macrophages and sup-
pression of inammatory responses. Macromol Res 23:485–492
Chandrasekar D, Sistla R, Ahmad FJ, Khar RK, Diwan PV (2007) Folate-coupled
poly(ethyleneglycol) conjugates of anionic poly(amidoamine) dendrimer for inammatory
tissue-specic drug delivery. J Biomed Mater Res A 82A:92–103
Chen J, Liu H, Zhao C, Qin G, Xi G, Li T, Wang X, Chen T (2014) One-step reduction and
PEGylation of graphene oxide for photothermally controlled drug delivery. Biomaterials
35:4986–4995
Chi Y, Yin X, Sun K, Feng S, Liu J, Chen D, Guo C, Wu Z (2017) Redox-sensitive and hyaluronic
acid functionalized liposomes for cytoplasmic drug delivery to osteosarcoma in animal models.
J Control Release 261:113–125. https://doi.org/10.1016/j.jconrel.2017.06.027
7 PEGylated Nanocarrier asaPromising Tool forSite-Specic Delivery ofTherapeutics
Choi CHJ, Alabi CA, Webster P, Davis ME (2010) Mechanism of active targeting in solid tumors
with transferrin-containing gold nanoparticles. Proc Natl Acad Sci 107(3):1235–1240
Choi KY, Min KH, Yoon HY, Kim K, Park JH, Kwon IC, Choi K, Jeong SY (2011) PEGylation
of hyaluronic acid nanoparticles improves tumour targetability in vivo. Biomaterials
32:1880–1889
Day ES, Bickford LR, Slater JH, Riggall NS, Drezek RA, West JL (2010) Antibody-conjugated
gold-gold sulde nanoparticles as multifunctional agents for imaging and therapy of breast
cancer. Int J Nanomedicine 5:445–454
Devulapally R, Lee T, Barghava-Shah A, Sekar TV, Foygel K, Bachawal SV, Willmann JK,
Paulmurugan R (2018) Ultrasound-guided delivery of thymidine kinase–nitroreductase dual
therapeutic genes by PEGylated-PLGA/PEI nanoparticles for enhanced triple negative breast
cancer therapy. Nanomedicine 13:1051–1066
Elhissi AMA, Ahmed W, Hassan IU, Dhanak VR, D’Emanuele A (2012) Carbon nanotubes in can-
cer therapy and drug delivery. J Drug Deliv 2012:1–10. https://doi.org/10.1155/2012/837327
Farani MR, Khadiv-Parsi P, Riazi GH, Ardestani MS, Rad HS (2020) PEGylation of graphene/
iron oxide nanocomposite: assessment of release of doxorubicin, magnetically targeted drug
delivery and photothermal therapy. Appl Nanosci 10:1205–1217
Farjadian F, Ghasemi A, Gohari O, Roointan A, Karimi M, Hamblin MR (2019)
Nanopharmaceuticals and nanomedicines currently on the market: challenges and opportuni-
ties. Nanomedicine (Lond) 14:93–126
Gajbhiye K, Pawar A, Mahadik K, Gajbhiye V (2020) PEGylated nanocarriers: a promising tool
for targeted delivery to the brain. Colloids Surf B: Biointerfaces 187:110770
Gautier J, Munnier E, Paillard A, Hervé K, Douziech-Eyrolles L, Soucé M, Dubois P, Chourpa I
(2012) A pharmaceutical study of doxorubicin-loaded PEGylated nanoparticles for magnetic
drug targeting. Int J Pharm 423:16–25
Ghosh S, Lalani R, Maiti K, Banerjee S, Bhatt H, Bobde YS, Patel V, Biswas S, Bhowmick S,
Misra A (2021) Synergistic co-loading of vincristine improved the chemotherapeutic potential
of pegylated liposomal doxorubicin against triple-negative breast cancer and non-small cell
lung cancer. Nanomedicine 31:102320
Guo X, Cheng Y, Zhao X, Luo Y, Chen J, Yuan W-E (2018) Advances in redox-responsive drug
delivery systems of tumor microenvironment. J Nanobiotechnol 16:74
Guo Z, Sui J, Ma M, Hu J, Sun Y, Yang L, Fan Y, Zhang X (2020) pH-responsive charge switchable
PEGylated ε-poly-l-lysine polymeric nanoparticles-assisted combination therapy for improv-
ing breast cancer treatment. J Control Release 326:350–364
Hassanzadeh P (2021) The biomedical signicance of multifunctional nanobiomaterials: the key
components for site-specic delivery of therapeutics. Life Sci 277:119400
Hatakeyama H, Akita H, Harashima H (2011) A multifunctional envelope type nano device
(MEND) for gene delivery to tumours based on the EPR effect: a strategy for overcoming the
PEG dilemma. Adv Drug Deliv Rev 63:152–160
Helmi O, Elshishiny F, Mamdouh W (2021) Targeted doxorubicin delivery and release within
breast cancer environment using PEGylated chitosan nanoparticles labeled with monoclonal
antibodies. Int J Biol Macromol 184:325–338. https://doi.org/10.1016/j.ijbiomac.2021.06.014
Herdiana Y, Wathoni N, Shamsuddin S, Joni IM, Muchtaridi M (2021) Chitosan-based nanopar-
ticles of targeted drug delivery system in breast cancer treatment. Polymers (Basel) 13:1717.
https://doi.org/10.3390/polym13111717
Insua I, Wilkinson A, Fernandez-Trillo F (2016) Polyion complex (PIC) particles: preparation and
biomedical applications. Eur Polym J 81:198–215
Ji F, Zhang K, Li J, Gu Y, Zhao J, Zhang J (2018) A dual pH/magnetic responsive nanocarrier
based on PEGylated Fe3O4 nanoparticles for doxorubicin delivery. J Nanosci Nanotechnol
18:4464–4470
Kang H, Rho S, Stiles WR, Hu S, Baek Y, Hwang DW, Kashiwagi S, Kim MS, Choi HS (2020)
Size-dependent EPR effect of polymeric nanoparticles on tumour targeting. Adv Healthc Mater
9:1901223
235
236
Kaushik N, Borkar SB, Nandanwar SK, Panda PK, Choi EH, Kaushik NK (2022) Nanocarrier
cancer therapeutics with functional stimuli-responsive mechanisms. J Nanobiotechnol 20:152.
https://doi.org/10.1186/s12951- 022- 01364- 2
Kim PH, Sohn JH, Choi JW, Jung Y, Kim SW, Haam S, Yun CO (2011) Active targeting and safety
prole of PEG-modied adenovirus conjugated with herceptin. Biomaterials 32(9):2314–2326
Kim SW, Kyung Lee Y, Yeon Lee J, Hee Hong J, Khang D (2017a) PEGylated anticancer-carbon
nanotubes complex targeting mitochondria of lung cancer cells. Nanotechnology 28:465102.
https://doi.org/10.1088/1361- 6528/aa8c31
Kim J, Ramasamy T, Choi JY, Kim ST, Youn YS, Choi H-G, Yong CS, Kim JO (2017b) PEGylated
polypeptide lipid nanocapsules to enhance the anticancer efcacy of erlotinib in non-small cell
lung cancer. Colloids Surf B: Biointerfaces 150:393–401
Kizelsztein P, Ovadia H, Garbuzenko O, Sigal A, Barenholz YJJON (2009) Pegylated nanolipo-
somes remote-loaded with the antioxidant tempamine ameliorate experimental autoimmune
encephalomyelitis. J Neuroimmunol 213:20–25
Kolte A, Patil S, Lesimple P, Hanrahan JW, Misra A (2017) PEGylated composite nanoparticles
of PLGA and polyethylenimine for safe and efcient delivery of pDNA to lungs. Int J Pharm
524:382–396
Kong FY, Zhang JW, Li RF, Wang ZX, Wang WJ, Wang W (2017) Unique roles of gold nanopar-
ticles in drug delivery, targeting and imaging applications. Molecules 22:1445. https://doi.
org/10.3390/molecules22091445
Kouchakzadeh H, Shojaosadati SA, Tahmasebi F, Shokri F (2013) Optimization of an anti-
HER2 monoclonal antibody targeted delivery system using PEGylated human serum albumin
nanoparticles. Int J Pharm 447:62–69. https://doi.org/10.1016/j.ijpharm.2013.02.043
Kulkarni P, Haldar MK, Karandish F, Confeld M, Hossain R, Borowicz P, Gange K, Xia L,
Sarkar K, Mallik S (2018) Tissue-penetrating, hypoxia-responsive echogenic polymersomes
for drug delivery to solid tumors. Chem Eur J 24:12490–12494. https://doi.org/10.1002/
chem.201802229
Kurinomaru T, Shiraki K (2015) Noncovalent PEGylation of l-asparaginase using PEGylated
polyelectrolyte. J Pharm Sci 104:587–592
Lee JE, Kim MG, Jang YL, Lee MS, Kim NW, Yin Y, Lee JH, Lim SY, Park JW, Kim J, Lee DS,
Kim SH, Jeong JH (2018) Self-assembled PEGylated albumin nanoparticles (SPAN) as a plat-
form for cancer chemotherapy and imaging. Drug Deliv 25:1570–1578
Lukyanov AN, Sawant RM, Hartner WC, Torchilin VP (2004) PEGylated dextran as a long-
circulating pharmaceutical carrier. J Biomater Sci Polym Ed 15:621–630
Madhu (2018) Difference between block and graft copolymer. https://www.differencebetween.
com/difference- between- block- and- graft- copolymer/#:~:text=The%20key%20difference%20
between%20block,other%20via%20covalent%20chemical%20bonds. Accessed 24 2023
Mcdonnell T, Ioannou Y, Rahman A (2013) PEGylated drugs in rheumatology—why develop them
and do they work? Rheumatology 53:391–396
McNeeley KM, Annapragada A, Bellamkonda RV (2007) Decreased circulation time off-
sets increased efcacy of PEGylated nanocarriers targeting folate receptors of glioma.
Nanotechnology 18(38):385101
Mehra NK, Jain NK (2015) One platform comparison of estrone and folic acid anchored sur-
face engineered MWCNTs for doxorubicin delivery. Mol Pharm 12:630–643. https://doi.
org/10.1021/mp500720a
Mi P (2020) Stimuli-responsive nanocarriers for drug delivery, tumor imaging, therapy and ther-
anostics. Theranostics 10:4557. https://doi.org/10.7150/thno.38069
Mishra V, Mahor S, Rawat A, Gupta PN, Dubey P, Khatri K, Vyas SP (2006) Targeted brain deliv-
ery of AZT via transferrin anchored pegylated albumin nanoparticles. J Drug Target 14:45–53.
https://doi.org/10.1080/10611860600612953
Mishra P, Nayak B, Dey R (2016) PEGylation in anti-cancer therapy: an overview. Asian J Pharm
Sci 11:337–348
Mozar FS, Chowdhury EH (2018) Impact of PEGylated nanoparticles on tumour targeted drug
delivery. Curr Pharm Des 24:3283–3296
S. Acharya et al.