This contribution reports a series of novel amphiphilic random copolymers based on biodegradable polyaspartamides that respond to three independent stimuli viz. temperature, pH and metal-ions. Architecturally, the attachment of 1-propylimidazole pendants (hydrophobic at physiological pH) and dimethylpropylammonium pendants (hydrophilic at physiological pH) to the hydrophilic polyamide backbone introduced well-defined, reversible thermosensitivity at and around physiological conditions (temp. = 37 °C and pH = 7.4) in phosphate buffer (PB). The cloud points could easily be tuned by varying the ratios of the two pendants. The anions of the Hofmeister series were found to affect the thermosensitivity. Aggregation behaviour of the copolymers as a function of pendant ratios, as well as their temperature-induced aggregation, was investigated by 1H NMR spectroscopy and dynamic light scattering (DLS). Importantly under salt-free conditions, thermosensitivity was observed only in heavy water and not in normal water due to the solvent isotope effect. Profound modulation of thermosensitivity was achieved through the variation of pH of polymer-solution and by the presence of metal ions in it. The morphology of metal ion-stabilized polymer globules was probed by atomic force microscopy (AFM).
