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Theranostics 2021; 11(11):5418-5429. doi:10.7150/thno.53346 This issue Cite

Research Paper

Manganese-deposited iron oxide promotes tumor-responsive ferroptosis that synergizes the apoptosis of cisplatin

Junjie Cheng^1#, Yang Zhu^1#, Xin Xing^2#, Jianmin Xiao³, Hui Chen⁴, Hongwei Zhang¹, Dan Wang⁴, Yuanyuan Zhang⁵, Guilong Zhang^6✉, Zhengyan Wu^3✉, Yangzhong Liu^1✉

1. Department of Pharmacy, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine; Department of Chemistry, University of Science and Technology of China, Hefei 230001, China.
2. Department of Stomatology, the First Affiliated Hospital of Wannan Medical College, Wuhu 241000, China.
3. Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China.
4. Department of Dental Implant Center, Stomatologic Hospital & College, Key Laboratory of Oral Diseases Research of Anhui Province, Anhui Medical University, Hefei 230032, China.
5. School of Life Science, Anhui Medical University, Hefei 230032, China.
6. School of Pharmacy, the Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, Binzhou Medical University, Yantai 264003, China.
#These authors contributed equally to this work.

✉ Corresponding authors: Yangzhong Liu, E-mail: liuyzedu.cn; Zhengyan Wu, E-mail: zywuac.cn; Guilong Zhang, E-mail: glzhangedu.cn.

Abstract

Background: Ferroptosis is a form of iron-dependent programmed cell death that differs from apoptosis with regards to both mechanism and cell morphology. Therefore, ferroptotic-based cancer therapy has shown significant potential to overcome the weaknesses of conventional therapeutics mediated by apoptosis pathways. Effective ferroptosis can be induced by the intracellular Fenton reaction that is dependent on the adequate supply of iron ions and H₂O₂ in cells. However, these are often insufficient due to intrinsic cellular regulation.

Methods: In this study, we designed a cisplatin prodrug-loaded manganese-deposited iron oxide nanoplatform (Pt-FMO) to trigger intracellular cascade reactions that lead to generation of reactive oxygen species (ROS) to enhance ferroptotic effect. The Pt-FMO causes the tumor microenvironment responsive to release manganese, iron ions and Pt-drugs. As manganese is an element that is able to catalyze the Fenton reaction more effectively than iron, coupled with the Pt-drugs that can promote generation of H₂O₂ in cells, the Pt-FMO is expected to significantly strengthen catalysis of the Fenton reaction, which favors the ferroptotic effect. Moreover, the Pt-drugs will eventually function as cisplatin. Thus, Pt-FMO is an ideal candidate for tumor ferroptotic combined with apoptotic treatment.

Results: In vivo results demonstrated that, at a dosage of only 8.89% Pt content, Pt-FMO is able to achieve a similar treatment effect as cisplatin. Hence, Pt-FMO exhibited significantly lower systemic toxicity compared to cisplatin. Additionally, Pt-FMO exhibits effective T₂-weighted MRI enhancement for tumor imaging.

Conclusion: The Pt-FMO nanoplatform is designed to introduce mutual beneficial cascade reactions for promoting ferroptosis and apoptosis in combination with tumor MRI. The Pt-FMO system, which causes ferroptosis combined with apoptosis, can efficiently induce tumor cell death.

Keywords: cisplatin, ferroptosis, anticancer, theranostics, manganese

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