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

In this work, we present a series of polymer-drug conjugates (PDCs) incorporating gemcitabine (GEM) and camptothecin (CPT), linked to polymethacrylate backbones <i>via</i> 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 <i>in vitro</i> 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 the PDC structure (<i>e.g.</i>, drug combinations and linkers) and ultrasound-triggered activation in the presence of a sonosensitizer significantly enhances the therapeutic potency of these nanomedicines.