PEGylation Technology in Nanomedicine - Polymers in Nanomedicine - page 121

Although the detailed mechanism of the longer circulation time of branched
PEGylated protein is unclear, the architecture of PEG affects the release profile, the
pharmacokinetics of the drug [ 29 ], and the behavior of the protein at the interface
(e.g., protein absorption on hydrophobic surfaces [ 30 ]).

2.5 Releasable PEGylation

Although covalent attachments of PEG to drugs prolongs the lifetime of the drug
in vivo, they often have the opposite effect on biological and pharmacological
properties because the active site of drugs is inactivated due to shielding by massive
PEG chains [ 31 , 32 ]. Even optimized site-specific PEGylation often results in
insufficient pharmacological properties. It also prevents internalization of the
drug into the cell [ 33 ]. New emerging technologies, such as de-PEGylation from
complex drugs, have been developed. Specific biodegradable linkages between the
drug and PEG chains are introduced to allow de-PEGylation. After the release of
PEG chains, drugs such as small molecules and proteins recover their original
structures, activities, and cellular-uptake capacities.
Roberts et al. reported the synthesis of PEG-drug conjugates via an ester bond
between the drug and PEG chain [ 34 ]. Despite its simplicity and efficacy, it is
difficult to regulate the release specificity because numerous esterases exist in the
cellular environment. In addition, many biologically active compounds often lack a
hydroxyl or carboxyl group, which is required for ester formation. In this system,
residues of linking reagent that connect PEG to the drug were left on the parent
molecules, even after the cleavage of PEG chains [ 34 ]. These residues may affect
the biological activities of

the drug and might be a potential source of

immunogenicity.
Shulman et al. synthesized bifunctional linking reagents containing 2-sulfo-
9-fluorenyl-methoxycarbonyl (FMS) to produce a PEG conjugate that can be
cleaved by spontaneous hydrolysis under physiological conditions, on the basis of
the FMS cleavable system (Scheme 1 )[ 35 ]. Amino groups in drugs can be utilized
for conjugation to PEG in this case.
Zalipsky et al. reported a drug-PEG conjugate via a benzyl carbamate linkage
(Scheme 2 )[ 36 ]. This linkage is cleaved by a benzyl elimination reaction initiated
by the thiolytic cleavage of disulfide in the para or ortho position. Filpula et al.
developed a series of releasable PEG linkers that enable the controlled release of
drugs [ 37 ]. In their system, the cleavage reaction is initiated by a trigger reaction,
such as ester bond cleavage by esterase (Scheme 3 ). By controlling the rate-
determining step with an optimized linker structure, the release rate of PEG chains
can be controlled. For example, the introduction of steric hindrance, which slows
the triggered hydrolysis reaction of esters, results in a diminishing release rate [ 37 ].
ProLynx LLC has developed another type of releasable PEGylation technology
based on the b -elimination reaction shown in Scheme 4 . In this system, the release
rate of the native drug is determined by the acidity of the proton adjacent to the