Cleavable Polyethylene Glycol: 3,4-Epoxy-1-butene as a Comonomer to Establish Degradability at Physiologically Relevant pH

Polyethylene glycol (PEG) has been used for decades to improve the pharmacokinetic properties of protein drugs, and several PEG-protein conjugates are approved by the FDA. However, the nondegradability of PEG restricts its use to a limiting molecular weight to permit renal excretion. In this work, we introduce a simple strategy to overcome the nondegradability of PEG by incorporating multiple pH-sensitive vinyl ether moieties into the polyether backbone. Copolymerization of 3,4-epoxy-1-butene (EPB) with ethylene oxide via anionic ring-opening polymerization (AROP) provides access to allyl moieties that can be isomerized to pH-cleavable propenyl units (isoEPB). Well-defined P­(EPB-co-EG) copolymers (Đ = 1.05–1.11) with EPB contents of ∼4 mol% were synthesized in a molecular weight range of 3000 to 10000 g mol^–1. ¹H NMR kinetic studies served to investigate acidic hydrolysis in a pH range of 4.4 to 5.4 and even allowed to distinguish between the hydrolysis rates of (E)- and (Z)-isoEPB units, demonstrating faster hydrolysis of the (Z)-isomer. SEC analysis of degradation products revealed moderate dispersities Đ of 1.6 to 1.8 and consistent average molecular weights M_n of ∼1000 g mol^–1. The presence of a defined hydroxyl end group permits attachment to other functional molecules. The novel pH-degradable PEGs combine various desirable properties such as excellent long-term storage stability and cleavage in a physiologically relevant pH-range that render them promising candidates for biomedical application.