Huanhuan Liu, Cangxia Li, Dandan Tang,
Xiaonan An, Yanfei Guo, Youliang Zhao*, “Multi-responsive graft copolymer micelles comprising acetal and disulfide linkages for stimuli-triggered drug delivery”, J. Mater. Chem. B, 2015, 3, 3959–3971.
http://pubs.rsc.org/en/content/articlelanding/2015/tb/c5tb00473j
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.