The synthetic polymers that are used to prepare polymer therapeutics reaching clinical use are predominantly nonbiodegradable, and this severely limits the molecular weight range that will give certainty of safe elimination. The aim of this study was to synthesize water-soluble, biocompatible, amino-functionalized polyacetals that would display pH-dependent degradation and, moreover, be suitable for drug conjugation. To test the feasibility of the synthetic procedure, polyacetals were first prepared by the reaction of a diol (e.g., poly(ethylene glycol) (PEG)) and a divinyl ether (e.g., tri(ethylene glycol) divinyl ether) using an acid catalyst. Using PEG3400, these polyacetals had a Mw of 36 000−43 000 g/mol (Mw/Mn = 1.6−1.8) and displayed pH-dependent degradation. An enhanced rate of hydrolysis was seen at pH 5.5 (41% Mw loss in 25 h) compared to pH 7.4 (10% Mw loss in 73 h). The polymers and their degradation products were nontoxic toward B16F10 cells in vitro (IC50 > 5 mg/mL), and they were also nonhe...