Multi-responsive graft copolymer micelles comprising acetal and disulfide linkages for stimuli-triggered drug delivery.

Thermo-, pH and reduction triggered drug delivery vehicles based on dual-cleavable polymeric micelles were investigated. A comblike copolymer (G3) comprising one disulfide linkage and PEG, PCL and acetal-bridged PCL-b-PNIPAM grafts was controllably synthesized by successive RAFT copolymerization, ring-opening polymerization and adductive reaction. G3 was liable to self-assemble into spherical micelles at 25 °C and toroidal micelles at 37 °C, and the aggregates formed at 37 °C could be further converted into multicompartment micelles (pH 5.3), spherical micelles (DTT) and hyperbranched or necklace-like cylinders (pH 5.3 + DTT) upon external stimuli due to the stimuli-triggered topological transformation and reaggregation of copolymer aggregates. Upon external stimuli, doxorubicin (DOX) loaded G3 and G3/β-CD (co)aggregates could exhibit accelerated drug release kinetics. The apparent release rates varied in the range 0.072-0.403 h-1 (for G3 aggregates) and 0.142-0.458 h-1 (for G3/β-CD coaggregates), revealing that the drug release system bearing host-guest interactions could further extend the ranges of the release rate and cumulative release. Although β-CD and G3 micelles lacked notable cytotoxicity, the cytotoxicity of DOX-loaded (co)aggregates to 4T1 cells was higher than free DOX. CLSM images revealed that DOX-loaded copolymer aggregates may enter cells via endocytosis in a manner of nanocomplexes. Our study can not only extend the potential of stimuli-cleavable copolymers toward biomedical applications but also enrich the family of multi-responsive copolymer aggregates.