Dual Thermo- and pH-Responsive Methacrylamide Polymers Containing Histidine/Histamine: Side-Chain Design Rules for LCST and UCST Behaviors in Physiological Media

Stimuli-responsive polymers are attractive for biomedical materials because coupling pH and temperature responsiveness can enable selective behavior in physiological media for precise drug delivery and tissue engineering. Histidine- and histamine-derived polymers leverage the biologically relevant imidazole moiety for pH responsiveness. Reversible switching of the imidazole between its protonated and deprotonated states modulates key physical properties, including charge, solution state, and water swellability, which can modulate thermo-responsiveness. However, designing polymers with reliable performance in physiological buffers remains a challenge, particularly for applications requiring precise dual responsiveness such as drug and gene delivery. Here, a library of seven methacrylamide and methacrylate homopolymers bearing tertiary amine or imidazole-containing side chains, including histamine- and histidine-derived structures, was synthesized and evaluated in phosphate-buffered saline across pH 4–8. Acid-base titration showed that the imidazole-containing polymers had apparent pKa values in the biologically relevant range of 5.7–6.5, and turbidity and dynamic light scattering measurements revealed that all but one imidazole-containing polymer were thermoresponsive. Histamine- and histidine-derived polymers bearing neutral side groups such as methyl ester or secondary amide displayed a lower critical solution temperature (LCST) behavior near or below their apparent pKa, whereas the primary amide derivative showed an upper critical solution temperature (UCST) behavior over the full pH range studied, and the carboxylic acid derivative remained soluble and nonthermoresponsive. These results show that introducing imidazole side chains can preserve the underlying LCST or UCST character of a (meth)acrylamide scaffold while adding pH dependence, establishing side-chain design rules for dual-responsive polymers in physiological media.