Temperature, ultrasound and redox triple-responsive poly(N-isopropylacrylamide) block copolymer: Synthesis, characterization and controlled release

Triple stimuli-responsive polymers PNiPAAm-S-S-PXCL containing a disulfide (-S-S-) bond as a junction point between hydrophilic and hydrophobic chains were synthesized through ring-opening polymerization (ROP) and nucleophilic substitution. When the polymer solutions were treated with reducing agents and exposed to ultrasound, significant hydrolysis of the amide bonds was observed. The morphology of the particles and the changes in the fluorescence intensity of Nile red revealed that the copolymers underwent micellization or dissociation transitions in water in response to temperature variation, reducing agent treatment, and ultrasound. The release rate could be greatly increased and adjusted remotely under high intensity focused ultrasound in the presence of dithiothreitol. The nanoparticles exhibited slight toxicity against HeLa cells in the concentration range 10-1000 μg mL^-1. The DOX-loaded PNiPAAm₂₁-S-S-PMCL₂₅ micelles effectively inhibited the proliferation of HeLa cells with a half-maximal inhibitory concentration of 2.33 μg mL^-1. The multiple stimuli-responsive polymeric nanoparticles show promising potential as new nanocarriers for controlled release.