Mitochondrial membrane anchored photosensitive nano-device for lipid hydroperoxides burst and inducing ferroptosis to surmount therapy-resistant cancer

Abstract

Rationale: Ferroptosis is a regulated process of cell death caused by iron-dependent accumulation of lipid hydroperoxides (LPO). It is sensitive to epithelial-to-mesenchymal transition (EMT) cells, a well-known therapy-resistant state of cancer. Previous studies on nanomaterials did not investigate the immense value of ferroptosis therapy (FT) in epithelial cell carcinoma during EMT. Herein, we describe an EMT-specific nanodevice for a comprehensive FT strategy involving LPO burst.Methods: Mitochondrial membrane anchored oxidation/reduction response and Fenton-Reaction-Accelerable magnetic nanophotosensitizer complex self-assemblies loading sorafenib (CSO-SS-Cy7-Hex/SPION/Srfn) were constructed in this study for LPO produced to overcome the therapy-resistant state of cancer. Both in vitro and in vivo experiments were performed using breast cancer cells to investigate the anti-tumor efficacy of the complex self-assemblies.Results: The nano-device enriched the tumor sites by magnetic targeting of enhanced permeability and retention effects (EPR), which were disassembled by the redox response under high levels of ROS and GSH in FT cells. Superparamagnetic iron oxide nanoparticles (SPION) released Fe2+ and Fe3+ in the acidic environment of lysosomes, and the NIR photosensitizer Cy7-Hex anchored to the mitochondrial membrane, combined sorafenib (Srfn) leading to LPO burst, which was accumulated ~18-fold of treatment group in breast cancer cells. In vivo pharmacodynamic test results showed that this nanodevice with small particle size and high cytotoxicity increased Srfn circulation and shortened the period of epithelial cancer treatment.Conclusion: Ferroptosis therapy had a successful effect on EMT cells. These findings have great potential in the treatment of therapy-resistant epithelial cell carcinomas.

Targeting Lipid Peroxidation for Cancer Treatment

“…Due to iron's high reactivity, GSH oxidation induced by the metal should be considered a therapeutical approach and could be the main triggering factor leading to ferroptosis activation. Some reports have been published describing ferroptosis induction thought combination therapy where iron NPs are conjugated with ferroptosis inducers, such as the xc-cystine-glutamate exchanger's inhibitor Sorafenib, that induces glutathione depletion [240], as well as with drugs promoting lysosomes disruption [241,242]. NQO1 cannot compete with FSP1 in the reaction with hydrophilic peroxides, the situation is reversed when the substrate is lipid hydroperoxides.…”

Utilizing Iron for Targeted Lipid Peroxidation as Anticancer Option of Integrative Biomedicine: A Short Review of Nanosystems Containing Iron

“…Recently, Sang and coworkers developed ferroptosis amplifier nanodevices for cancer treatment. Mitochondria targeted the nanophotosensitizer complex containing superparamagnetic IONPs (SPIONs), and when loaded with Sorafenib, exhibited antitumor activity by inducing ROS formation, lipid peroxidation, and ferroptosis of therapy resistant epithelial-to-mesenchymal transition cells [43]. The same group later described another mitochondrial membrane that targeted a photosensitive nanodevice.…”

Superparamagnetic iron oxide nanoparticles promote ferroptosis of ischemic cardiomyocytes

“…Furthermore, SPION could elicit IL‐1βrelease and pyroptosis in macrophages, especially with the octapod and plate morphology 16 . Notably, it has been recently reported that sorafenib or cisplatin assembled into nano‐devices containing SPION, which are phagocytized by tumour cells and degraded into free divalent iron to accelerate Fenton reaction, leading to the lipid peroxidation burst to promote ferroptosis of tumour cells 17,18 …”