Universal Concept for
the Implementation of a Single
Cleavable Unit at Tunable Position in Functional Poly(ethylene glycol)s
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Abstract
Poly(ethylene glycol) (PEG) with acid-sensitive moieties
gained
attention particularly for various biomedical applications, such as
the covalent attachment of PEG (PEGylation) to protein therapeutics,
the synthesis of stealth liposomes, and polymeric carriers for low-molecular-weight
drugs. Cleavable PEGs are favored over their inert analogues because
of superior pharmacodynamic and/or pharmacokinetic properties of their
formulations. However, synthetic routes to acetal-containing PEGs
published up to date either require enormous efforts or result in
ill-defined materials with a lack of control over the molecular weight.
Herein, we describe a novel methodology to implement a single acetaldehyde
acetal in well-defined (hetero)functional poly(ethylene glycol)s with
total control over its position. To underline its general applicability,
a diverse set of initiators for the anionic polymerization of ethylene
oxide (cholesterol, dibenzylamino ethanol, and poly(ethylene glycol)
monomethyl ether (mPEG)) was modified and used to synthesize the analogous
labile PEGs. The polyether bearing the cleavable lipid had a degree
of polymerization of 46, was amphiphilic and exhibited a critical
micelle concentration of 4.20 mg·L<sup>–1</sup>. From
dibenzylamino ethanol, three heterofunctional PEGs with different
molecular weights and labile amino termini were generated. The transformation
of the amino functionality into the corresponding squaric acid ester
amide demonstrated the accessibility of the cleavable functional group
and activated the PEG for protein PEGylation, which was exemplarily
shown by the attachment to bovine serum albumin (BSA). Furthermore,
turning mPEG into a macroinitiator with a cleavable hydroxyl group
granted access to a well-defined poly(ethylene glycol) derivative
bearing a single cleavable moiety within its backbone. All the acetal-containing
PEGs and PEG/protein conjugates were proven to degrade upon acidic
treatment