Thermoresponsive Poly(2-Oxazoline)s with pH-Degradable Acetal Side Chains as Potential Drug Delivery Vehicles

pH-responsive polymers that degrade under acidic conditions while remaining stable at pH 7.4 are ideal for controlled drug delivery. This study reports pH- and thermoresponsive poly(2-oxazoline)s (PAOx) with lower critical solution temperature behavior below physiological temperature that are stable at pH 7.4 and degrade under mild acidic conditions. Poly(2-methoxycarboxyethyl-2-oxazoline) (PC2MestOx) was modified with acetal glycerol amine (AGA) and N-butylamine (BA), yielding P(C2AGAOx)x-co-P(C2BAOx)y with tunable cloud point temperature, depending on the copolymer composition. The acetal groups were stable at pH 7.4 but hydrolyzed into strongly hydrophilic glycerol units at pH 4, leading to polymer solubilization. Coamidation of a poly(2-methyl-2-oxazoline)100-b-PC2MestOx50 block copolymer with varying AGA/BA ratios led to thermoresponsive PMeOx100-block-[P(C2AGAOx)10-co-P(C2BAOx)40] copolymers that formed micelles (Dh = 20–24 nm) at 35 °C. These micelles were used to encapsulate Nile red, which was released only at pH 4, not at pH 7.4 or 5. Thus, AGA-modified PAOx copolymers are versatile for pH- and temperature-triggered drug delivery under physiological conditions.