“矛/盾”功能转换型纳米系统逆转脑胶质瘤与神经细胞放疗敏感性及机制研究

Radiosensitivity of nerve cells is higher than that of glioma cells, which is the bottleneck of glioma radiotherapy. The essence is the difference of reactive oxygen species (ROS) and oxygen content. Based on this key issue, Mn3O4 nanoparticles with antioxidant enzyme activity were proposed as "regulators" of ROS levels in two cells, the oxygen transporter hemoglobin (Hb) was coupled to the surface of Mn3O4 and modified TGN peptides that efficiently cross the blood-brain barrier (BBB), constructing a small-sized and efficient brain-entry nanosystem. In nerve cells, Mn3O4 maintains nanozyme activity and effectively scavenges ROS, which reduces the radiosensitivity. In glioma cells, Mn3O4 is rapidly degraded by high concentration of glutathione (GSH), losing its antioxidant activity and ROS scavenging ability, and at the same time the consumption of GSH increases ROS, which increases the radiosensitivity; and then exerts its "spear/shield" function conversion. In addition, Hb increased the biocompatibility of Mn3O4, which in turn increased the oxygen-carrying stability of Hb, and then selectively increased the oxygen content of glioma, finally synergizes Mn3O4 to reverse the radiosensitivity of both cells. Clarifying the mechanism of reversaling radiosensitivity through research on its degradation behavior, ROS regulation ability and stable oxygen supply rule, which provided a new strategy for attenuating and enhancing radiotherapy of glioma.

神经细胞放疗敏感性高于脑胶质瘤细胞是制约脑胶质瘤放疗的瓶颈，其本质由两者的活性氧（ROS）水平和氧含量差异所致。鉴于此，本项目拟以具有抗氧化酶活性的Mn3O4纳米粒作为两种细胞ROS水平“调控器”，将氧转运载体血红蛋白（Hb）偶联至Mn3O4表面并修饰高效跨血脑屏障的TGN肽，构建小尺寸高效入脑的纳米系统。在神经细胞内Mn3O4保持纳米酶活性高效清除ROS，降低放疗敏感性；在胶质瘤细胞内Mn3O4被高浓度谷胱甘肽(GSH)快速降解，丧失抗氧化活性及ROS清除能力，同时由于消耗GSH而使ROS升高，增加放疗敏感性，发挥其“矛/盾”功能转换。此外，Hb增加Mn3O4生物相容性，Mn3O4反过来增加Hb携氧稳定性，选择性提高胶质瘤氧含量，协同Mn3O4逆转两者的放疗敏感性。通过对纳米系统降解行为、ROS调控能力及稳定供氧规律等研究，阐明其逆转放疗敏感性机制，为脑胶质瘤的减毒增效放疗提供新策略。

项目围绕肿瘤高抗氧化和乏氧特性限制ROS治疗效果的问题，成功构建“矛/盾”功能转换型Mn3O4纳米酶，阐明了其逆转肿瘤与正常细胞放疗敏感性差异的规律，同时实现了对正常细胞的放疗保护和对肿瘤细胞的放疗增敏；进一步研究了Mn3O4纳米酶降解释放的锰离子的类芬顿反应特性和对cGAS-STING激活的促进特性，并将该特性延伸应用到增强ROS治疗和肿瘤免疫治疗等相关治疗方式上。同时，针对肿瘤乏氧的问题，我们也发展了不依赖氧气的ROS产生体系、钙离子抑制有氧呼吸缓解乏氧等策略，有效逆转了肿瘤乏氧抗性。此外，也拓展了通过肿瘤细胞内铁离子干扰策略提高ROS治疗的研究，上述研究为克服肿瘤抗性提高ROS临床治疗收益提供新思路和实验支撑。通过本项目的支持，申请人以第一或通讯作者在Advanced Materials, Nano Letters, Advanced Functional Materials, Theranostics, Acta Pharmaceutica Sinica B等期刊发表SCI论文8篇，并入选了河南省自然科学优秀学术论文奖。