Abstract
A novel disulfide- and acetal-linked graft copolymer (SACG) comprising acetal-bridged poly(e-caprolactone)-b-poly(ethylene glycol) and PEG pendent chains and relatively short polymethacrylate backbone (DP ≈ 24) was synthesized and self-assembled for in vitro encapsulation and release of an anticancer drug, doxorubicin (DOX). Three-step reactions involving (i) RAFT copolymerization of 2-hydroxyethyl methacrylate and poly(ethylene glycol) methyl ether methacrylate, (ii) ring-opening polymerization to generate PCL chains, and (iii) hydroxyl-vinyloxy adductive reaction to introduce acid-cleavable PEG segments were used to achieve the target copolymer. Meanwhile, well-defined normal (CP) and disulfide-linked (SCP) poly(PEG-co-PCL) comb-like copolymers and acid-cleavable poly(PEG-co-PCL)-graft-MVPEG copolymer (ACG) were synthesized and acted as analogues of SACG upon external stimuli. The macromolecular architecture significantly affected the melting and crystallization behaviors and aggregation properties of copolymers, and the difference in topology and location of cleavable linkages resulted in distinctly different stimuli-triggered drug release behaviors. Owing to the dissociation and reaggregation of cleaved copolymer aggregates, stimuli-cleavable aggregates in response to external stimuli (pH 5.0, 10 mM DTT) could exhibit faster release kinetics than CP aggregates, and the maximum increment of cumulative release from various aggregates for 72 h was liable to decrease in the order SACG > ACG > SCP > CP. The cumulative release from SACG aggregates could be adjusted in the widest range via addition of different stimuli, revealing the great potential of dually cleavable copolymer aggregates in smart drug delivery systems.
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