The intelligent triggering of drug release at targeted sites is essential for the safety and efficacy of cancer therapies. This study aimed to design and synthesize a novel prodrug (DHA-S-CA) using a reactive oxygen species (ROS)-responsive moiety, thioacetal, to bridge cinnamaldehyde (CA) and dihydroartemisinin (DHA). As ROS are highly expressed in tumor tissues, the design uses the ROS-responsive moiety as an effective target for the nanodrug delivery system. Furthermore, the near-infrared dye IR808 and the prodrug were adopted to prepare co-loaded Soluplus®/TPGS nanomicelles (IR808/DHA-S-CA NMs). The photosensitized agent IR808 exhibited both tumor accumulation and cancer imaging properties while generating ROS during laser irradiation. Intracellular ROS detection indicated that the prodrug DHA-S-CA could degrade via the high concentration of ROS in cancer cells induced by laser irradiation, and the released CA stimulated mitochondria to regenerate additional ROS to further improve the antitumor effect of DHA. Combined with photodynamic therapy (PDT), IR808/DHA-S-CA (+) NMs outperformed free DHA, DHA NMs, and IR808/DHA-S-CA (−) in a comparison of their pharmacokinetic profiles because it had a longer circulation time and a greater area under the curve (AUC). Compared with other DHA groups, the ROS-responsive IR808/DHA-S-CA (+) micelles had comparable cytotoxic activity. Furthermore, the ROS-responsive IR808/DHA-S-CA (+) micelles exhibited markedly higher anticancer efficiency on lung cancer cells than the other DHA groups. Overall, these results indicated that the therapeutic strategy of our novel small-molecule prodrug combined with PDT has great potential for the treatment of tumors.

在目标部位智能触发药物释放对于癌症治疗的安全性和有效性至关重要。本研究旨在设计和合成一种新型前药 (DHA-S-CA)，使用活性氧 (ROS) 响应部分硫缩醛连接肉桂醛 (CA) 和双氢青蒿素 (DHA)。由于 ROS 在肿瘤组织中高度表达，该设计使用 ROS 响应部分作为纳米药物递送系统的有效靶标。此外，采用近红外染料IR808和前药制备共负载Soluplus®/TPGS纳米胶束（IR808/DHA-S-CA NMs）。光敏剂 IR808 表现出肿瘤积累和癌症成像特性，同时在激光照射期间产生 ROS。细胞内 ROS 检测表明，前药 DHA-S-CA 可通过激光照射诱导的癌细胞中高浓度的 ROS 降解，释放的 CA 刺激线粒体再生额外的 ROS，进一步提高 DHA 的抗肿瘤作用。与光动力疗法 (PDT) 相结合，IR808/DHA-S-CA (+) NM 在比较它们的药代动力学特征时优于游离 DHA、DHA NM 和 IR808/DHA-S-CA (-)，因为它具有更长的循环时间和更大的曲线下面积（AUC）。与其他 DHA 组相比，ROS 反应性 IR808/DHA-S-CA (+) 胶束具有相当的细胞毒活性。此外，与其他 DHA 组相比，ROS 反应性 IR808/DHA-S-CA (+) 胶束对肺癌细胞的抗癌效率显着提高。全面的，