Switching Apoptosis to Ferroptosis: Metal–Organic Network for High-Efficiency Anticancer Therapy

Abstract

Discovering advanced materials for regulating cell death is of great importance in the development of anticancer therapy. Herein, by harnessing the recently discovered oxidative stress regulation ability of p53 and the Fenton reaction inducing capability of metal-organic network (MON), MON encapsulated with p53 plasmid (MON-p53) was designed to eradicate cancer cells via ferroptosis/apoptosis hybrid pathway. After confirming the detailed mechanism of MON-p53 in evoking ferroptosis, we further discovered that MON-p53 mediated a "bystander effect" to further sensitize cancer cells toward the MON-p53 induced ferroptosis. A 75-day anticancer experiment indicated that MON-p53 treatment not only suppressed the tumor growth but also prolonged the life-span of tumor bearing mice. Owing to its ability to promote intracellular oxidative stress, MON-p53 decreased the blood metastasis, lung metastasis, and liver metastasis. As a consequence, discovering methods to induce cell ferroptosis would provide a new insight in designing anticancer materials.

Emerging Strategies of Cancer Therapy Based on Ferroptosis

“…[55] As shown in Figure 9A, tannic acid, a FDA approved food additive extracted from green tea, was combined with ferric ions to form MON on the surface of the PEI/p53 plasmid complex (PEI/p53) (Figure 9B), obtaining MON-p53 (Figure 9C), and MON coating was used to enhance the ferroptosis inducing ability of p53. As shown in Figure 9D, once MON-p53 was internalized, ferric ions could induce Fenton reaction to produce ROS, and high intracellular ROS concentration could cause serious lipid peroxidation in biomembranes.…”

“…Besides, MON-p53 treatment was found to have a higher efficiency in inhibiting tumor growth than PEI/p53, MONP (metal-organic nanoprecipitate), or PBS treatments (Figure 9L). [55] …”

Chemodynamic Therapy: Tumour Microenvironment‐Mediated Fenton and Fenton‐like Reactions

“…In addition to inorganic nanomaterials,n anomaterials with am etal-organic frameworks (MOFs) and macromolecular nanoparticles (an assembly of small molecules that does not have the periodic network structure) also have the potential to be utilized for CDT.C ompared with stable inorganic nanomaterials,M OFs and macromolecular nanomaterials have been designed for therapies or imaging [39] because of their flexibility and better responsiveness.Z heng et al synthesized am etal-organic network (MON)-p53 with ac ore-shell structure based on aM OF,a nd the resulting network resulted from the coordination between Fe 3+ and tannic acid (Figure 2a). [40] In the system, ferric ions generated COH, and the expression of p53 protein inhibited the expression of the SLC7A11 protein, thereby inducing GSH depletion to further enhance the COH yield ( Figure 2b). Va rious metal ions (Fe 2+ ,F e 3+ ,A l 3+ ,C o 2+ ,N i 2+ ,C u 2+ ,M n 2+ , and Ca 2+ )h ad been introduced to evaluate the cytotoxicity towards HT1080 cells,a nd significant cytotoxicities were detected in cells co-incubated with MON-p53 and Fe 2+ and Fe 3+ ,c onfirming that the MON-p53-induced cell death was mediated by an iron-dependent mechanism (Figure 2c).…”

Porous Inorganic and Hybrid Systems for Drug Delivery: Future Promise in Combatting Drug Resistance and Translation to Botanical Applications

“…Metals also often have inherent catalytic properties, and the incorporation of Fe 3+ ions on the p53 plasmid-loaded particles was designed to eradicate cancer cells via ferroptosis/apoptosis hybrid pathway. 93 This apoptosis pathway harnessed the oxidative stress regulation ability of p53 and the Fenton reaction induced from Fe III -TA complexes. A recent study by Guo et al focused on the catalytic effects of Fe III -based MPNs for breaking down H2O2 into O2 for ultrasound imaging purposes.…”