Ultrasonic activation of polymer-drug conjugates for targeted and combinational pancreatic cancer therapy

Abstract

In this work, we present a series of polymer–drug conjugates (PDCs) incorporating gemcitabine (GEM) and camptothecin (CPT), linked to polymethacrylate backbones via ester and disulfide linkers. Using monomeric prodrug precursors, we employed reversible addition–fragmentation chain transfer (RAFT) polymerization to synthesize colloidally stable PDCs. Upon ultrasound irradiation, these PDCs exhibited accelerated drug release, which was further enhanced by the presence of a sonosensitizer due to reactive oxygen species (ROS) generation. Systematic in vitro testing across different treatment modalities revealed formulations capable of outperforming the IC50 values of the parent drugs by up to five orders of magnitude. Our findings highlight how the interplay between PDC structure (e.g., drug combinations, linkers) and ultrasound-triggered activation in the presence of a sonosensitizer significantly enhances the therapeutic potency of these nanomedicines.