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4 PEGylated Nanocarriers forDrug Delivery Applications
117
PEG antibodies, which are highly sensitive in picomolar ranges, can specically
bind PEG molecules. In some biological processes, this phenomenon can be utilized
to quantify PEG density (Cheng et al. 2005; Su et al. 2010; Zillies et al. 2007).
However, this binding could be inuenced by steric interactions in densely packed
neighboring PEG chains. Determination of the unreacted PEG molecules could be
done with a refractive index (RI) detector or evaporative light scattering detector;
hence, the amount of free PEG could be quantied after chromatographic separation, such as HPLC (Nair etal. 2006; Liu etal. 2004). Therefore, HPLC is unable to
determine PEG localization within the NPs but is used when coupled with other
techniques such as mass spectrometry, evaporative light scattering detection
(ELSD), and refractive index detection (RID) due to the lack of a chromophore in
PEG for UV detection (Nair etal. 2006; Gauchel et al. 2003; Auriola etal. 1993;
Zhang etal. 2007). Comparison of the thickness and particle size of non-PEGylated
NPs is employed during the determination of the grafting thickness (Howard
etal. 2008).
XPS (X-Ray Photoelectron Spectroscopy) This parameter provides useful information on the elements present on the surface of PEGylated nanocarrier (from the
NPs surface, ~ 8–10nm depth with a margin of error of ~10–20%) and is ideal for
quantitative determination (Howard etal. 2008; Suk etal. 2016). Here, spectra are
obtained before and after PEGylation (Suk etal. 2016). This technique could validate the presence of PEG on NPs. Many researchers have utilized XPS to evaluate
PEGylated nanoparticles successfully and conrmed that the values obtained corresponded very well to the amount of PEG added (Churae and Nikologorskaja
1991; Yang and Lai 2015). However, the limitations of XPS here include the dif-
culty in quantifying PEG when the NPs core has a similar composition of elements
as the PEG within a probing depth of 1–10nm, and there is the possibility of contaminants interfering with results (Howard etal. 2008).
Colorimetric Assays This method is utilized in the determination of the localiza-
tion and concentration of PEG molecules (Howard etal. 2008; Hu etal. 2006). The
amount of PEG measured before and after alkaline hydrolysis of NPs is compared.
Here, the potassium iodide complex method is utilized, and this gives information
on the positions of PEG on the surface of the nanocarrier. For particles that have a
homogenous surface, the surface density PEG and distance between neighboring
molecule chains could be determined with reference to the measured particle size of
NPs (Howard etal. 2008).
4.5 Drug Delivery Applications ofPEGylated Nanocarriers
PEGylation of nanocarriers is applied in various routes of drug delivery, including
systemic and nonsystemic routes, passive and active targeting, and vaccine delivery,
as discussed below.
118
S. A. Chime and M. A. Momoh
4.5.1 Systemic Drug Delivery
The systemic drug delivery of NPs has many advantages compared to the traditional
delivery system. NPs have the potential to deliver therapeutic payloads to various
tissues and organs of the body, prolonging the blood circulation time and partitioning into target organs. However, as earlier stated, conventional NPs are generally
cleared from the blood circulation within 10min after systemic administration, notwithstanding the composition of the NPs (Suk etal. 2016; Moghimi etal. 2001; Yoo
etal. 2010), hence the need to PEGylate. Therefore, PEG molecules are hydrophilic
and could be grafted on NPs to create a hydrated environment around the NP that
sterically hinders their interaction with other NPs or blood components (Klibanov
etal. 1990). The PEG chains are exible, imparting them with high conformational
freedom, which opposes the penetration of foreign bodies into the corona of PEG
(Vonarbourg etal. 2006). PEGylation improves the half-life of systemically administered drug-loaded NPs and minimizes the liver uptake (Suk etal. 2016; Matsumura
and Maeda 1986). Following the systemic administration of PEGylated NPs, it provides enhanced permeability and retention (EPR), resulting in the prolonged circulation of PEGylated NPs, which can be benecial in drug targeting of various
tumors, for example, Human studies showed that Doxil® provided long circulation
half-life of 3–4days and passive accumulation in tumors (Dawidczyk etal. 2014;
Nance etal. 2014a). Also, the systemic administration of PEGylated NPs could be
used to target other diseases caused by abnormal neovascularization, such as multiple sclerosis, ocular disorders, asthma, and diabetes (Alexis etal. 2008). PEGylated
NPs could be decorated with specic ligands for specic targeting to different body
organs such as the brain (Suk etal. 2016; van der Meel etal. 2013; Dobrovolskaia
etal. 2008).
PEGylation of NPs confers on the NPs the ability to minimize the hemotoxicity
of some NPs. The systemic toxicity of NPs is not to be overlooked because NPs
administered via systemic delivery route would reach most vascularized tissues in
the body. Hence, NPs may directly associate with erythrocytes in the bloodstream,
resulting in aggregation of erythrocytes and/or hemolysis followed by the release of
hemoglobin (Suk etal. 2016; Fischer etal. 2003). Erythrocytes’ disruption is often
seen in cationic NPs because of their interaction with cells that are negatively
charged by electrostatic interactions (Ziemba et al. 2012; Eliyahu et al. 2002).
PEGylation has been shown to circumvent the hemotoxic properties of nanocarriers. PEGylation reduces aggregation and hemolysis of erythrocytes induced by
polyethyleneimine (PEI-based) nanocarriers (Petersen etal. 2002b; Rukmani etal.
2009). Hemolysis reduction could be another mechanism of improving the blood
circulation of NPs by PEGylation (Suk etal. 2016).
4.5.2 Nonsystemic Drug Delivery
PEGylation of NPs is not only advantageous in systemic drug delivery, but it could
also be employed in the delivery of drugs through nonparenteral routes and controls
4 PEGylated Nanocarriers forDrug Delivery Applications
119
drug release after oral administration. The nonsystemic applications of PEGylation
are summarized below.
4.5.2.1 Oral Administration ofPEGylated Nanocarriers
Oral drug delivery remains one of the most convenient, efcacious, and safe routes
of drug delivery to the gastro intestinal tract (GIT). The GIT, being complex in
nature, requires specialized formulation techniques like PEGylation to target drugs
to various locations of the GIT, as well as protect some drugs from denaturation by
the acidic upper GIT or design the drug to release at a location of utmost absorption.
PEGylated oral insulin NPs protect this drug from stomach-induced acidic degradation (Yuan etal. 2013). Nonsteroidal anti-inammatory drugs, for example, diclofenac, may be PEGylated, preventing its release in the stomach and avoiding
ulceration. Chime etal. prepared an oral PEGylated nanostructured lipid carrier and
found out that PEGylation resulted in enhanced physical stability on the NLC,
which resulted in signicantly higher controlled drug release over time compared to
non-PEGylated NLC.The NLC also showed potential for preventing gastric ulceration often seen in patients on diclofenac sodium (Chime etal. 2022). PEGylation,
therefore, improves the oral bioavailability of most orally administered NPs,
enhances the hydrophilicity of the SLN, and reduces mucoadhesion (Suk et al.
2009, 2016).
4.5.2.2 PEGylated Nanocarriers forImproved Nasal
andPulmonary Administration
NPs are often administered through the pulmonary route for local and systemic
actions in some disease conditions. The mucus layer covers the pulmonary system,
which rapidly regenerates and clears via mucociliary clearance (MCC) mechanisms
(Suk etal. 2016). In cystic brosis (CF) and chronic obstructive pulmonary disease
(COPD), the airway mucus creates a complex penetrating barrier due to the viscoelasticity of the mucus barrier. However, PEG coatings on NP enhance its penetration through the mucus membrane of the airways, leading to reduced toxicity and
uniform distribution of NPs payload (Lai etal. 2011).
PEGylated NPs are also an effective DDS through the mucosa of the nostrils
lined by the mucus. This mucus serves as a barrier to NP and drug absorption. In
patients with chronic rhinosinusitis (CRS), highly viscoelastic mucus accumulates
in the sinuses, leading to immobilization of non-PEGylated NPs in CRS mucus.
PEGylated NPs, at about 200nm, could penetrate CRS mucus rapidly (Brooking
etal. 2001). Some researchers found that PEGylation reduced intranasal NP uptake
attributed to reduced interactions between the PEG-coated nanocarrier and the
nasal-associated lymphoid tissue (NALT), some other researchers found that PEG
coatings enhance nanocarrier absorption across the nasal mucosa (Suk etal. 2016;
Tobio etal. 1998; Kenechukwu etal. 2018).
4.5.2.3 PEGylated Intravaginal Nanocarriers
PEGylation techniques offer enhanced drug efcacy by enhancing dwelling time
and increasing the drug concentration at the site of action (Dawidczyk etal. 2014;
120
S. A. Chime and M. A. Momoh
Lee etal. 2005; Ensign etal. 2012). PEGylation could be employed to develop local
delivery to the vaginal tract for controlled vaginal delivery of drugs for effective
treatment of infections such as vulvovaginal candidiasis and other diseases that
affect the female reproductive tract, for example, bacterial vaginosis, cervical cancer, and sexually transmitted diseases (Suk etal. 2016; Lee etal. 2005).
The primary barrier to NP-based drugs in the vaginal tract is the rapidly cleared
mucus layers coating the cervicovaginal area and the viscoelasticity of the vaginal
mucosa (Ensign etal. 2012; Cone 2009; Lai etal. 2009). Hence, non-PEGylated
NPs are trapped in mucus by adhesive interactions (Lai etal. 2007). Due to their
mucoadhesiveness, PEGylated NPs interpenetrate the vaginal mucosa (Suk et al.
2016; Huang etal. 2000; Gu etal. 2008; Sahlin and Peppas 1997). When NPs are
coated with PEG of low MW (2 or 5kDa) and with a particle size of 200nm, PEG
rapidly diffuse through the cervical mucous, but when coated with PEG of about
10kDa, PEG becomes trapped in the mucosa (Suk etal. 2016). Also, the dense coating of NP with low MW PEG leads to the shielding of the core of the NP, preventing
its interactions with mucin and mucus (Wang etal. 2008).
4.5.2.4 Brain Delivery ofPEGylated Nanocarriers
PEGylated NPs could be used to increase drug-brain delivery. The extracellular
matrix (ECM) in the brain presents an extra barrier that prevents drugs entrapped in
NPs from reaching target cells (Thorne and Nicholson 2006). However, the density
of PEGylated NPs is critical in delivering drugs to the brain. Researchers observed
that exceptionally densely coated PEGylated NPs of about 114nm could rapidly
diffuse more across the brain tissues of rats (Nance etal. 2012; Mastorakos etal.
2015). In contrast, non-PEGylated NPs of any size were adhesively immobilized in
the various types of brain tissues. Densely PEG-coated NPs also would enhance
drug delivery and efcacy in malignant glioma due to increased nanoparticle spread
and distribution (Nance etal. 2014b). PEG coatings improve the stability of the NPs
in cerebrospinal uid and reduce cell toxicity without signicantly compromising
cellular uptake (Suk etal. 2016).
4.5.2.5 Ocular Delivery ofPEGylated Nanocarriers
A good number of barriers prevent the eyes from effectively utilizing various drug
delivery systems/dosage forms designed to treat different ocular diseases that may
predispose one to blindness. The traditional dosage forms in eye drops undergo poor
absorption and rapid clearance; hence, less than 5% of the applied drops reach the
intraocular tissues (Jarvinen etal. 1995). Therefore, other more efcient delivery
systems, such as NPs and PEGylated NPs, have been explored to enhance drug residence time (DRT) and absorption via the ocular route. PEG enhances mucoadhesion
via hydrogen bonding to the mucus and interpenetration (Suk etal. 2016; Wang
etal. 2008). Hence, PEGylated NPs could serve as a mucoadhesive to promote DRT
in the mucosal area of the eye (Suk etal. 2016; Giannavola etal. 2003). PEGylated
NPs are primarily stable with enhanced mobility. Hence, PEGylation increases the
mobility of NPs in the vitreous, while non-PEGylated NPs form large, immobile
aggregates, whereas most are in the vitreous gel (Martens etal. 2013).
4 PEGylated Nanocarriers forDrug Delivery Applications
121
4.5.2.6 Vaccines Entrapped PEGylated Nanocarriers
Vaccine-entrapped PEGylated nanocarriers increase the circulation time and, hence,
enhance the properties of the entrapped vaccines than the non-PEGylated nanocarriers. PEGylation is often employed in reducing reactions between nanocarriers and
proteins, cells, etc. During circulation to reduce clearance, (Suk et al. 2016)
PEGylation will also minimize desirable cell uptake, for example, NP-based vaccine delivery to antigen-presenting cells (APCs). Coating NPs with PEG protects
vectors from existing neutralizing antibodies against the virus (Weaver and Barry
2008). PEGylation of NPs was found to increase the relative ratio of dendritic cells
to B cells. Also, there was an increase in the amount of NPs internalized by the
dendritic cell, suggesting a relative increase in cellular uptake invivo (Zhan etal.
2012). Vaccine-entrapped PEGylated liposome, PEGylated lipoplexes, PEG-
polyplexes, and PEGylated nanoparticles could be formulated and administered via
nonsystemic routes, including dermal route of administration for improved delivery
of vaccines (van den Berg etal. 2010). Also, the intravaginal delivery of vaccines
has been recently explored (Xie etal. 2014).
4.5.3 Roles ofPEGylation inPassive andActive Targeting
ofDrugs
PEGylated NPs cause a signicant improvement in the penetration of drugs into
various tumors and cancer cells. PEGylation enhances drug solubility and serum
stability of drugs; hence, they have been utilized for drug-targeting cancer cells,
especially (Deepa and Hitesh 2020). Targeting of cancer cells via PEGylatyed nanocarriers can be active or passive targeting (Sutradhar and Amin 2014).
Active Targeting In active targeting, PEGylated NPs containing therapeutic
agent(s) may be designed to interact directly with the cancer cells. Active targeting
is initiated by molecular recognition, which involves surface modication of the
PEGylated NPs through antibody–antigen recognition or ligand–receptor interaction (Cho etal. 2008; Yezhelyev etal. 2006). Overexpressed receptors on cancerous
cell surfaces abound and are different from normal cells at the molecular level.
When complementary ligands attach to PEGylated NPs surfaces, it allows them to
specically target cancerous cells. Once the ligand PEG NPs bind to these receptors, they undergo phagocytosis, or receptor-mediated endocytosis by cells, resulting in cell internalization entrapped drug in the NPs (Sutradhar and Amin 2014).
Some of these receptors and their targeting ligands used for cancerous cells specic
targeting include ligand–receptor interaction, viz. Folate Receptor, Transferrin
Receptor, Asialoglycoprotein (ASGPRs) receptors and Luteinizing HormoneReleasing Hormone Receptor (LHRHR). Active targeting can also occur by
antibody- mediated targeting. Immunoglobulin (Ig) antibodies have gained popularity due to their high specicity and unique invivo properties (Sutradhar and Amin
2014). These classes of Ig could be used as ligands to target different cancer cells,
viz. IgG, IgA, IgM, IgD, and IgE (Sutradhar and Amin 2014), for example,
122
Trastuzumab (Herceptin, Genentech, Inc., South San Francisco, California) is a
highly puried recombinant DNA-derived humanized monoclonal immunoglobulin
G1 used for the design of NPs for (MDA-MB-468 BT-474, NCI-H520, PC9,
SK-BR-3) breast and (PC3) prostate cancers (Sutradhar and Amin 2014).
Angiogenesis is one of the hallmarks of cancer, as it allows the tumor to gain oxygen in large amounts and allows nutrients to thrive (Sudarshan et al. 2005).
PEGylated NPs encapsulating anticancer drugs can be conjugated to antibodies that
bind to receptors overexpressed in angiogenic endothelial cells, thus majoring in
both antiangiogenic and cytotoxic effects to improve therapeutic efciency. The
angiogenic targets of antibody-functionalized NPs for cancer include the vascular
endothelial growth factor (VEGF) and its receptors and matrix metalloproteinases
(Ferrara 2005).
Passive Targeting Nanoparticles and indeed PEGylated nanocarriers can also tar-
get cancer through passive targeting. The size of the pores in leaky endothelial cancerous cells ranges from 100 to 780nm, depending on the type of cancer. Hence,
PEGylated nanocarriers below that size can easily penetrate these pores (Shubik
1982; Baban and Seymour 1998). PEGylated NPs can be targeted to specic areas
of capillary endothelium to increase drug concentration within a particular organ,
perforating the tumor cells by convection or passive diffusion (Sutradhar and
Amin 2014).
S. A. Chime and M. A. Momoh
4.6 Factors That Affect theCirculation Time
ofPEGylated Nanocarriers
Several factors affect the circulation time of PEGylated nanocarriers. These factors
include the molecular weight of PEG used during the formulation, surface density
of PEG, physicochemical parameters of NPs, and other physicochemical properties
that inuence the systemic circulation of nanocarriers (Suk etal. 2016; Alexis etal.
2008; Vonarbourg etal. 2006; Gref etal. 1995; Mozar and Chowdhury 2018).
4.6.1 Physicochemical Properties ofNanoparticles
The physicochemical parameters of NPs, viz. size and surface charge are important
parameters (Albanese etal. 2012). They inuence the interactions between the biological environment and the NPs, affecting internalization, distribution, and clearance. The binding of NPs to drug components like the opsonins and particle
aggregation in circulation is inuenced by the hydrophobicity of NPs (Mozar and
Chowdhury 2018; Karra and Benita 2012; Brigger etal. 2002). In aqueous systems,
uncharged and hydrophobic NPs are easily aggregated via hydrophobic and Van der
Waals forces, while highly charged hydrophilic nanocarriers maintain their colloidal stability due to repulsive forces in them (Tenzer et al. 2013; Mozar and
4 PEGylated Nanocarriers forDrug Delivery Applications
123
Chowdhury 2018). Therefore, PEG coating of NPs is highly desirable to prevent
opsonization by serum factors (Bhadra etal. 2002). PEG coating on nanoparticles
neutralizes the surface charges, yielding “stealth” properties, minimizing RES
opsonization, and improving blood retention time. Hydrophilicity and steric hindrance offered by surface-anchored PEG prevent nonspecic interactions between
NPs and proteins; hence, reducing phagocytosis mediated by opsonin, causing prolonged residence time of NPs in circulation (Mozar and Chowdhury 2018; Pai etal.
2006; Harrington etal. 2000). Drug encapsulation and loading into NPs may be
affected by factors such as matrix composition and the physicochemical properties
of drugs (Mozar and Chowdhury 2018; Govender etal. 1999, 2000).
The physicochemical properties of the NPs core inuence the adsorption of proteins and their circulation time. Smaller size NPs interact less with the end groups
within cell surfaces of PEG chains. In contrast, NPs of larger sizes at a given PEG
surface density may attach themselves to MPS cells more rmly than smaller NPs
due to weak, multivalent interactions between the PEG chains and/or terminal
groups with cell surfaces (Unsworth etal. 2008). Hence, smaller NPs show more
resistance against macrophage uptake than larger NPs and have increased surface
curvature, which may need larger PEG density to shield them effectively (Suk etal.
2016; Choi etal. 2011; Perrault etal. 2009; Fang etal. 2006).
4.6.2 PEG Molecular Weight (MW)
PEG MW is crucial for effective shielding of the surface of NPs in order to prevent
interactions with MPS cells and serum proteins (Suk etal. 2016). Protein adsorption
on PEGylated NPs is affected by the MW.Hence, the association between the ligand
and PEGylated NPs is affected by PEG surface coating density on NPs. PEG with
MW of 10kDa is more effective in reducing protein absorption than PEG with MW
of 2kDa and 5kDa, respectively. Therefore, high MW PEGs prevent phagocytic
uptake protein adsorption and increase circulation time (Suk etal. 2016; Fang etal.
2006). Generally, the MW of grafted PEG chains is proportional to the polymer
chain length. Increasing the MW of PEG from 2kDa to 20kDa prevents the adsorption and aggregation of NP to blood components, thereby increasing its circulation
time (Suk etal. 2016; Mozar and Chowdhury 2018). PEG with MW of 2kDa or
higher could shield particle surfaces, circumventing recognition by the MPS and
protein adsorption (Mozar and Chowdhury 2018; Pai etal. 2006).
4.6.3 Surface Density, PEG Content andConformation
The surface density of the grafted PEG layer is a crucial parameter that inuences
the PEGylated NPs’ ability to resist protein adsorption and clearance after systemic
administration (Suk etal. 2016; Vonarbourg etal. 2006). PEGylated liposomes prepared with 10mol % of PEGylated lipids prevented liposome aggregation in whole
blood, while formulations with 5 and 3 mol % of PEG agglomerated over time
124
Flor
/
= aN
35
S. A. Chime and M. A. Momoh
(Braeckmans etal. 2010). Also, increasing the content of PEG on nanocarriers may
not ensure more excellent surface coverage of PEG.There is a threshold for maximum achievable PEG surface density, which depends on the type of NPs and formulation methods. Hence, an accurate determination of the surface PEG density during
the interpretation of the effect of PEG density on NP circulation is essential (Suk
etal. 2016).
The structural conformation of PEG molecules on the surface and the effectiveness of the PEG in shielding the NP surface is calculated by the average distance
between neighboring PEG chains on an NP surface (D). If D is greater than the
Flory radius of the PEG chain,
yradiusRF,
(4.2)
In the above equation, N=the degree of polymerization, which increases with
an increase in PEG MW, and a=the effective monomer length=0.35nm; then,
the neighboring PEG chains are said to be in a “mushroom” conformational
regime and will not overlap (RF/D≤1) (Suk etal. 2016). Increasing the surface
PEG density such that adjacent PEG chains overlap (RF/D> 1) will cause the
PEG chain to stretch away from the nanocarrier surface, resulting in a “brush”
layer. When the surfaces of PEG densities change from mushroom-to-brush transitions, it is benecial to circumvent the adsorption of serum proteins, avoiding
NPs uptake by MPS cells (Owens and Peppas 2006; Mozar and Chowdhury 2018;
Jokerst etal. 2011). Also, higher RF/D values could result in longer PEG chains
(≥ 10kDa) because of entanglement in the neighboring chains (Suk etal. 2016;
Yang etal. 2014a).
Mushroom state conformation results from low-density PEGylation, whereas
brush state conguration results from high-density PEGylation and is more effective in prolonging the circulation time of PEGylated NPs by higher anti- opsonization
effect (Mozar and Chowdhury 2018). However, having an opsonization effect that
is too strong could prevent the interactions between NPs and cells, reducing some
properties like their tumor uptake, an effect called “PEG Dilemma.” (Mozar and
Chowdhury 2018)
4.7 PEGylated Nanocarriers Products
There are currently so many PEGylated nanocarriers in the market, some of which
are shown in Table4.1 (Mozar and Chowdhury 2018; Abdellatif and Alsowinea
2021; Patra etal. 2018). It is also worth noting that an uncountable number of dif-
ferent nanocarriers are undergoing various stages of clinical trials (Mozar and
Chowdhury 2018).
Adagen® (Pegademase bovine) is a PEGylated polymeric nanocarrier approved
in 1990 for the treatment of severe combined immunodeciency disease (SCID)
(Abdellatif and Alsowinea 2021; Patra etal. 2018). Doxil® is a PEGylated liposomal
doxorubicin approved by FDA and European Medicines Evaluation Agency (EMA)
4 PEGylated Nanocarriers forDrug Delivery Applications
125
in 1999 and 2000, respectively, (Mozar and Chowdhury 2018; Abdellatif and
Alsowinea 2021) for the treatment of advanced ovarian cancer patients with
platinum- based therapy resistance. Doxil® has reduced toxicity with ve to tenfold
higher tumor levels and improved circulation time, especially cardiotoxicity. Also,
various marketed PEGylated protein products are available, viz. PEGylated
Table 4.1 PEGylated nanocarriers products
Loaded drug
Pegademase
bovine
(Abdellatif and
Alsowinea 2021;
Patra etal. 2018)
Glatopa Polymeric
Peglgrastim PEGylated GCSF
Peginterferon
alfa-2A
Peginterferon
alfa-2B
Pegvisomant PEGylated HGH
Pegaspargase Polymer–protein
Pegloticase Polymer–protein
Peginterferon
beta-1A
PEGylated factor
VIII
Paclitaxel Polymeric
Doxorubicin PEGylated
Nanocarrier Brand (Company) Use
Polymeric
nanoparticles
nanoparticles
protein
PEGylated IFN
alpha-2a protein
PEGylated IFN
alpha-2b protein
receptor
antagonist
conjugate
PEGylated
-asparaginase
conjugate
(PEGylated
porcinelikeuricase)
Polymer–protein
conjugate
(PEGylated
IFNbeta-1a)
Polymer–protein
conjugate
(PEGylated
factor VIII)
micelle
liposomal
Adagen®
(Sigma-Tau
Pharmaceuticals)
Copaxone® (Teva) Multiple sclerosis
Neulasta (Amgen) Leukopenia by
Pegasys
(Hoffman-La
Roche)
PegIntron
(Schering)
Somavert
(Pharmacia)
Oncaspar (Sigma
Tau)
Krystexxa
(Horizon)
Plegridy (Biogen) Multiple sclerosis 2014
Adynovate
(Baxalta)
Genexol-PM
(Samyang)
DOXIL (Ben
Venue
Laboratories)
Severe combined
immunodeciency
disease (SCID)
(MS)
chemotherapy
Hepatitis B and C 2002
Hepatitis C 2001
Acromegaly 2003
Acute lymphocytic
blood clot
Chronic gout 2010
Hemophilia 2015
Metastatic breast and
lung cancer
Ovarian, Kaposi’s
sarcoma, and
Multiple myeloma
Date of
approval
1990
1996
2002
1994
2007
1999 and
2000
126
interferon, PEGylated arginine deaminase, and PEGylated L-asparaginase (Mozar
and Chowdhury 2018; Abdellatif and Alsowinea 2021; Patra etal. 2018).
S. A. Chime and M. A. Momoh
4.8 Limitations ofNanocarriers PEGylation
Despite an array of the advantages of PEGylation of NPs in drug delivery, it suffers
from some major limitations such as particle size enlargement, batch-to-batch variability, high variability, and diversity of results obtained with PEGylated NPs and
nonbiodegradability of PEG polymers among others (Howard et al. 2008; Suk
etal. 2016).
4.8.1 High Variability andDiversity ofResults Obtained
withPEGylated NPs
PEGylated nanocarriers may show signicant variability in results outcomes
depending on the type of NPs PEGylated due to the individual properties of the
excipient or composition of the NPs (Sebak 2018). Variability in outcomes of
PEGylation may also arise due to the desorption of PEG, nonhomogeneity of PEG
on particle surfaces, and the attraction of a variety of plasma proteins (Suk
etal. 2016).
4.8.2 Nonbiodegradability ofPEG Polymers
PEG polymers are nonbiodegradable despite their advantages and their biocompatibility. Hence, there could be some potential side effects occurring from their nonbiodegradability (Sebak 2018). There may be situations that can lead to lysosome
bioaccumulation in healthy tissue (Verhoef and Anchordoquy 2013; Lowe
etal. 2015).
4.8.3 Disadvantageous Physicochemical Properties
The PEGylation of NPs affects their physicochemical properties and could lead to
particle size enlargement, predisposing NPs to enhance RES uptake. This could be
worsened by the use of considerable molecular weight PEG, resulting in the sudden
release of loaded drugs from NPs. The loaded drugs could be released from
PEGylated NPs before degradation of the polymer (Sebak 2018). Hence, particles
could be circulating without the loaded drugs before their degradation. There have
been several reports of rapid release of hydrophilic drugs from PEGylated NPs,
which could be due to the hydrophilic nature of PEG chains, which attract water
molecules, causing wetting of PEGylated NPs and faster drug release (Sebak 2018;
Chen etal. 2013; Yang etal. 2014b).