Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, 215123, P.R. China.
Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, 215123, P.R. China; College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, P.R. China.
Biomaterials. 2022 Jan;280:121287. doi: 10.1016/j.biomaterials.2021.121287. Epub 2021 Nov 29.
Radio-resistance of glioblastoma (GBM) remains a leading cause of radiotherapy failure because of the protective autophagy induced by X-Ray irradiation and tumor cells' strong capability of repairing damaged DNA. It is of great importance to overcome the radio-resistance for improving the efficacy of radiotherapy. Herein, we report the novel mechanism of core-shell copper selenide coated gold nanoparticles (Au@CuSe NPs) inhibiting the protective autophagy and DNA repair of tumor cells to drastically boost the radiotherapy efficacy of glioblastoma. We reveal that the core-shell Au@CuSe NPs can inhibit the autophagy flux by effectively alkalizing lysosomes. They can increase the SQSTM1/p62 protein levels of tumor cells without influencing their mRNA. We also reveal that Au@CuSe NPs can increase the ubiquitination of DNA repair protein Rad51, and promote the degradation of Rad51 by proteasomes to prevent the DNA repair. The simultaneous inhibition of protective autophagy and DNA repair significantly suppress the growth of orthotopic GBM by using radiotherapy and our novel Au@CuSe NPs. Our work provides a new insight and paradigm to significantly improve the efficacy of radiotherapy by rationally designing theranostic nano-agents to simultaneously inhibit protective autophagy and DNA repair of tumor cells.
脑胶质瘤（GBM）的放射抵抗仍然是放射治疗失败的主要原因，这是由于 X 射线照射诱导的保护性自噬和肿瘤细胞修复受损 DNA 的能力很强。克服放射抵抗对于提高放射治疗的疗效非常重要。本文报道了核壳结构的硒化铜包覆金纳米粒子（Au@CuSe NPs）抑制肿瘤细胞保护性自噬和 DNA 修复的新机制，从而极大地提高了脑胶质瘤的放射治疗效果。我们揭示了核壳结构的 Au@CuSe NPs 可以通过有效碱化溶酶体来抑制自噬流。它们可以增加肿瘤细胞的 SQSTM1/p62 蛋白水平，而不影响其 mRNA。我们还揭示了 Au@CuSe NPs 可以增加 DNA 修复蛋白 Rad51 的泛素化，并通过蛋白酶体促进 Rad51 的降解，从而防止 DNA 修复。通过放疗和我们新的 Au@CuSe NPs 同时抑制保护性自噬和 DNA 修复，显著抑制了原位 GBM 的生长。我们的工作为通过合理设计治疗性纳米制剂来同时抑制肿瘤细胞的保护性自噬和 DNA 修复，从而显著提高放射治疗的疗效提供了新的见解和范例。
