Reduction-responsive sulfur dioxide polymer prodrug nanoparticles loaded with irinotecan for combination osteosarcoma therapy.

Combination therapy can boost the therapeutic effectiveness of monotherapies by achieving synergy between therapeutic agents. Herein, a reduction-responsive sulfur dioxide (SO2) polymer prodrug was synthesized as a nanocarrier to load irinotecan to be used in combination osteosarcoma therapy. The SO2 prodrug (denoted as mPEG-PLG(DNs)) was synthesized by coupling a small-molecule SO2 donor, N-(3-azidopropyl)-2,4-dinitrobenzenesulfonamide (AP-DNs), to the side chains of methoxy poly (ethylene glycol)-block-poly (γ-propargyl-L-glutamate) block copolymer. The mPEG-PLG(DNs) had the ability to self-assemble to micelles together with simultaneously encapsulate irinotecan in aqueous media. The formed micelles led to enhanced SO2 and irinotecan release in reductive conditions. Using nile red to be a model drug, the loaded micelles were efficiently internalized by cancer cells, demonstrated by confocal laser scanning microscopy and flow cytometry. Release of SO2 within nanoparticles in tumor cells led to enhanced intracellular reactive oxygen species (ROS) amounts together with induced oxidative destruction to cancer cells. Furthermore, the irinotecan-loaded SO2 polymer prodrug nanoparticles mediated synergistic therapeutic effects against osteosarcoma cells, leading to improved biodistribution and enhanced tumor growth inhibition over control groups in a murine osteosarcoma model. Taken together, this work highlights the potential of SO2 polymer prodrugs as reduction-responsive nanocarriers to load chemotherapeutics for effective combination osteosarcoma therapy.