Salt- and Temperature-Responsive Poly(ethyleneimine)/Phenylthioacetic Acid Ion-Pair Assemblies

Background: BackgroundIon pairs formed through electrostatic attraction between poly(ethyleneimine) (PEI) and phenylthioacetic acid (PTA) underwent self-assembly in aqueous solution. This interaction, and consequently the structural stability of the ion-pair self-assemblies (IPSAMs), can be affected by salt ions present in the body (e.g., Na+ and Ca2+) through charge screening or competitive interactions. Therefore, the prepared IPSAMs were expected to exhibit salt-responsive behavior. IPSAMs can undergo phase transitions following ion-pair formation, suggesting that temperature-dependent and salt-responsive release behavior may also occur. Methods: IPSAMs were prepared at PEI/PTA molar ratios of 3/7, 4/6, 5/5, 6/4, and 7/3, and their phase transition temperatures were measured to select a representative formulation. The selected IPSAM was treated with NaCl and CaCl2, and the resulting structural changes were evaluated using instrumental (Fourier transform infrared spectroscopy, surface tension, particle size, zeta potential, and transmission electron microscopy) analyses. Nile Red was used as a model hydrophobic compound to investigate release behavior under different temperature and salt conditions. Results: Among the prepared formulations, IPSAM(3/7) exhibited an upper critical solution temperature of 38.37 °C, which is remarkably close to the human body’s fever threshold and active metabolic states. Therefore, IPSAM(3/7) showed potential as a tunable bioswitch capable of operating under physiologically relevant thermal conditions and was selected as a representative formulation for further experiments. After salt treatment, the phase transition temperature of this IPSAM decreased. Instrumental analyses confirmed that salt treatment reduced the colloidal stability of the IPSAM and induced structural changes. CaCl2 showed a greater effect than NaCl, which suggests that compared with Na+ ions, Ca2+ ions more strongly perturbed the PEI/PTA ion-pair structure through their stronger charge screening effect and, possibly, interactions with carboxylate groups. Nile Red release experiments confirmed the salt-responsive and temperature-responsive release behavior of IPSAMs. Conclusions: The developed PEI/PTA IPSAM can function as a stimulus-responsive nanocarrier responding to both temperature and ionic conditions. The proximity of the phase transition temperature of IPSAM(3/7) to a physiologically meaningful temperature range supports its potential application as a tunable bioswitch for targeted delivery.