The nanozyme with NADPH oxidase (NOX)-like activity can promote the consumption of NADPH and the generation of free radicals. In consideration of that the upregulation of glucose-6-phosphate dehydrogenase (G6PD) would accelerate the compensation production of NADPH, for inhibition of G6PD activity, our designed bioorthogonal nanozyme can in situ catalyze pro-DHEA to produce G6PD inhibitor and dehydroepiandrosterone (DHEA) drugs to inhibit G6PD activity. Therefore, the well-defined platform can disrupt NADPH homeostasis, leading to the collapse of the antioxidant defense system in the tumor cells. The enzyme-like activity of PdCuFe is further enhanced when irradiated by NIR-II light. The destruction of NADPH homeostasis can promote ferroptosis and, in turn, facilitate mild photothermal therapy. Our design can realize NADPH depletion and greatly improve the therapeutic effect through metabolic regulation, which may provide inspiration for the design of bioorthogonal catalysis
Ferroptosis plays an important role in radiotherapy (RT), and the induction of ferroptosis can effectively sensitize radiotherapy. However, the therapeutic efficiency is always affected by ferroptosis resistance, especially SLC7A11 (Solute Carrier Family 7 Member 11)-cystine-cysteine-GSH (glutathione)-GPX4 (glutathione peroxidase 4) pathway-mediated resistance. In this study, tumor-microenvironment self-activated high-Z element-containing nanoferroptosis inducers, PEGylated Fe–Bi–SS metal–organic frameworks (FBSP MOFs), were developed to sensitize RT. Unexpectedly, ferroptosis-resistant SLC7A11 would be self-adaptively upregulated, leading to self-responsive ferroptosis resistance. Since the conversion from SLC7A11-transported cystine to cysteine is highly glucose-dependent, glucose oxidase (GOx) was incorporated in the MOFs, causing the depletion of NADPH (nicotinamide adenine dinucleotide phosphate) to terminate the conversion from cystine to cysteine, relieving the self-adaptive ferroptosis resistance. Excitingly, the accumulation of cystine would synergistically lead to disulfide stress and trigger disulfidptosis, making a new contribution to enhance therapeutic efficiency. Moreover, the hydrogen peroxide produced during glucose oxidation could also cascade-react with the Fenton reaction, therefore enhancing ferropotosis. Both in vitro and in vivo results suggested that therapeutic efficiency of ferroptosis-mediated radiosensitization could be enhanced benefiting from synergistic disulfidptosis induction, indicating that disulfidptosis might be an efficient strategy to relieve ferroptosis resistance and enhance RT efficiency.
Glucose-6-phosphate dehydrogenase (G6PD) is a promising target in cancer therapy. However, poor cellular uptake and off-target toxicity impeded the clinical translation of a canonical G6PD inhibitor (6-aminonicotinamide/6AN). Here, we report a prodrug strategy to address this issue. The tailored 6AN prodrug contains an azo-bearing protection moiety. The hydrophobic prodrug showed increased cellular uptake than 6AN and is vulnerable to hypoxia, resulting in NAD(P)H quinone dehydrogenase 1 (NQO1)-triggered cleavage of azo bonds. Intriguingly, the prodrug shows configuration-dependent anti-cancer potency. Despite the lower thermodynamic stability, the cis isomer showed enhanced cellular uptake compared to the trans counterpart due to the increased aqueous solubility. Moreover, the boosted potency of cis isomer compared to the trans isomer resulted from the enhancement of NOQ1-catalyzed 6AN release under hypoxia, a hallmark of solid tumors. The discovery of hypoxia-responsive 6AN prodrugs in the current work opens new avenues of G6PD-targeting cancer medicines via redox manipulation.
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