Theranostics 2019; 9(21):6209-6223. doi:10.7150/thno.36283

Research Paper

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

Mangmang Sang1, Renjie Luo1, Yidan Bai1, Jun Dou1, Zhongtao Zhang2, Fulei Liu3,4, Feng Feng2,5,✉, Jian Xu2,✉, Wenyuan Liu1,6✉

1. Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China
2. Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China
3. The Joint Laboratory of Chinese Pharmaceutical University and Taian City Central Hospital, Taian City Central Hospital, Taian, 271000, China
4. Pharmaceutical Department, Taian City Central Hospital, Taian, 271000, China
5. Jiangsu Food & Pharmaceutical Science College, 4 Meicheng Donglu, Huaian 223003, China
6. Hangzhou Institute of Pharmaceutical Innovation, China Pharmaceutical University, 291 Fucheng Lu, Hangzhou 310018, China

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Citation:
Sang M, Luo R, Bai Y, Dou J, Zhang Z, Liu F, Feng F, Xu J, Liu W. Mitochondrial membrane anchored photosensitive nano-device for lipid hydroperoxides burst and inducing ferroptosis to surmount therapy-resistant cancer. Theranostics 2019; 9(21):6209-6223. doi:10.7150/thno.36283. Available from http://www.thno.org/v09p6209.htm

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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.

Keywords: Ferroptosis, lipid hydroperoxides, epithelial-to-mesenchymal transition