Abstract
To strengthen the antitumor efficacy and avoid toxicity to normal cells of cisplatin and triptolide,herein, an acid and glutathione (GSH) dual-controlled nanoplatform for enhanced cancer treatment through the synergy of both "1+1" apoptosis and "1+1" ferroptosis is designed. Remarkably,ZIF8in response totumor microenvironmentenhances drug targeting and protects drugs from premature degradation. Meanwhile, the PtIV center can be easily reducedtocisplatin because of the large amount of GSH, thus liberating the triptolide as the coordinated ligand. The releasedcisplatin and hemin in turn boost the tumor cell "1+1" apoptosis through chemotherapy and photodynamic therapy, respectively. Furthermore, GSH reduction throughPtIV weakens the activation of glutathione peroxidase 4 (GPX4) effectively. The released triptolide can inhibit the expressions of GSH by regulating nuclear factor E2 related factor 2 (Nrf2), further promoting membrane lipid peroxidation, thus "1+1"ferroptosis can be achieved. Bothinvitroandinvivoresults demonstrate that the nanosystem can not only perform superior specificity and therapeutic outcomes but also reducethe toxicity to normal cells/tissues of cisplatin and triptolide effectively. Overall, the prodrug-based smart system provides an efficient therapeutic strategy for cancer treatment by virtue of the effect of enhanced "1+1" apoptosis and "1+1" ferroptosis therapies.
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