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

Abstract

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.

Thiol- and Disulfide-Based Stimulus-Responsive Soft Materials and Self-Assembling Systems

“…Bej and coworkers [ 118 ] used a polycondensation reaction between a hydroxyl-containing dithiol and pyridyl disulfide to create a poly(disulfide) with a free hydroxyl group on each monomer unit. Post-polymerization modification was used to incorporate the anticancer drug camptothecin (CPT) via an ester linkage.…”

“…( b ) Proposed mechanism for the degradation of polydisulfide-CPT by GSH. Adapted with permission from [ 118 ]. Copyright (2019) American Chemical Society.…”

Application of Nano-Drug Delivery System Based on Cascade Technology in Cancer Treatment

“…Therefore, the reduction of GSH in TME is of great significance for promoting ROS production and ROS-induced tumor treatment. In recent years, a large number of studies have reported a variety of cascade reactions involving GSH-eliminating and catalytic ROS-generating cascade process for enhancing ROS-induced cancer treatments [ 78 , 79 , 80 , 81 , 82 ]. GSH is involved in the cascade of ROS-induced tumor therapy through various exhaustion ways.…”

Strategies To Design and Synthesize Polymer‐Based Stimuli‐Responsive Drug‐Delivery Nanosystems

“…2.1.1. Introduction of stimuli‐responsive linkages into polymer chains : In recent decades, many cleavable bonds (Scheme B), such as hydrazone, Schiff base, acetal, disulfide, and amide bonds, have been incorporated into polymer backbones or applied as the linkers of different polymeric blocks. These polymer chains can form the corresponding nanocarriers and rupture in the tumor sites, as triggered by different stimuli.…”

“…Responsive polymers are those in which different polymer segments are generally linked by responsive bonds or segments, such as Schiff base (C=N), thioketal, amide, disulfide, and diselenide bonds, and responsive peptides, and the anticancer drugs are loaded through electrostatic or hydrophilic–hydrophobic interactions. In addition, another widely developed strategy is to add stimuli‐responsive functional groups to the polymer backbones .…”