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A shell-crosslinked polymeric micelle system for pH/redox dual stimuli-triggered DOX on-demand release and enhanced antitumor activity.
Colloids and Surfaces. B, Biointerfaces 2017 April 2
Based on targeted amphiphilic block copolymer N-acetyl glucosamine-poly (styrene-alt-maleic anhydride)58-b-polystyrene130 (NAG-P(St-alt-MA)58-b-PSt130), a pH/redox dual-triggered shell-crosslinked polymeric micelle system was constructed. The shell-crosslinked micelles (CLM) were prepared by post-crosslinking method to regulate drug release kinetics using cystamine as linkers between carboxy groups of the shell. Compared with non-crosslinked micelles (NCLM), CLM showed spherical shapes with little increased mean diameter of 102.40±0.54nm, low polydispersity index (PDI) of 0.19±0.36, enlarged zeta potential value from -41.46±0.99 to -9.31±0.50mV, indicating the successful modification of disulfide bonds in shell. In vitro drug release study clearly exhibited a pH and redox dual-sensitive drug release profile with significantly accelerated drug release under pH 5.0 and 10mM GSH conditions (46.84% in 96h) without burst release. Both CLM and NCLM showed quite different release profiles between physiological (pH 7.4) and tumoral microenvironment (pH 5.0), effectively avoiding the premature drug leakage and realizing on-demand drug release. The MTT assay implied that CLM presented a time- and concentration-dependent manner to inhibit proliferation of A549 and MCF-7 cells and much lower IC50 values in comparison with that of NCLM after 72h incubation. Both FCM and CLSM results showed that CLM displayed much higher cellular uptake efficiency and anti-tumor activities than NCLM and free DOX. CLM and NCLM could be internalized by energy-dependent endocytosis mechanism due to similar surface properties. Overall, this dual-stimuli triggered micelle system provided a promising tumor-responsive platform for cancer therapy.
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