the used low molecular weight PEG precursor and the added PEG block. These
degradable mPEGs might be applicable as substitutes for commercial mPEGs,
relying on established protocols for conjugation to proteins or low molecular
weight drugs in order to increase the maximum molecular weight of the polyether
that can be used in the human body, avoiding the risk of accumulation of PEG in
the liver.
3 Different Labile Units for Different Triggers
3.1 Acid-Sensitive PEGs
Most of the labile units listed in Table 2, including most of the PEGs synthesized by
previously discussed EO polymerization methods, are cleaved at acidic pH. Acidity
is a popular degradation trigger [156], especially for polymeric carriers of anticancer drugs making use of passive targeting of tumors (EPR effect) and the potentially
increased acidity of such tissue [157, 158]. Reduced pH is further found in
lysosomes (pH 5.5) and endosomes (pH 6.5), extending the possible application
of acid-sensitive polymer therapeutics beyond antitumor therapies.
The first attempt to synthesize acid-sensitive PEGs based on a PEG coupling
approach capitalized on cis-aconitic acid linkers. The obtained polymer was aciddegradable and most likely biocompatible, as shown in a cell viability assay using
B16F10 cells as well as a red blood cell lysis assay. However, decarboxylation and
crosslinking reactions led to nondegradable linkages [71]. Better results were
achieved with the incorporation of acetal moieties in PEGs. Pioneering work
by Duncan, Brocchini and coworkers capitalized on the copolymerization of
triethylene glycol (TEG) divinyl ether with dihydroxyl PEGs and functional
diols, such as protected serinol [53] and diphenols [56, 57]. The former diol allows
postpolymerization modification of the resulting amino-pendent polyacetal
(APEGs, Scheme 5) with pendant doxorubicin (DOX) moieties [55], whereas
among the latter, drugs can be incorporated directly in the main chain [56, 66,
67]. Using telechelic PEG with M w ¼ 3,400, degradable PEGs with molecular
weights up to 100,000 g mol
À1 and PDIs of 1.6-2.0 were synthesized. Other
synthetic routes to PEG polyacetals involve condensation of PEG diols with the
corresponding aldehyde [60, 65] or Williamson ether synthesis from an acetalcontaining diol and PEG ditosylate [58, 63, 64]. Although conceptually interesting,
these routes do not lead to high molecular weight polyethers, but result in polydisperse (PDI > 2) or, in case of the etherification, ill-defined (5.8 < PDI < 11.6)
polymers.
The degradation of acetals in PEG is strongly pH and temperature dependent
and, not surprisingly, faster in more acidic media [53, 56, 57, 59, 64–68, 70]. At pH
5.5 and 37
C, total degradation of PEG acetaldehyde acetals requires approximately 3 weeks, but also at pH 7.4 (pH of blood), a significant amount of the labile
176
C. Dingels and H. Frey
degradable mPEGs might be applicable as substitutes for commercial mPEGs,
relying on established protocols for conjugation to proteins or low molecular
weight drugs in order to increase the maximum molecular weight of the polyether
that can be used in the human body, avoiding the risk of accumulation of PEG in
the liver.
3 Different Labile Units for Different Triggers
3.1 Acid-Sensitive PEGs
Most of the labile units listed in Table 2, including most of the PEGs synthesized by
previously discussed EO polymerization methods, are cleaved at acidic pH. Acidity
is a popular degradation trigger [156], especially for polymeric carriers of anticancer drugs making use of passive targeting of tumors (EPR effect) and the potentially
increased acidity of such tissue [157, 158]. Reduced pH is further found in
lysosomes (pH 5.5) and endosomes (pH 6.5), extending the possible application
of acid-sensitive polymer therapeutics beyond antitumor therapies.
The first attempt to synthesize acid-sensitive PEGs based on a PEG coupling
approach capitalized on cis-aconitic acid linkers. The obtained polymer was aciddegradable and most likely biocompatible, as shown in a cell viability assay using
B16F10 cells as well as a red blood cell lysis assay. However, decarboxylation and
crosslinking reactions led to nondegradable linkages [71]. Better results were
achieved with the incorporation of acetal moieties in PEGs. Pioneering work
by Duncan, Brocchini and coworkers capitalized on the copolymerization of
triethylene glycol (TEG) divinyl ether with dihydroxyl PEGs and functional
diols, such as protected serinol [53] and diphenols [56, 57]. The former diol allows
postpolymerization modification of the resulting amino-pendent polyacetal
(APEGs, Scheme 5) with pendant doxorubicin (DOX) moieties [55], whereas
among the latter, drugs can be incorporated directly in the main chain [56, 66,
67]. Using telechelic PEG with M w ¼ 3,400, degradable PEGs with molecular
weights up to 100,000 g mol
À1 and PDIs of 1.6-2.0 were synthesized. Other
synthetic routes to PEG polyacetals involve condensation of PEG diols with the
corresponding aldehyde [60, 65] or Williamson ether synthesis from an acetalcontaining diol and PEG ditosylate [58, 63, 64]. Although conceptually interesting,
these routes do not lead to high molecular weight polyethers, but result in polydisperse (PDI > 2) or, in case of the etherification, ill-defined (5.8 < PDI < 11.6)
polymers.
The degradation of acetals in PEG is strongly pH and temperature dependent
and, not surprisingly, faster in more acidic media [53, 56, 57, 59, 64–68, 70]. At pH
5.5 and 37
C, total degradation of PEG acetaldehyde acetals requires approximately 3 weeks, but also at pH 7.4 (pH of blood), a significant amount of the labile
176
C. Dingels and H. Frey