Trisulfide-Bridged Polymer-Drug Conjugates for Synergistic H₂S and Doxorubicin Delivery

Effective gas-chemotherapy requires the synchronized intratumoral release of therapeutic agents, which is hindered by physiological barriers and unsynchronized delivery. Herein, we address this hurdle by covalently conjugating doxorubicin (DOX) to polymer backbones via trisulfide bonds. This bond cleaves specifically in the high-glutathione tumor microenvironment, triggering simultaneous release of DOX and H₂S. The optimal random copolymer, PCB₆₁-3S₂₈-D₁₀ with the polymerization degrees of 61, 28, and 10 for poly(carboxybetaine methacrylate) (PCB), trisulfide-containing segments, and DOX amount, respectively, can self-assemble into stable micelles and exhibit minimal protein adsorption for efficient tumor accumulation. PCB₆₁-3S₂₈-D₁₀ shows enhanced cytotoxicity with an IC₅₀ of 2.16 μg mL^–1, which is a 2-fold increase in potency compared with free DOX. PCB₆₁-3S₂₈-D₁₀ achieves a remarkable in vivo tumor inhibition rate of 87.9%, significantly surpassing free DOX and the comparable disulfide bond-containing group. This study underscores the potential of trisulfide-bridged zwitterionic nanocarriers as a robust platform for synchronized gas-chemotherapy.