11
side effects. The Mw of PEG within a certain range, plays a role in the therapeutic
drug efficacy. Among the PEG-protein conjugate products, the Mw of PEG is not
less than 12,000 Da.
Due to the considerable advances in PEGylation chemistry, existing PEG conjugation techniques allow link PEG strands to hydrophobic agents permanently or
releasably. The main difference between these two patterns is based a chemical or
enzymatic liable linker. The glycosylated PEG to a target molecule through a hydrolytically labile linker can thus release the drug from the conjugate via the breakdown of the linker (Pelegri-O’Day et al. 2014). The releasable PEGylation is
attractive to modulate the pharmacokinetics of bioactive agents (control of the maximal drug concentration and total drug exposure). For example, PEGylation of complement factor D via a cleavable phenylglyoxal linker was tested by Machinaga
et al. (2018) on rabbits, finding that the releasable PEG drug platform maintained
the drug concentration at therapeutic levels and allowed a sustained drug release for
up to 7 days. Non-covalent PEGylation has received greater attention compared to
covalently linked releasable-PEGylation PEGylation for the release of some bioactive compounds susceptible to loss of activity under environmental stimuli (Reichert
and Borchard 2016). Non-covalent PEGylation allows to minimize the undesirable
loss in the bioactivity of the drug because it does not involve any chemical
modification.
2.3.2 Small PEGylated Bioactive Compounds
PEG conjugation is also applicable to small bioactive compounds. Table 2.3 shows
conjugates of selected small PEGylated biomolecules. The pristine biomolecules
reported here share a similarity in structure regarding the hydroxyl and carboxyl
groups, which offer the possibility of conjugation of PEG. For example, MedinaO’Donnell et al. (2016, 2018) linked the PEG polymer to hydroxyl groups of the
A-ring at C2 or C3 and the carboxyl group at C28 of oleanolic acid, thus producing
twelve conjugates where four of them showed significantly higher antitumor activities than their corresponding parent compounds. However, the resulting conjugate
underwent a reduction in bioactivity once PEGylation occupied the key structures
responsible for bioactivity. For example, Abu-Fayyad et al. (2015) found by conjugating PEG polymers to 6-OH group of a γ-tocotrienol isomer of vitamin E for the
treatment of breast cancer, that the anticancer activity decreased substantially even
despite the improvement in water solubility by binding PEG strands. These findings
underscore the importance of the conjugation site for biomolecules when PEGylation
is conducted. It should also be noted that PEGylation cannot improve bioactivity
because no additional functional moiety is created, except for PEG molecules that
lack biological activity. The evidence for this could be the case of PEGylated ferulic
acid developed by Nicks et al. (2012) where the integration of PEG polymers into
their molecular structure only improved water solubility.
2 Biodegradable and Functional Synthetic Polymers in Nanomedicine: Controlled…
side effects. The Mw of PEG within a certain range, plays a role in the therapeutic
drug efficacy. Among the PEG-protein conjugate products, the Mw of PEG is not
less than 12,000 Da.
Due to the considerable advances in PEGylation chemistry, existing PEG conjugation techniques allow link PEG strands to hydrophobic agents permanently or
releasably. The main difference between these two patterns is based a chemical or
enzymatic liable linker. The glycosylated PEG to a target molecule through a hydrolytically labile linker can thus release the drug from the conjugate via the breakdown of the linker (Pelegri-O’Day et al. 2014). The releasable PEGylation is
attractive to modulate the pharmacokinetics of bioactive agents (control of the maximal drug concentration and total drug exposure). For example, PEGylation of complement factor D via a cleavable phenylglyoxal linker was tested by Machinaga
et al. (2018) on rabbits, finding that the releasable PEG drug platform maintained
the drug concentration at therapeutic levels and allowed a sustained drug release for
up to 7 days. Non-covalent PEGylation has received greater attention compared to
covalently linked releasable-PEGylation PEGylation for the release of some bioactive compounds susceptible to loss of activity under environmental stimuli (Reichert
and Borchard 2016). Non-covalent PEGylation allows to minimize the undesirable
loss in the bioactivity of the drug because it does not involve any chemical
modification.
2.3.2 Small PEGylated Bioactive Compounds
PEG conjugation is also applicable to small bioactive compounds. Table 2.3 shows
conjugates of selected small PEGylated biomolecules. The pristine biomolecules
reported here share a similarity in structure regarding the hydroxyl and carboxyl
groups, which offer the possibility of conjugation of PEG. For example, MedinaO’Donnell et al. (2016, 2018) linked the PEG polymer to hydroxyl groups of the
A-ring at C2 or C3 and the carboxyl group at C28 of oleanolic acid, thus producing
twelve conjugates where four of them showed significantly higher antitumor activities than their corresponding parent compounds. However, the resulting conjugate
underwent a reduction in bioactivity once PEGylation occupied the key structures
responsible for bioactivity. For example, Abu-Fayyad et al. (2015) found by conjugating PEG polymers to 6-OH group of a γ-tocotrienol isomer of vitamin E for the
treatment of breast cancer, that the anticancer activity decreased substantially even
despite the improvement in water solubility by binding PEG strands. These findings
underscore the importance of the conjugation site for biomolecules when PEGylation
is conducted. It should also be noted that PEGylation cannot improve bioactivity
because no additional functional moiety is created, except for PEG molecules that
lack biological activity. The evidence for this could be the case of PEGylated ferulic
acid developed by Nicks et al. (2012) where the integration of PEG polymers into
their molecular structure only improved water solubility.
2 Biodegradable and Functional Synthetic Polymers in Nanomedicine: Controlled…