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6 PEGylation asaTool toAlter Immunological Properties ofNanocarriers
187
6.6.7 Cardiovascular (CVS) Drug Delivery
PEGylated nanocarriers can be utilized to deliver drugs for treating cardiovascular
diseases, such as atherosclerosis or hypertension. The nanocarriers can target specic sites in the vasculature, improving drug efcacy and reducing off-target effects
(Mohamed etal. 2022). PEGylated nanocarriers have shown great potential as drug
delivery systems for various therapeutic applications. The PEGylation strategy must
be carefully optimized to achieve the desired pharmacokinetic and biodistribution
properties while minimizing the risk of adverse reactions.
6.7 Challenges andFuture Perspectives
PEGylation is a complex technique often involving multistep synthesis methods.
Achieving high conjugation efciency and uniform distribution of PEG chains on
the nanocarrier surface is crucial for consistent performance. PEGylation involves
the use of PEG chains of varying lengths. The choice of PEG chain length can inuence the pharmacokinetics, biodistribution, and clearance of the nanocarriers.
Achieving consistent and controlled PEGylation with precise chain lengths can be
challenging, and variations in chain length can lead to unpredictable behavior and
efcacy. These issues highlight the manufacturing challenges associated with
PEGylated products. Hence, developing efcient PEGylation methods that ensure
uniform coverage and minimal batch-to-batch variability is an ongoing challenge
(Rabanel etal. 2014). The stability of the PEG coating is another concern related to
the PEGylated molecules. PEG chains can undergo degradation or detachment from
the nanocarriers’ surface over time, potentially impacting the stability and performance of PEGylated nanocarriers. Strategies to improve the stability and prevent
premature shedding of PEG chains are being explored (Sun etal. 2017).
PEGylation can limit the interaction of nanocarriers with target cells or tissues,
as the PEG chains create a steric barrier. Overcoming this challenge involves designing strategies to enhance targeting and cellular penetration while maintaining the
benets of PEGylation. PEGylated moieties can further be conjugated with targeting ligands to improve the targeting efciency of the designed nanocarriers. Few
individuals may develop antibodies against PEG, leading to reduced efcacy and
increased clearance of PEGylated nanocarriers. Developing strategies to overcome
immune responses and minimize PEG-related immunogenicity is an active area of
research (McSweeney et al. 2019). Despite the challenges associated with the
PEGylation technique, it remains a most lucrative area of research endeavors related
to drug delivery. Researchers are exploring innovative PEGylation methods, such as
site-specic or controlled PEGylation, which allow for precise control over the
location and density of PEG chains. These techniques aim to optimize the benets
of PEGylation while minimizing its potential drawbacks. Current developments in
the formulation of PEGylated nanocarriers focus on designing nanocarriers with
integrated functionalities beyond PEGylation. These may include incorporating targeting ligands, stimuli-responsive components, or imaging agents, thereby
188
A. Tiwari et al.
expanding the capabilities of nanocarriers for personalized and targeted therapy
(Ekladious etal. 2019).
Researchers are investigating alternative polymers or coatings that can provide
similar benets to PEGylation while addressing some of its challenges. These
include zwitterionic polymers, biomimetic coatings, or self-assembled monolayers,
which offer improved stability, reduced immunogenicity, and enhanced targeting
capabilities (Amoozgar and Yeo 2012). The future of nanocarrier-based drug delivery lies in combination therapies, where multiple therapeutic agents, such as drugs,
siRNA, or immunotherapies, are co-delivered using PEGylated nanocarriers. This
approach enables synergistic effects and improved treatment outcomes (Zhang etal.
2016b). Furthermore, with advancements in nanotechnology and PEGylation tech-
niques, the future of nanocarriers lies in personalized medicine. Tailoring nanocarriers to specic patient proles, disease characteristics, and therapeutic requirements
holds excellent potential for improving treatment efcacy and minimizing side
effects (Sakamoto etal. 2010).
While challenges exist, the eld of PEGylation and nanocarrier-based drug
delivery continues to evolve rapidly. With ongoing research, innovative techniques,
and a better understanding of nanocarrier behavior, the future looks promising for
overcoming current challenges and harnessing the full potential of PEGylated nanocarriers in clinical applications.
6.8 Conclusion
Nanocarriers are lucrative drug delivery vehicles, considering the unique advantages they offer. However, the immunogenicity concerns associated with nanocarriers constitute a signicant obstacle in their applications. Various surface modication
strategies have been explored to tackle the immune recognition of nanocarriers. One
of the most prominent approaches is surface modication of nanocarriers with PEG,
also known as PEGylation. The PEGylation has been regarded as a widely utilized
strategy to improve the performance of nanocarriers in drug delivery. It offers benets such as enhanced stability, prolonged circulation time, improved biocompatibility, and reduced immunogenicity.
Research in PEGylation continues to advance, exploring alternative coatings,
site-specic PEGylation, controlled release systems, immunogenicity mitigation,
combination therapies, advanced characterization techniques, and standardization.
These future directions aim to overcome the limitations of PEGylation, expand its
applications, optimize its performance, and ensure its safe and effective translation
into clinical use. As research progresses, it is expected that PEGylation-based technologies will continue to play a signicant role in drug delivery, biotechnology, and
diagnostics. Through ongoing efforts and advancements, the eld of PEGylation
holds promise for addressing current challenges and further improving the effectiveness and safety of nanocarriers in various therapeutic applications.
6 PEGylation asaTool toAlter Immunological Properties ofNanocarriers
189
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PEGylated Nanocarrier asaPromising
Tool forSite-Specific Delivery
ofTherapeutics
SwetaAcharya, NiyatiLad, AniketNavale, SimranjitKaur,
AprameyaGaneshPrasad, andRakeshKumarTekade
Abstract
Nanocarrier systems have gained popularity for drug delivery and diagnostic
purposes, offering targeted and site-specic transport of highly efcacious medi-
cations. These systems connect biological and physical sciences, allowing for the
treatment of various diseases and disorders. They can avoid severe side effects,
improve target specicity, and reduce doses. Modifying carrier properties, such
as targeted delivery, regulated distribution, and shielding from biological milieus,
can further enhance their benets. Several targeted nanocarrier systems such as
nano-crystals, lipid nanoparticles (NPs), PEGylated polymeric nanocarriers,
nanobers, quantum dots, liposomes, dendrimers, micelles, protein-based
nanoparticles, and metal-based nanoparticles are well explored for their benets
over conventional drug delivery systems. This chapter specically highlights the
different types of PEGylated nanocarriers and their uses in targeted drug delivery.
7
Keywords
PEGylated nanocarriers · Liposomes · Cancer · Brain disorders · Pulmonary dis-
orders · Targeted delivery · EPR effect · RES system
S. Acharya · N. Lad · A. Navale · S. Kaur · R. K. Tekade (*)
National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, An
Institute of National Importance, Government of India, Department of Pharmaceuticals,
Ministry of Chemicals and Fertilizers, Palaj, Opp. Air force stations, Gandhinagar,
Gujarat, India
A. G. Prasad
Department of Chemical and Biomolecular Engineering, Johns Hopkins University,
Baltimore, MD, USA
195
196
S. Acharya et al.
Abbreviations
Anti-hMAM Anti-human mammaglobin
BBB Blood brain barrier
Bcl-2 B-cell lymphoma-2
BPQDs Black phosphorus quantum dots
BSA Bovine serum albumin
CaP Calcium phosphate
CAT Catalase
ChNPs Chitosan nanoparticles
CNTs Carbon nanotubes
DDS Drug delivery systems
DMARDs Disease-modifying anti-rheumatic drugs
DMMA-P-DOX/LAP 2,3-Dimethylmaleic-anhydride-poly(ethylene glycol)-ε-
poly- -lysine-doxorubicin/lapatinib polymeric
DOPE 1,2-Dioleyl-sn-glycero-3-phosphoethanolamine
DOX Doxorubicin
DPI Dry powder inhaler
EAE Encephalomyelitis
EGFP Enhanced green uorescent protein
EGFR Epidermal growth factor receptor
EPR Enhanced permeability and retention
ERs Estrogen receptors
FA Folic acid
FMN Formononetin
GBM Glioblastoma multiforme
GCs Glucocorticoids
GEM Gemcitabine
GFLG Glycylphenylalanylleucylglycine
GO Graphene oxide
GOD Glucose oxidase
GSH Glutathione
HA Hyaluronic acid
Has Human serum albumin
HEL Hen egg-white lysozyme
HER2 Human epidermal growth factor receptor 2
HPMA Hydroxy propyl methacrylamide-methacid
IA Intra-articular
LRP Low-density lipoprotein receptor
mAbs Monoclonal antibodies
MCF-7 Michigan cancer foundation-7
Mcl-1 Myeloid cell leukemia-1
MMP Mitochondrial membrane potential
MWNTs Multi-walled carbon nanotubes
NCs Nanocarriers