obtained via AROP in a well-defined manner with low polydispersity. In contrast to
the multifunctional PEGs, an oxirane co-monomer for the degradable PEGs can
hardly, if at all, be synthesized. The degradable moiety would have to resist the
harsh basic conditions of the AROP, limiting the choices to acetals, ketals,
disulfides, ortho esters, and vinyl ethers. Three-membered cycles including these
groups are highly energetic and have not been synthesized or are stable only at very
low temperatures, e.g., allene oxide [148] or cyc-S 2 O [149, 150]. The direct
synthesis of polyethers with in-chain acetals by cationic copolymerization of EO
and 1,3,5-trioxane is of course known, but the degradation of the resulting polymeric formaldehyde acetals requires low pH conditions, the resulting formaldehyde
is toxic, the PDIs are higher than those of anionically synthesized polymers, and the
acetal content reported is rather high because the EO units serve as stabilizing
fractions to stop the unzipping of terminal oligoacetal blocks [151–153].
2.1 Modification of Commercial PEGs
The majority of all cleavable groups incorporated into the backbone of PEG
(summarized in Table 2 along with the corresponding synthetic approaches) can
be introduced by coupling of homotelechelic PEGs via addition or condensation
reactions. A detailed discussion of the applicable labile units, as well as the
synthesis and properties of the obtained materials will be presented in Sect. 3.
The main drawbacks common for all of these telechelic-based coupling strategies
are the broad molecular weight distributions (M w /M n 1.6 to >10) and poor control
of the degree of polymerization. These issues are avoided if just two PEG chains are
linked to one (multi)functional degradable coupling unit [59, 90, 104, 112, 113,
119, 123], resulting in cleavable PEGs with a single (functional) cleavable joint;
however low yields are obtained when none of the termini is blocked as a methyl
ether [61]. The PEG coupling approaches are popular because the required
dihydroxy PEG telechelics are inexpensive and soluble in many organic solvents,
enabling a variety of coupling reactions. In cases where the telechelic PEGs are
coupled via a multihetero-functional unit, degradable multifunctional PEGs can be
synthesized, as presented by Ulbrich, R ˇ ı
´hova ´ and coworkers [89, 107, 113] and the
groups of Lee [85, 86] and Brocchini [53, 55], (vide infra, Scheme 5) for example.
Furthermore, PEG is, as mentioned before, nontoxic and non-immunogenic and
thus easy to handle, whereas all of the strategies that involve the synthesis of the
polyether require polymerization of the gaseous EO under anhydrous conditions. A
one-step synthetic route to acid-degradable PEGs that relies neither on EO polymerization nor on a PEG coupling reaction was presented by Elisseeff and
coworkers [109]. Some of the methylene groups of commercial PEG were oxidized
to hemiacetals using Fenton’s reagent, thereby introducing acid-labile breaking
points. Unfortunately, degradation of the hemiacetals occurred during the synthesis
at low degrees of oxidation, which is a drawback that will have to be overcome.
172
C. Dingels and H. Frey
the multifunctional PEGs, an oxirane co-monomer for the degradable PEGs can
hardly, if at all, be synthesized. The degradable moiety would have to resist the
harsh basic conditions of the AROP, limiting the choices to acetals, ketals,
disulfides, ortho esters, and vinyl ethers. Three-membered cycles including these
groups are highly energetic and have not been synthesized or are stable only at very
low temperatures, e.g., allene oxide [148] or cyc-S 2 O [149, 150]. The direct
synthesis of polyethers with in-chain acetals by cationic copolymerization of EO
and 1,3,5-trioxane is of course known, but the degradation of the resulting polymeric formaldehyde acetals requires low pH conditions, the resulting formaldehyde
is toxic, the PDIs are higher than those of anionically synthesized polymers, and the
acetal content reported is rather high because the EO units serve as stabilizing
fractions to stop the unzipping of terminal oligoacetal blocks [151–153].
2.1 Modification of Commercial PEGs
The majority of all cleavable groups incorporated into the backbone of PEG
(summarized in Table 2 along with the corresponding synthetic approaches) can
be introduced by coupling of homotelechelic PEGs via addition or condensation
reactions. A detailed discussion of the applicable labile units, as well as the
synthesis and properties of the obtained materials will be presented in Sect. 3.
The main drawbacks common for all of these telechelic-based coupling strategies
are the broad molecular weight distributions (M w /M n 1.6 to >10) and poor control
of the degree of polymerization. These issues are avoided if just two PEG chains are
linked to one (multi)functional degradable coupling unit [59, 90, 104, 112, 113,
119, 123], resulting in cleavable PEGs with a single (functional) cleavable joint;
however low yields are obtained when none of the termini is blocked as a methyl
ether [61]. The PEG coupling approaches are popular because the required
dihydroxy PEG telechelics are inexpensive and soluble in many organic solvents,
enabling a variety of coupling reactions. In cases where the telechelic PEGs are
coupled via a multihetero-functional unit, degradable multifunctional PEGs can be
synthesized, as presented by Ulbrich, R ˇ ı
´hova ´ and coworkers [89, 107, 113] and the
groups of Lee [85, 86] and Brocchini [53, 55], (vide infra, Scheme 5) for example.
Furthermore, PEG is, as mentioned before, nontoxic and non-immunogenic and
thus easy to handle, whereas all of the strategies that involve the synthesis of the
polyether require polymerization of the gaseous EO under anhydrous conditions. A
one-step synthetic route to acid-degradable PEGs that relies neither on EO polymerization nor on a PEG coupling reaction was presented by Elisseeff and
coworkers [109]. Some of the methylene groups of commercial PEG were oxidized
to hemiacetals using Fenton’s reagent, thereby introducing acid-labile breaking
points. Unfortunately, degradation of the hemiacetals occurred during the synthesis
at low degrees of oxidation, which is a drawback that will have to be overcome.
172
C. Dingels and H. Frey