Combination therapy using multiple drugs with time-programmed administration is promising for enhanced cancer treatment. However, it is still challenging to achieve time-programmed drug release from a single nanocarrier. Here, dual polyprodrugs of hemicyanine dye (CyNH₂) and doxorubicin (DOX) are developed to achieve time-programmed prodrug activation for synergistic cascade oxidation therapy and chemotherapy. The polyprodrug NP_DOX/Cy, composed of CyNH₂, is modified with a glutathione (GSH)-responsive disulfate group, while DOX is modified with a reactive oxygen species (ROS)-response thioketal (TK) group. Upon uptake by cancer cells overexpressing GSH, CyNH₂ can be activated quickly and accumulate in the mitochondria to induce mitochondrial damage and ROS upregulation, thus achieving subsequent burst activation of DOX through the ROS-triggered cleavage of the TK linker. The early activation of CyNH₂ makes the cancer cells more sensitive to subsequent DOX treatment for a synergistic effect of from oxidation therapy and chemotherapy. Therefore, the polyprodrug with time-programmed drug activation developed in this work provides a promising strategy for synergistic cancer therapy.

使用多种药物进行时间编程的联合治疗有望增强癌症治疗。然而，从单个纳米载体中实现时间程序化的药物释放仍然具有挑战性。在这里，开发了半花青染料 (CyNH ₂ ) 和多柔比星 (DOX) 的双重多前药，以实现时间编程的前药激活，用于协同级联氧化治疗和化学疗法。多前体药物 NP _DOX/Cy由 CyNH ₂组成，用谷胱甘肽 (GSH) 反应性二硫酸盐基团修饰，而 DOX 用活性氧 (ROS) 反应性硫缩酮 (TK) 基团修饰。在被过度表达 GSH 的癌细胞摄取后，CyNH ₂可以快速激活并在线粒体中积累以诱导线粒体损伤和 ROS 上调，从而通过 ROS 触发的 TK 接头裂解实现 DOX 的后续爆发激活。CyNH ₂的早期激活使癌细胞对随后的 DOX 治疗更敏感，以实现氧化疗法和化学疗法的协同作用。因此，在这项工作中开发的具有时间程序化药物激活的多前体药物为协同癌症治疗提供了有前景的策略。