rates, and reduced immunogenicity of the protein/synthetic polymer conjugate
compared to the native protein. Together, these effects result in extremely
prolonged blood circulation times and thus improved bioavailability of the conjugates. The success of this concept is underlined by the fact that several
PEG/protein conjugate drugs have already been approved by the Food and Drug
Administration (FDA) [21]. “Stealth liposomes” consist of phospholipid vesicles
decorated with PEG chains, anchored to the vesicle’s membrane via lipid anchor
groups, and are designed as transporters for low molecular weight drugs. Similar to
the PEGylation of proteins, the fastening of PEG chains prolongs blood circulation
times of the liposomes [17, 22]. Polymeric carriers for low molecular weight drugs
rely on Ringsdorf’s drug delivery concept [23], which describes the use of a
multifunctional, biocompatible synthetic polymer to transport pharmacons along
with targeting moieties. These systems became even more important when Maeda
and coworkers described the enhanced permeability and retention (EPR) effect for
passive tumor targeting with large molecules [24, 25], a central concept in today’s
anticancer research. PEG has been studied in this context, but suffers from a lack of
polyfunctionality, which results in low drug payloads [13, 16, 18, 26]. Therefore,
several different strategies have been explored for the synthesis of PEGs with
increased numbers of functional groups, such as multi-arm PEGs [27–29],
dendrimer-like PEGs [30–35], dendronized PEGs [36, 37], and multifunctional
PEGs [38].
The benefits and drawbacks of the use of PEG in drug delivery systems along
with those of possible alternative polymeric structures have recently been reviewed
[39]. One of the major concerns regarding the application of PEG in the human
body is its non-biodegradability. As the blood circulation times rise with increasing
molecular weight of PEG [40], the use of high molecular weight polyethers appears
to be advantageous. However, the hydrodynamic volume of PEG must not exceed
the kidney excretion limit (40–60 kDa) to prevent accumulation of the polymer in
the liver [41]. Consequently, degradable high molecular weight PEG derivatives
that carry frangible joints in the backbone, but retain all of PEG’s valuable
properties, are highly desirable. To avoid toxic effects, the degradation products
of such systems must not fall below 400 g mol
À1 [39].
This review focuses on the different synthetic approaches for the incorporation
of labile moieties into the PEG chain as predetermined breaking points. The
majority of the systems that have been reported to date are based on step-growth
polymerization reactions of functional PEG precursors and suitable co-monomers.
These strategies suffer from an inherent disadvantage: They yield poorly defined
PEG analogues with broadly distributed molecular weights. Very recently, a number of more sophisticated synthetic routes have been investigated that yield degradable PEGs with narrow molecular weight distributions. Although highly interesting,
PEGs with cleavable linkers [42] or with cleavable lipids [43–52], which were
found to decrease the reduction in bioactivity of PEGylated proteins or increase the
bioavailability of pharmacons transported in stealth liposomes, respectively, will
not be discussed in this chapter.
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C. Dingels and H. Frey
compared to the native protein. Together, these effects result in extremely
prolonged blood circulation times and thus improved bioavailability of the conjugates. The success of this concept is underlined by the fact that several
PEG/protein conjugate drugs have already been approved by the Food and Drug
Administration (FDA) [21]. “Stealth liposomes” consist of phospholipid vesicles
decorated with PEG chains, anchored to the vesicle’s membrane via lipid anchor
groups, and are designed as transporters for low molecular weight drugs. Similar to
the PEGylation of proteins, the fastening of PEG chains prolongs blood circulation
times of the liposomes [17, 22]. Polymeric carriers for low molecular weight drugs
rely on Ringsdorf’s drug delivery concept [23], which describes the use of a
multifunctional, biocompatible synthetic polymer to transport pharmacons along
with targeting moieties. These systems became even more important when Maeda
and coworkers described the enhanced permeability and retention (EPR) effect for
passive tumor targeting with large molecules [24, 25], a central concept in today’s
anticancer research. PEG has been studied in this context, but suffers from a lack of
polyfunctionality, which results in low drug payloads [13, 16, 18, 26]. Therefore,
several different strategies have been explored for the synthesis of PEGs with
increased numbers of functional groups, such as multi-arm PEGs [27–29],
dendrimer-like PEGs [30–35], dendronized PEGs [36, 37], and multifunctional
PEGs [38].
The benefits and drawbacks of the use of PEG in drug delivery systems along
with those of possible alternative polymeric structures have recently been reviewed
[39]. One of the major concerns regarding the application of PEG in the human
body is its non-biodegradability. As the blood circulation times rise with increasing
molecular weight of PEG [40], the use of high molecular weight polyethers appears
to be advantageous. However, the hydrodynamic volume of PEG must not exceed
the kidney excretion limit (40–60 kDa) to prevent accumulation of the polymer in
the liver [41]. Consequently, degradable high molecular weight PEG derivatives
that carry frangible joints in the backbone, but retain all of PEG’s valuable
properties, are highly desirable. To avoid toxic effects, the degradation products
of such systems must not fall below 400 g mol
À1 [39].
This review focuses on the different synthetic approaches for the incorporation
of labile moieties into the PEG chain as predetermined breaking points. The
majority of the systems that have been reported to date are based on step-growth
polymerization reactions of functional PEG precursors and suitable co-monomers.
These strategies suffer from an inherent disadvantage: They yield poorly defined
PEG analogues with broadly distributed molecular weights. Very recently, a number of more sophisticated synthetic routes have been investigated that yield degradable PEGs with narrow molecular weight distributions. Although highly interesting,
PEGs with cleavable linkers [42] or with cleavable lipids [43–52], which were
found to decrease the reduction in bioactivity of PEGylated proteins or increase the
bioavailability of pharmacons transported in stealth liposomes, respectively, will
not be discussed in this chapter.
170
C. Dingels and H. Frey