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5 PEGylated Nanocarriers forSolubilization
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PEGylation asaTool toAlter
Immunological Properties
ofNanocarriers
AkhileshTiwari, SourajyotiGoswami, MeghaJoshi,
SanyamGandhi, PranaySoni, MuktikaTekade,
ShubhamRamdasMule, andRakeshKumarTekade
Abstract
Nanocarriers hold immense potential for targeted drug delivery, but their thera-
peutic efcacy is often hindered by immunological interactions. The covalent
attachment of polyethylene glycol chains, known as PEGylation, has emerged as
a promising approach to modifying the immunological properties of nanocarri-
ers. PEGylation offers several advantages, including steric stabilization, reduced
protein adsorption, and decreased recognition by the immune system, resulting
in prolonged circulation time and improved biodistribution. By shielding nano-
carriers from immune recognition, PEGylation can mitigate undesired immune
6
A. Tiwari (*) · S. Goswami · P. Soni
Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak,
Anuppur, Madhya Pradesh, India
M. Joshi
PHC, Amarkantak, Amarkantak, Madhya Pradesh, India
S. Gandhi
Takeda Pharmaceuticals, Boston, MA, USA
M. Tekade
School of Pharmacy, Devi Ahilya Vishwavidyalaya, Takshila Campus,
Indore, Madhya Pradesh, India
School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
S. R. Mule · 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 station, Gandhinagar,
Gujarat, India
171
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A. Tiwari et al.
responses, such as rapid clearance by the mononuclear phagocyte system or
induction of pro-inammatory reactions. This chapter hereby highlights the
nuances of the PEGylation technique while emphasizing the altered immuno-
logical properties of the PEGylated nanocarriers, which positively impact the
various aspects of drug delivery.
Keywords
Nanocarriers · Polyethylene glycol (PEGylation) · Immune system · Drug deliv-
ery system
6.1 Introduction
Nanocarriers are microscopic structures that are designed to carry and deliver drugs,
genes, and other therapeutic agents to specic target sites in the body. They comprise
various materials, including proteins, lipids, and polymers, and are typically nanoparticles with diameters ranging from 10nm to a few hundred nanometers (Rawat etal.
2006). These are essential tools in drug delivery due to their advantages of targeted
drug delivery, improved bioavailability, and reduced toxicity. Nanoparticles such as
liposomes, dendrimers, and polymeric micelles can be engineered to encapsulate
drugs and deliver them directly to the site of interest, such as cancer cells or inammatory tissues (Parhi etal. 2012). They can also protect the drugs from degradation
and clearance by the immune system, prolonging their circulation time in the bloodstream (Lombardo etal. 2019). However, nanocarriers pose a challenge in terms of
immunogenicity. The immune system is designed to recognize and eliminate foreign
materials from the body, and nanoparticles can trigger an immune response that may
result in the clearance of the carriers or cause adverse effects (Dobrovolskaia and
McNeil 2007). The immune system can recognize the surface properties, size, and
charge of the nanoparticles and mount an immune response against them, leading to
inammation, cytotoxicity, and allergic reactions (Qin etal. 2020).
Several strategies have been developed to overcome the immunogenicity challenge, such as surface modications with stealth materials that can reduce interaction with the immune system (Fu etal. 2021). Researchers are also exploring the use
of biocompatible and biodegradable materials that can be quickly metabolized or
eliminated by the body, reducing the risk of immunogenicity. Overall, the immunogenicity of nanocarriers is a critical consideration when developing novel drug
delivery systems, and researchers need to carefully balance the benets and risks of
nanocarriers in drug delivery (Cheng etal. 2021). Modifying nanocarriers can signicantly improve drug delivery by addressing some of the challenges of traditional
drug delivery methods.
Nanocarriers can be engineered to selectively target specic tissues or cells
within the body (Cheng etal. 2021). This can increase the concentration of the drug
at the desired site while reducing exposure to non-target tissues and thus minimizing side effects. Nanocarriers can be designed to release drugs in a controlled manner over a prolonged period, which can improve drug efcacy and reduce dosing
6 PEGylation asaTool toAlter Immunological Properties ofNanocarriers
173
frequency (Lee and Yeo 2015). Nanocarriers can be engineered to improve drug
solubility, stability, and bioavailability. This can increase drug absorption, distribution, and elimination, leading to better therapeutic outcomes (Din et al. 2017).
Nanocarriers can protect drugs from enzymatic degradation, clearance by the
immune system, and premature elimination from the body, thus increasing the
drug’s half-life and bioavailability. Nanocarriers can be used to deliver multiple
drugs or diagnostic agents simultaneously, allowing for synergistic effects and
improved treatment outcomes.
6.2 Introduction toPEGylation
PEGylation is a technique that involves covalently attaching polyethylene glycol
(PEG) to a nanocarrier surface (Howard etal. 2008). This modication has been
extensively used to alter the immunological properties of nanocarriers, including
nanoparticles, liposomes, and micelles. PEGylation as a tool to modify the immunological properties of nanocarriers has dramatically impacted the eld of drug
delivery and nanomedicine. It can potentially revolutionize the treatment of many
diseases (Vllasaliu etal. 2014). Before PEGylation, the use of nanocarriers for drug
delivery faced signicant challenges, including rapid clearance from the bloodstream, poor targeting efciency, and immune reactions (Mitchell et al. 2021).
PEGylation has helped to overcome many of these challenges by altering the
immunological properties of nanocarriers and improving their stability and
biocompatibility.
The use of PEGylated nanocarriers has several advantages over traditional drug
delivery methods. PEGylation can increase the circulation time of nanocarriers in
the bloodstream, which can enhance their accumulation at the target site and
improve their therapeutic efcacy. PEGylation can also reduce the clearance of
nanocarriers by the immune system, enhancing their safety and reducing the risk of
adverse reactions (Su and Kang 2020). In addition, PEGylation can improve the
targeting efciency of nanocarriers by reducing non-specic binding to tissues and
cells. This can increase the specicity and efcacy of drug delivery and reduce the
dose required for therapeutic effect.
6.2.1 Properties ofPEG
PEG is a water-soluble, synthetic, and non-toxic polymer with repeating ethylene
oxide units. It is a linear, exible, and hydrophilic polymer that can be synthesized
with different molecular weights (MW) and chain lengths. PEG is commonly used
in various applications, including pharmaceuticals, biotechnology, and cosmetics
(Su and Kang 2020). PEG is highly soluble in water and can form stable aqueous
solutions with a wide range of concentrations. It is also miscible with many organic
solvents, making it a versatile polymer for various applications. PEG has a low
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A. Tiwari et al.
toxicity prole and is generally considered safe for human use, although some individuals may experience allergic reactions (Kolate etal. 2014).
The properties of PEG are highly dependent on its molecular weight and chain
length; as the molecular weight of PEG increases, its viscosity, melting point, and
boiling point also increase. Longer PEG chains tend to have greater hydrophilicity,
solubility, and biocompatibility than shorter chains (Zheng etal. 2023). PEG has
several unique properties, making it a valuable polymer for various applications.
PEG is widely used in biomedical applications because of its excellent biocompatibility, low toxicity, and non-immunogenicity. Being highly hydrophilic, PEG
serves as an ideal polymer for enhancing the solubility and bioavailability of poorly
soluble drugs. PEG is a exible polymer that can adopt a range of conformations,
allowing it to adapt to different environments and surfaces. Outer PEG coating on
the surface of nanocarriers renders them non-reactive toward many biomolecules.
Hence, PEG is an ideal coating material to overcome the immune recognition of
such nanocarriers.
6.2.2 Mechanisms ofPEGylation
The mechanisms of PEGylation involve the creation of a covalent bond between the
PEG molecule and the target molecule. This can be achieved through several methods, such as chemical crosslinking, enzymatic conjugation, and click chemistry
techniques. Chemical crosslinking involves using a reactive group, such as a carboxyl or amine group, on the PEG molecule to form a covalent bond with a corresponding reactive group on the target molecule (Sinz 2006) whereas, enzymatic
conjugation involves the use of an enzyme, such as transglutaminase or microbial
transglutaminase, to catalyze the formation of a covalent bond between the PEG
molecule and a specic amino acid residue on the target molecule (Fontana etal.
2008). Click chemistry, on the other hand, utilizes a small molecule linker that can
react with both the PEG molecule and the target molecule to form a covalent bond
between them (Moses and Moorhouse 2007).
Once the PEG molecule is covalently attached to the target molecule, it can modify the properties of the molecule in several ways. For example, the PEG molecule
can sterically hinder interactions between the target molecule and other proteins or
cells, which can increase the half-life of the molecule in the bloodstream.
Additionally, the PEG molecule can increase the hydrophilicity of the target molecule, which can improve its solubility and reduce its aggregation (Harris etal. 2001).
The mechanism of action of PEGylation in altering the immunological properties of
nanocarriers is based on the “stealth effect” (Wen etal. 2023).
The PEG chains create a steric barrier around the nanocarriers, which prevents
recognition and uptake by the reticuloendothelial system (RES)—a network of cells
and tissues that play a role in immune defense and clearance of foreign particles
from the blood. The RES includes macrophages, dendritic cells, and Kupffer cells,
which can recognize and phagocytose foreign particles (Hadjesfandiari and
Parambath 2018). This can improve the therapeutic efcacy and safety of drugs and
6 PEGylation asaTool toAlter Immunological Properties ofNanocarriers
175
nanocarriers for various biomedical applications (Caliceti and Veronese 2003). By
preventing recognition by the immune system and the RES, PEGylation can increase
the circulation time of the molecule in the blood, leading to improved pharmacokinetics and pharmacodynamics. The prolonged circulation time allows for enhanced
drug delivery to the target site, increasing the drug’s efcacy and reducing the
required dose (Tian etal. 2022). Moreover, PEGylation can also reduce the immunogenicity of the molecule by masking its surface antigens, which can reduce the
risk of immune reactions, such as antibody formation. This can improve the safety
and tolerability of the drug or protein (Baker etal. 2010).
The mechanism of PEGylation can be broadly described in the following steps.
6.2.2.1 Activation ofPEG
PEG is usually activated by converting one end of the molecule into a reactive
group, such as an amine or a thiol, which can then attach to the target molecule
(Zalipsky 1995). This process is often called “PEGylation chemistry” and is usually
accomplished using a coupling agent or a cross-linker. The choice of coupling agent
or cross-linker will depend on the type of functional group used to activate the PEG
and the chemistry of the target molecule (Gupta etal. 2019). Once the PEG has been
activated, it can be conjugated to the target molecule through a covalent bond,
resulting in a PEGylated product with improved properties (Saito etal. 2003).
6.2.2.2 Conjugation ofPEG totheTarget Molecule
The activated PEG is then attached to the target molecule through a covalent bond,
usually using a coupling agent or a cross-linker (Wildling etal. 2011). Once the
PEG has been activated by converting one end of the molecule into a reactive group,
it can be attached to the target molecule through a covalent bond (Ebner etal. 2007).
This is typically achieved using a coupling agent or a cross-linker, which allows for
forming a stable and durable bond between the PEG and the target molecule (Jia and
Li 2015). The choice of coupling agent or cross-linker will depend on various factors, such as the chemistry of the target molecule, the type of reactive group on the
PEG, and the desired length and conguration of the PEG chain (Ebner etal. 2007).
The coupling reaction is typically carried out under carefully controlled conditions
to ensure the formation of a high-quality PEGylated product with the desired
properties.
6.2.3 Advantages andDisadvantages ofPEGylation
PEGylation has several advantages and disadvantages, which should be considered
when deciding whether to use this approach for a particular application. Therefore,
The PEGylation strategy usually involves striking a balance between its advantages
and disadvantages to suit the desired end outcome. The advantages and disadvantages of PEGylation are listed in Fig.6.1.
176
Fig. 6.1 Advantages and
disadvantages of
PEGylation
A. Tiwari et al.
6.2.3.1 Advantages ofPEGylation
PEGylation of nanocarriers offers a variety of advantages over their non-PEGylated
counterparts. The most relevant benets of PEGylation from the pharmaceutical
perspective are mentioned below.
Increased Solubility
PEGylation can increase the solubility of a molecule in aqueous solutions, making
it easier to administer or use in various applications. PEG chains are highly hydrophilic, exhibiting a strong afnity to water or aqueous solvents (Le Dévédec etal.
2013). PEGylation of poorly soluble compounds, including proteins and peptides,
can enhance their water solubility and render them more convenient from a formulation perspective.
Improved Stability
PEGylation can increase the stability of a molecule, making it less prone to degradation or denaturation. The PEG chains around the PEGylated molecules form a steric
barrier and prevent the molecules from aggregating (Suk etal. 2016). This steric
barrier improves the stability of PEGylated moieties by preventing their aggregation. On the other hand, surrounding PEG chains reduce the exposure of PEGylated
moieties to the surrounding metabolizing enzymes (Totten etal. 2019). This strategy is benecial for drugs or proteins prone to degradation in biological uids.
Reduced Immunogenicity
PEGylation can reduce the immunogenicity of a molecule, making it less likely to
trigger an immune response when administered to humans. The coating of PEG
around the molecules of interest helps in hiding their antigenic determinants, which