All-stage targeted nanodiscs for glioma treatment by inducing cuproptosis and apoptosis of cancer cells and cancer stem cells

Abstract

There remain several intractable challenges for chemotherapy in glioma treatment, including the blood-brain barrier (BBB), blood-brain tumor barrier (BBTB), and tumor heterogeneity caused by cancer stem cells (CSCs), which are resistant to conventional chemotherapy. Here, we established a nano strategy to kill glioma cells and CSCs, combining carfilzomib and bis(diethyldithiocarbamate)copper. The synergistic drug combination disturbed cell protein metabolism at different stages and induced apoptosis and cuproptosis. The Y-shaped targeting ligand pHA-VAP-modified nanodiscs were designed to help the chemotherapeutic agents cross the BBB/BBTB and finally accumulate in tumor site. This all-stage targeting and all-stage treatment nanomedicine significantly prolonged the survival in glioma-bearing mice and might inspire the rational design of advanced drug delivery platforms.

Keywords

Glioma / All-stage targeted therapy / Synergistic combination / Cancer stem cells / Ubiquitin-proteasome system / Cuproptosis

Conflicts of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Acknowledgments

This work was sponsored by Shanghai Education Commission Major Project (2017-01-07-00-07-E00052), National Natural Science Foundation of China (No.81773657), Shanghai Sailing Program (No. 20YF1404500) and Scientific Research Foundation of Huashan Hospital, Fudan University (No. 2019QD012). We thank the staff members (especially Jialin Duan and Lihui Xin) of the Electron Microscopy System at the National Facility for Protein Science in Shanghai (NFPS), Shanghai Advanced Research Institute, Chinese Academy of Sciences, China for providing technical support and assistance in data collection and analysis.

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ajps.2024.101010. The figures and tables with " S " before the serial number are included in the Supplementary material.

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