Glutathione Triggered Cascade Degradation of an Amphiphilic Poly(disulfide)-Drug Conjugate and Targeted Release.

A bioreducible poly(disulfide)-derived amphiphilic block copolymer-drug conjugate (loading content 31%) was synthesized by post-polymerization modification. It shows redox-responsive polymersome assembly in water with aggregation induced emission property arising from the appended Camptothecin (CPT) drug. Glutathione (GSH), a tripeptide overexpressed in cancer cells, triggers a cascade reaction resulting in simultaneous degradation of the polymer backbone (consisting of disulfide linkage) and the release of the pendant drug. The cascade reaction involves GSH trigger cleavage of the backbone disulfide bond producing free thiol followed by its intrachain nucleophilic attack to the adjacent carbonate group that links the appended drug molecule. The polymeric pro-drug exhibits killing efficiency to a cancer cell with remarkably low IC50 value of 3.1 μg/mL (based on the CPT concentration) while it shows negligible toxicity to a normal cell up to polymer concentration 300 μg/mL.