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  • br Fenton reaction based nanomaterials for

    2022-05-19


    Fenton reaction-based nanomaterials for ferroptosis In Fenton reaction, H2O2 is converted by Fe2+ or Fe3+ to highly oxidative ROS (Eqs. (1) and (2)), which is commonly used to catalyze the degradation of refractory organics [34]. Since the tumor microenvironment is characterized by low acidity and high-level H2O2, it is expected that, by introducing a plethora of iron ions, Fenton reaction can be exploited in this context to generate intense oxidative stress [35]. Based on this, many iron-based agents, mostly nano-formulated, have been designed to release iron ions in response to the tumor microenvironment, which can promote overproduction of ROS by Fenton reaction. Consequently, the cancer CEP 1347 accumulate a large amount of lipid peroxides and eventually undergo ferroptosis [18,19]. Notably, some non-ferrous metal ions can also catalyze the generation of ROS from H2O2 in a Fenton-like reaction, and they exhibit some advantages over iron, as will be described in below [25,26,34].
    GPX4-inhibitory nanomaterials for ferroptosis Recently, Stockwell’s group has demonstrated that the GPX4 plays an essential role in the conversion of lipid peroxides to non-toxic lipid alcohols [39,40]. Therefore, inactivating GPX4 is considered to be another approach to kill cancer cells via ferroptosis [41]. Based on this rationale, Zheng et al. designed a metal-organic network (MON) coated on the surface of polyethylenimine/p53 plasmid complex (MON-p53), which can kill the cancer cell by inducing ferroptosis (Fig. 4a) [24]. The preparation process of MON-p53 is shown in Fig. 4b. The polyethylenimine/p53 plasmid complex is prepared at first (Fig. 4c), which is then assembled as MON-p53 using the tannic-acid and ferric ions (Fig. 4d). When the MON-p53 is internalized into tumor cells, it will degrade and release iron ions that subsequently take part in the Fenton reaction, leading to elevated intracellular ROS levels (Fig. 4e). Meanwhile, the overexpression of the plasmid p53 can inhibit SLC7A11, a constitutive component of the cystine/glutamate antiporter system xc-, thus blocking the biosynthesis of GSH in cells. Without sufficient GSH supply, GPX4 can no longer protect the cells from the overwhelming ROS generated by MON-p53, which eventually leads to irreversible lipid peroxidation and cell death. Notably, the poisoned cell viability after treatments with MON-p53 can be rescued by ferroptosis inhibitors or lipid-soluble antioxidants, corroborating that MON-p53 induces cell death by ferroptosis (Fig. 4f). Additionally, in support of the ROS-generating capability of MON-p53, the intracellular levels of lipid peroxides, ROS and NADP+/NADPH, which indicate oxidative stress, are all evidently elevated after MON-p53 exposure (Fig. 4g). Moreover, the in vivo study has shown that the MON-p53 can significantly suppress tumor growth and prolong the survival time of tumor-bearing mice in comparison to PEI/p53 or MON alone (Figs. 4h and i). GSH is the predominant thiolated species in mammalian cells, which serves as a reducing agent lying at the core of the antioxidant systems of cells [42]. In the tumor microenvironment, the intracellular GSH concentration is much higher than extracellular levels [43,44]. Previous studies have demonstrated that the GSH is an essential cofactor for GPX4 to eliminate the lipid peroxides in cells. Once the GSH pool is depleted, GPX4 will be inactivated, leading to ferroptosis [39,45]. Our group has designed an arginine-rich manganese silicate nanobubbles (AMSNs) to promote ferroptosis by consuming the GSH pool and suppressing the activity of GPX4 (Fig. 5a) [46]. Consistent with the mechanism of action of AMSNs, the cytotoxicity induced by AMSNs can be relieved by the addition of ferroptosis inhibitor Fer-1and iron chelating agent desferrioxamine mesylate (DFOM) (Figs. 5b and c). The AMSNs effectively deplete GSH, as shown that the GSH level drops drastically within a short time after the treatment with AMSNs (Fig. 5d). Correspondingly, the activity of GPX4 is inhibited by AMSNs, though in a delayed manner (Fig. 5e). Importantly, this formulation exhibits potent in vivo efficacy in suppressing tumor growth and can be further strengthened when loaded with chemotherapeutic drugs (Figs. 5f and g).