Bioresponsive polymers can enable the development of more effective drug delivery vehicles and medical materials. Acetal-modified polysaccharides allow pH-triggered solubility switching in a versatile and effective manner, but prior work has been limited to a combination of acyclic alkoxyisopropyl and cyclic isopropylidene acetals. We describe here the preparation and characterization of spirocyclic acetal-modified dextran (SpAc-Dex), which comprises dextran decorated with cyclopentyl, cyclohexyl, or cycloheptyl acetals (SpAc5-, SpAc6-, and SpAc7-Dex, respectively). A library of materials with varying acyclic and cyclic acetal contents was synthesized, and organic-soluble materials were formed into microparticles and assessed for degradability and cytocompatibility. At high levels of modification, SpAc5-Dex degraded most quickly and SpAc7-Dex degraded most slowly. SpAc6-Dex features lower degrees of substitution but spans a wide range of degradability. These materials were found to be noncytotoxic and may find future use in biomedical applications.