One-pot syntheses of dual-responsive core cross-linked polymeric micelles and covalently entrapped drug by click chemistry

• Dual-responsive core cross-linked micelles was prepared by using “click” chemistry.
• Covalently entrapped drug and core cross-linked micelles were prepared simultaneously.
• High drug loading efficiency was demonstrated.
• Decross-linked micelles took place in reduction circumstance.
• Core cross-linked micelles presented a burst release of the drug at pH 5.0 and 37 °C.

A facile drug delivery system for prednisolone 21-acetate (PA) based on dual-responsive core cross-linked (CCL) micelles was prepared efficiently by alkyne-azide click chemistry. Poly(ethylene oxide)-b-poly(glycidyl methacrylate), PEO-b-PGMA, was firstly synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization, and the PGMA parts were subsequently functionalized with azido groups. The CCL micelles of the PEO-b-PGMA-N3 and covalently entrapped PA were prepared simultaneously using the alkyne-functionalized hydrazone-containing PA and disulfide-containing cross-linking agent in the presence of CuSO4·5H2O and sodium ascorbate. The CCL micelles showed a much improved PA loading efficiency (83%) compared to physically loaded micellar system. The CCL micelles illustrated the structural stability of the micelles under physiological condition, while decross-linking through the cleavage of disulfide groups took place rapidly in dithiothreitol reduction circumstance. In addition, the pH-sensitive hydrolysis of the hydrazone groups in PA derivative in the micellar core presented a burst release of the drug at pH 5 and 37 °C in marked contrast to little release at pH 7.4.

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