18.2 Variety of Hydrophilization of the Surface
of Nanoparticles
Polyethylene glycol (H–(O–CH 2 –CH 2 ) n –OH) (synonym; polyethylene oxide or
polyoxyethylene) was the most popular substrate to hydrophilize the surface of
hydrophobic nanomaterials. Linear or branched PEGs of variable length can be
coated on the surface of the nanoparticles. Or there were reported an easy way of
PEGylation of hydrophobic nanoparticles by making micelle capsule and encapsulation, which were applied to various nanoparticles including quantum dots
[42, 43], iron oxide [44, 45], upconversion nanoparticles [46], surface-enhanced
Raman scattering (SERS) dots [47, 48]. Methods of PEGylation of peptides or
proteins was classified as (1) acylation, (2) alkylation and (3) thioether formation
[11] (Fig. 18.5). These methods were used to manufacture the biopharmaceuticals
of peptide, aptamer, protein and antibody. Mostly linear PEGs and rarely branched
PEG were used with the molecular weights of 5–40 kD. 1–82 molecules of PEGs
were attached per molecules (Table 18.1).
The eloquent goal of PEGylation of nanoparticles is hydrophilization as
hydrophobicity cause two problems for nanoparticles; (1) aggregation and making
huge cluster which will block alveolar capillaries of the lungs and (2) stimulation of
hostile innate immune response. Aggregation is immediately noticed and though
detergents are mixed, immune response cannot be avoided. When the gold
nanoparticles were decorated with PEGs having tuned functionalities at the terminal
having different log P (0.63–5.35) representing hydrophobic values of these functional head-groups. While IL-10 gene expression did not differ between tuned
PEGylated gold nanoparticles, TNFa gene expression was correlated with the
hydrophobicity [4]. Next parameter was the length of PEG along with the composition or the shape [5, 6]. There is a tendency that longer and more dense (not
sparse) and brush type (not mushroom type) of PEGs’ configuration are the key to
increase circulation time and to decrease macrophage uptake. The exact effect of
configuration, shape, and constitution are being elucidated ever and ever.
Though the details are mostly not known regarding the effect of zwitterion
coating and the determining parameters thereof, PEGs are being challenged to be
replaced by zwitterions as PEGs are eliciting IgM response and in certain cases
even preexisting IgG responses, and consequently PEGs do not achieve sufficient
circulation time. In several reports proposing low immunogenicity and longer circulation time, we don’t have enough data by which we can sort out the effects of the
polymer length, zwitterion density, characteristics of head-group on circulation
time, innate immune response, targeting capability and cellular uptake [35, 36].
What we know currently are mainly based on molecular dynamics modeling [36],
using sulfobetaine or carboxybetaine materials (Fig. 18.6). Jiang and coworkers
explain principles of sulfobetaines and carboxybetaines which will endow the
zwitterions the characteristics of plenty of hydration, less self-association and
resistance to the protein adsorption [49]. The most important of these characteristics
is the resistance to the protein adsorption, which should be validated by in vitro
18 Polyethylene Glycolation (PEGylation) and the Similar
337
of Nanoparticles
Polyethylene glycol (H–(O–CH 2 –CH 2 ) n –OH) (synonym; polyethylene oxide or
polyoxyethylene) was the most popular substrate to hydrophilize the surface of
hydrophobic nanomaterials. Linear or branched PEGs of variable length can be
coated on the surface of the nanoparticles. Or there were reported an easy way of
PEGylation of hydrophobic nanoparticles by making micelle capsule and encapsulation, which were applied to various nanoparticles including quantum dots
[42, 43], iron oxide [44, 45], upconversion nanoparticles [46], surface-enhanced
Raman scattering (SERS) dots [47, 48]. Methods of PEGylation of peptides or
proteins was classified as (1) acylation, (2) alkylation and (3) thioether formation
[11] (Fig. 18.5). These methods were used to manufacture the biopharmaceuticals
of peptide, aptamer, protein and antibody. Mostly linear PEGs and rarely branched
PEG were used with the molecular weights of 5–40 kD. 1–82 molecules of PEGs
were attached per molecules (Table 18.1).
The eloquent goal of PEGylation of nanoparticles is hydrophilization as
hydrophobicity cause two problems for nanoparticles; (1) aggregation and making
huge cluster which will block alveolar capillaries of the lungs and (2) stimulation of
hostile innate immune response. Aggregation is immediately noticed and though
detergents are mixed, immune response cannot be avoided. When the gold
nanoparticles were decorated with PEGs having tuned functionalities at the terminal
having different log P (0.63–5.35) representing hydrophobic values of these functional head-groups. While IL-10 gene expression did not differ between tuned
PEGylated gold nanoparticles, TNFa gene expression was correlated with the
hydrophobicity [4]. Next parameter was the length of PEG along with the composition or the shape [5, 6]. There is a tendency that longer and more dense (not
sparse) and brush type (not mushroom type) of PEGs’ configuration are the key to
increase circulation time and to decrease macrophage uptake. The exact effect of
configuration, shape, and constitution are being elucidated ever and ever.
Though the details are mostly not known regarding the effect of zwitterion
coating and the determining parameters thereof, PEGs are being challenged to be
replaced by zwitterions as PEGs are eliciting IgM response and in certain cases
even preexisting IgG responses, and consequently PEGs do not achieve sufficient
circulation time. In several reports proposing low immunogenicity and longer circulation time, we don’t have enough data by which we can sort out the effects of the
polymer length, zwitterion density, characteristics of head-group on circulation
time, innate immune response, targeting capability and cellular uptake [35, 36].
What we know currently are mainly based on molecular dynamics modeling [36],
using sulfobetaine or carboxybetaine materials (Fig. 18.6). Jiang and coworkers
explain principles of sulfobetaines and carboxybetaines which will endow the
zwitterions the characteristics of plenty of hydration, less self-association and
resistance to the protein adsorption [49]. The most important of these characteristics
is the resistance to the protein adsorption, which should be validated by in vitro
18 Polyethylene Glycolation (PEGylation) and the Similar
337