Dual acid/glutathione-responsive core-degradable/shell-sheddable block copolymer nanoassemblies bearing benzoic imines for enhanced drug release

Abstract

The development of amphiphilic block copolymer (ABP)-based nanoassemblies that degrade in response to dual stimuli at dual locations (e.g. hydrophobic cores and core/corona interfaces) offers a promising platform for controlled drug delivery. This work harnesses the features of an acid-labile benzoic imine (BzIm) bond and a glutathione (GSH)-cleavable disulfide linkage. We synthesized a poly(ethylene glycol) (PEG)-based dual location dual acid/GSH-degradable ABP with BzIm pendants in a hydrophobic polymethacrylate block and a disulfide at the block junction. The acid-catalyzed hydrolysis rate of BzIm depends on substituents attached to its para-position. Hydrolysis is faster with electron-donating substituents (methoxy), and slower with electron-withdrawing ones (bromo and nitro). Well-defined ABP synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization of a methoxy-substituted BzIm methacrylate in the presence of a disulfide-labeled PEG-based chain transfer agent, enables self-assembly to form colloidally-stable, monomodal, and spherical nanoassemblies. These nanoassemblies are capable of encapsulating cancer drug doxorubicin (Dox) and exhibit enhanced release of Dox through core degradation upon the cleavage of BzIm bonds in acidic pH and shell detachment upon the cleavage of disulfide bonds in the presence of GSH. Moreover, Dox-loaded nanoassemblies show excellent uptake by HeLa cell multi-tumor spheroids, demonstrating their potential as drug delivery nanocarriers. This study highlights the importance of substituent effects on the hydrolysis of BzIm and the dual acid/GSH-responsive strategy for developing a promising drug delivery system with precise control over drug release.