Dual thermo-responsive pH-Sensitive amino acid-derived zwitterionic copolymers: Balancing electrostatic and hydrophilic interactions in LCST–UCST behavior

Thermo-responsive polymers are widely applied in various fields, including drug delivery and surface coating. Dual thermo-responsive polymers, which exhibit both lower and upper critical solution temperatures (LCST and UCST), enable notable temperature-dependent behaviors within a tunable range. However, the structure–property relationships governing dual temperature-responsiveness are still insufficiently understood, particularly for polymers including pH-sensitive zwitterionic groups. In this study, LCST–UCST polymers, P(MEO 2 MA x MEOMA y GAASt 20 ), composed of mono/di(ethylene glycol) methyl ether methacrylate (MEOMA/MEO 2 MA) and a zwitterionic monomer derived from glutamic acid (GAASt), were designed. By varying the ethylene glycol (EG) side chain length, pH, and salts, it was investigated how the balance between hydrophilic and electrostatic interactions governs the thermo-responsive behavior of the copolymers. In 10 mM phosphate buffer (PB, pH 7), UCST behavior was observed with only P(MEOMA 79 GAASt 21 ), likely because shorter EG chains increased the relative contribution of zwitterionic units. The UCST of this polymer increased with the addition of salt, unlike typical zwitterionic UCST-type polymers. Polymers containing MEO 2 MA exhibited LCST behavior in 10 mM PB (pH 7) containing 100 mM NaCl, and the LCST decreased with shorter EG chains and kosmotropic ions. Under acidic and basic conditions, the thermo-responsive transition was not observed. Furthermore, P(MEO 2 MA 19 MEOMA 61 GAASt 20 ) exhibited LCST–UCST behavior induced by NaCl. The diameter of the polymer in solution varied with temperature: terpolymer chains below the LCST, the largest aggregates between the LCST and UCST, and small globules above the UCST. Our findings provide insight into the molecular design strategies for thermo-responsive polymers in bioapplications. • Thermo-responsive polymers using OEGMA and zwitterionic monomers • •Shorter EG chain induced UCST by relatively enhancing electrostatic interactions • •UCST of the copolymer decreased with increased salt concentration • •Thermo-responsive behavior was no longer observed at pH 2 and 12 • •LCST–UCST behavior appeared by the balance of hydrophobic and electrostatic forces