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Achieving selective release of chemical anticancer agents and improving therapeutic efficacy has always been a hot spot in the field of cancer research, yet how to achieve this remains a great challenge. In this work, we constructed a novel chemical anticancer agent (named MCLOP) by introducing naphthalimide into the skeleton of methylene blue (MB). Under the stimulation by cellular hypochlorous acid (HClO) and visible light, selective release of active naphthalimide can be achieved within breast cancer cell lines, the release process of which can be tracked visually using near-infrared fluorescence of MB (685 nm). More importantly, we developed biotinylated curcumin (Cur-Bio) as a new chemosensitizer, which significantly enhanced the ability of MCLOP to induce autophagic cell death of breast cancer cells. This synergistic treatment strategy exhibited an excellent anti-proliferation effect on breast cancer cells in vitro , three-dimensional (3D) cell sphere model, and mouse tumor model in vivo. This work provides a new strategy for the treatment of breast cancer and also opens new opportunities for the efficient treatment of cancer with curcumin-based chemosensitizer. [Display omitted] • New anticancer agent MCLOP was developed based on naphthalimide and methylene blue. • Stimulation with HClO and visible light release active naphthalimide in MCF-7 cells. • The biotinylated curcumin (Cur-Bio) was constructed as a new chemosensitizer. • Cur-Bio enhances the ability of MCLOP to induce autophagic cell death of MCF-7 cells. • Treatment with MCLOP and Cur-Bio exhibits a synergistic anticancer effect in vivo. [ABSTRACT FROM AUTHOR]

Lung cancer is the second most common malignant tumor worldwide. The problem of drug resistance in lung cancer leads to treatment failure and recurrence in more than 90% of cancer patients. Thus, developing chemical probes that can observe drug-resistant lung cancer cells in real-time and eliminate them is of great interest. However, such tools that can simultaneously probe drug-resistant lung cancer cells and therapeutic modes of action have not yet been developed. In this work, we reported a fluorescent prodrug that can be activated in cancer cell lysosomes to release amonafide (ANF) and aniline mustard, where the fluorescent signal of ANF (λ ex /λ em = 405/570 −620 nm) can be tracked by super-resolution imaging in live cancer cells. With imaging studies, we found that this new fluorescent prodrug uniquely displays an autophagy-driven ferroptosis-inducing effect, accompanied by the accumulation of intracellular ferrous ions and lipid peroxidation. More importantly, the fluorescent prodrug exhibits potential anti-proliferative activity, especially against drug-resistant A549R lung cancer cells (IC 50 , ∼ 3 μM), better than the positive control drug cisplatin (IC 50 , ∼ 27 μM). This work indicates that the development of fluorescent prodrugs as autophagy-driven ferroptosis inducers may represent a viable approach for targeting drug-resistant cancer cells. [Display omitted] • A new fluorescent prodrug for fighting drug-resistant lung cancer cells was developed. • This fluorescent prodrug can be activated in cancer cell lysosomes to release ANF. • The fluorescent signal of ANF can be tracked by super-resolution imaging in live cells. • This new fluorescent prodrug displays an autophagy-driven ferroptosis-inducing effect. [ABSTRACT FROM AUTHOR]