Abstract
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.
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