3.3 Alternative Labile Groups and Triggers
In analogy to azo units, disulfide linkages have been studied as reductively cleavable joints for the reversible connection of PEG telechelics [89, 105–108]. In
contrast to the former, disulfides are reduced by a reduced glutathione (GSH)
derivative in the cytosol. The disulfide-containing polyethers can either be synthesized from PEG dithiol precursors under oxidative conditions [89, 105–107] or
by a polycondensation of telechelic PEGs and a suitable difunctional disulfide
[89]. Depending on the synthetic route, size of the telechelic PEGs, and the reaction
conditions, it was possible to obtain poly(ether sulfide)s with molecular weights up
to 180,000 g mol
À1 . In contrast to poly(ether sulfide)s with degrees of polymerization exceeding 12, those prepared from tri-, tetra-, or hexa(ethylene glycol) were
almost insoluble in water. Pendant functionalities have been incorporated in these
polymers by coupling PEG chains to cystine via urethane or ester bonds. The
reductive degradation rate is dependent on the hydrophobicity of the pendant
functional groups. Although the disulfides of a polyester from PEG and cystine at
cytosolic glutathione concentrations (5 mmol) are reduced even faster than the ester
moieties are hydrolyzed at pH 8.0 (Fig. 4), reductive degradation of a
corresponding polymer with pendant p-nitrophenyl succinates is rather slow
under the same conditions (<50% within 2 days) [89]. As poly(ether sulfide)s
also undergo reductive degradation when incubated with EL4 T cells [107] and
were nontoxic to HepG2 cells [105], these polymers appear to be promising drug
carriers.
Besides carboxylates, esters of other biologically relevant acids have been used
to synthesize PEG-based polyesters. Physical properties of PEG-derived
polycarbonates have been explored since the 1960s [74–78]. More recent studies
have focused on the degradability and cell interactions of these materials, but the
PEG contents were low (<25%) [80–83]. Water-soluble polymers with higher PEG
fractions have been prepared, but no degradation data has been reported for these
[160, 161]. PEGs with a single carbonate linker were solely mentioned in patent
literature [79, 84].
Poly(H-phosphonate)s from PEG diols are generated by the polycondensation of
the telechelic polyethers and dialkyl H-phosphonates [124–135]. The degradation
of PEG polyphosphonates occurs randomly along the polymer chain under slightly
basic conditions (pH 8.8, 40% degradation in 12 h) and is more rapid at low pH
(pH 1.66, almost complete after 11 h). The degradation rate is further influenced by
the polymer concentration because the degradation affords acidic products [134,
137]. These polymers might also undergo enzymatic degradation [137]. Poly(PEG
H-phosphonate)s carry highly reactive P-H bonds that allow further functionalization, such as the attachment of pharmaceutically active compounds or linker
moieties for the conjugation to such molecules [124, 135], as well as oxidation to
the corresponding poly(PEG phosphate)s [126–133]. Another synthetic pathway to
such polyphosphates is the condensation of PEG diols and alkyl dichlorophosphates
[136]. Further information on these interesting materials and their applicability in
From Biocompatible to Biodegradable: Poly(Ethylene Glycol)s with. . .
181
In analogy to azo units, disulfide linkages have been studied as reductively cleavable joints for the reversible connection of PEG telechelics [89, 105–108]. In
contrast to the former, disulfides are reduced by a reduced glutathione (GSH)
derivative in the cytosol. The disulfide-containing polyethers can either be synthesized from PEG dithiol precursors under oxidative conditions [89, 105–107] or
by a polycondensation of telechelic PEGs and a suitable difunctional disulfide
[89]. Depending on the synthetic route, size of the telechelic PEGs, and the reaction
conditions, it was possible to obtain poly(ether sulfide)s with molecular weights up
to 180,000 g mol
À1 . In contrast to poly(ether sulfide)s with degrees of polymerization exceeding 12, those prepared from tri-, tetra-, or hexa(ethylene glycol) were
almost insoluble in water. Pendant functionalities have been incorporated in these
polymers by coupling PEG chains to cystine via urethane or ester bonds. The
reductive degradation rate is dependent on the hydrophobicity of the pendant
functional groups. Although the disulfides of a polyester from PEG and cystine at
cytosolic glutathione concentrations (5 mmol) are reduced even faster than the ester
moieties are hydrolyzed at pH 8.0 (Fig. 4), reductive degradation of a
corresponding polymer with pendant p-nitrophenyl succinates is rather slow
under the same conditions (<50% within 2 days) [89]. As poly(ether sulfide)s
also undergo reductive degradation when incubated with EL4 T cells [107] and
were nontoxic to HepG2 cells [105], these polymers appear to be promising drug
carriers.
Besides carboxylates, esters of other biologically relevant acids have been used
to synthesize PEG-based polyesters. Physical properties of PEG-derived
polycarbonates have been explored since the 1960s [74–78]. More recent studies
have focused on the degradability and cell interactions of these materials, but the
PEG contents were low (<25%) [80–83]. Water-soluble polymers with higher PEG
fractions have been prepared, but no degradation data has been reported for these
[160, 161]. PEGs with a single carbonate linker were solely mentioned in patent
literature [79, 84].
Poly(H-phosphonate)s from PEG diols are generated by the polycondensation of
the telechelic polyethers and dialkyl H-phosphonates [124–135]. The degradation
of PEG polyphosphonates occurs randomly along the polymer chain under slightly
basic conditions (pH 8.8, 40% degradation in 12 h) and is more rapid at low pH
(pH 1.66, almost complete after 11 h). The degradation rate is further influenced by
the polymer concentration because the degradation affords acidic products [134,
137]. These polymers might also undergo enzymatic degradation [137]. Poly(PEG
H-phosphonate)s carry highly reactive P-H bonds that allow further functionalization, such as the attachment of pharmaceutically active compounds or linker
moieties for the conjugation to such molecules [124, 135], as well as oxidation to
the corresponding poly(PEG phosphate)s [126–133]. Another synthetic pathway to
such polyphosphates is the condensation of PEG diols and alkyl dichlorophosphates
[136]. Further information on these interesting materials and their applicability in
From Biocompatible to Biodegradable: Poly(Ethylene Glycol)s with. . .
181