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4 PEGylated Nanocarriers forDrug Delivery Applications
127
4.8.4 Unfavorable Cellular andSubcellular Fate
PEGylated NPs sometimes exhibit limited intracellular uptake signicantly lower
than non-PEGylated NPs, resulting from steric hindrance from polymer chains of
PEG and the hydrophilic nature of the surfaces of NPs. Hence, hydrophilic and
neutral NPs form of PEGylated NPs exhibit slower internalization in target cells
than Nps with charges (Oh and Park 2014; Mao etal. 2013). Therefore, despite
being able to prevent the isolation of drug-loaded NP by RES cells and increasing
extravasation of NPs through the unstable tumor vasculature, PEGylation reduces
target tissue interaction (Verhoef and Anchordoquy 2013), and inhibits endosomal
escape, leading to the loss of activity of some delivery systems like nucleic acid and
gene delivery systems in the treatment of cancer where the NPs degrade in the
acidic digestive medium of the endolysosomal system (Sebak 2018; Hatakeyama
etal. 2013).
4.8.5 Limited RES Evasion Capacity
Improper selection and optimization of PEG molecular weight and density, coatings
of PEG, and inadequate nanocarrier core properties could affect RES evasion capacity. Hence, despite the ability of PEG to provide steric hindrance and mask the surface charge of NPs, preventing opsonization, their ability to avoid this opsonization
has been shown to be limited, leading to several reports of opsonization and RES
clearance even after PEGylation (Sebak 2018; Verhoef and Anchordoquy 2013;
Wan etal. 2017; Zhang etal. 2016).
Reduced RES evasion capacity by PEGylated NPs could be caused majorly by
the production of anti-PEG antibodies, size enlargement of nanocarriers, and development of an immune response that leads to faster clearance of PEGylated NPs
from the bloodstream and removal of PEG from surfaces of NPs (Sebak 2018).
Particle Size Enlargement PEGylation of NPs leads to the particle size increase,
which could affect some pharmacokinetics of NPs and may also lead to an abnormal
reduction in the MRT of nanocarriers in blood, affecting RES avoidance by PEG
(Raei and Haddadi 2017; Xu etal. 2013).
Insufcient PEG Coating or Desorption of PEG Layer Improper surface coating of PEG or polymer desorption from the surface of NPs could present surfaces or
holes where opsonins can bind (Sebak 2018; Kettiger etal. 2013).
Immunogenicity of PEG PEG polymers were once known to be nonantigenic.
However, recent reports showed that they could develop an immune response, causing an effect known as the ABC phenomenon, because of the generation of antiPEG IgM antibodies produced from the spleen in response to a previous dose
128
S. A. Chime and M. A. Momoh
(Kettiger etal. 2013; Chen etal. 2016). These antibodies form a complex with other
serum components, resulting in more sequestration by RES (Verhoef and
Anchordoquy 2013; Zhang etal. 2014). It has been discovered that a second dose of
PEGylated injected liposomes exhibited poor circulation time and high accumulation in the spleen and liver, more than the rst dose (Zhang etal. 2014). Also, in 250
healthy blood donors screened, isotypes of anti-PEG antibodies of both IgG and
IgM were discovered in 25%. This could be due to increased exposure of the masses
to PEG-containing pharmaceutical and cosmetics products for a prolonged period
of time (Sebak 2018; Hatakeyama etal. 2013). This explains the loss of activity that
could occur with repeated dosing of PEGylated products.
4.9 Conclusion
Nanocarriers consist of polymeric and lipid-based NPs arrays with different constituents, formulation methods, and functionalities. Adequate selection of the particular type of NP to coat with PEG for effective and enhanced NP properties is
essential to achieve better results with PEGylation. Also, proper preformulation
studies should be carried out to choose an optimized coating composition in terms
of PEG MW, density, and layer of coating to avoid desorption that could lead to the
failure of PEGylated NPs and abnormal functioning in the body. PEGylation of NPs
remains an area for scientists to explore further so that all the advantages embodied
in these nanocarriers and PEG polymers can be utilized for better treatment of diseases of man and better treatment outcomes.
PEGylation has become an essential aspect of drug delivery utilized effectively
in the formulation of challenging delivery systems used to treat many chronic and
life-threatening illnesses like different forms of cancers. Its use in the formulation
of herbal formulations and nutraceuticals is yet to be fully explored; hence, it should
be an area for future development. Also, methods and processes that will prevent the
problems encountered in the coating of NPs to avoid RES reversal and developing
antiPEG antibodies are all areas under study.
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