Fn14-AuNNP联合光热治疗克服放疗抵抗防治脑胶质瘤复发的功能及机制研究

局部复发是胶质母细胞瘤（GBM）放疗失败的主要模式，提高常规放疗剂量下肿瘤的辐射损伤效应是防治复发的关键。我们前期研究发现，恶性胶质瘤放射治疗后Fn14阳性肿瘤细胞呈活跃状态，是GBM残留/复发灶内肿瘤细胞的主体；新型纳米间隙金颗粒介导的光-热效应加剧了放疗引起的DNA损伤，延缓DSB修复。本项目拟在上述基础上，对AuNNP进行改构和Fn14靶向修饰，构筑具备近红外Ⅱ区光热效应的单抗-金纳米共轭物Fn14-AuNNP，利用辐射抵抗肿瘤细胞表面抗原抗体复合物介导的内吞作用实现纳米金的主动和被动靶向，以期在活体水平开展精准、无创的放疗/Ⅱ区光热联合治疗，靶向清除残存和复发灶内的肿瘤细胞。同时系统和动态地分析Fn14-AuNNP联合光热治疗对GBM细胞PI3K/Akt信号通路、DNA DSB修复及辐射敏感性的影响。本项目将有助于探索胶质瘤新的联合治疗模式，为肿瘤放射增敏和局部复发防治提供新策略。

Glioblastoma (GBM) is the most aggressive primary malignant brain tumor with poor prognosis. Although radiotherapy has brought the greatest improvement to the survival of these patients, local recurrence occurs in most patients due to radioresistant infiltrating cancer cells. Improving the radiation damage effect of conventional radiotherapy is the key to the prevention and treatment of recurrence. In our previous study, we found that the TNF receptor family member Fn14 positive tumor cells were active after radiotherapy in glioblastoma, which were the main population in residual / recurrent glioblastoma with radioresistance. Strikingly, photothermal therapy (PTT) mediated by a novel rod-in-shell nano-gapped gold nanoparticles (AuNNP) could significantly improve the radiosensitivity of GBM and prolong the duration of DNA DSB marker γ-H2AX in the nucleus, suggesting that photothermal therapy may play a radiosensitizing effect by aggravating DNA damage and inhibiting DSB repair. Moreover, we provided proof-of-principle evidence that the nanogap size plays a key role in tailoring the plasmonic coupling of core and shell toward broadly tunable LSPR across the visible and near-infrared (NIR) spectral range. These findings provide proof that localized hyperthermia administered using optically active AuNNP serves as a simple strategy to selectively sensitize GBM to radiotherapy. In this proposal, we will build on these discoveries to fabricate nanotechnology-based, Fn14 targeting and responsible to the second NIR windows nanoparticles, Fn14-GNPs. We tailor the UV-vis-NIR spectrum of the rod-in-shell structure by changing the gap distance between the Au NR core and the Au nanoshell, to enable the therapeutic effect of using a 1064 nm diode laser. Model systems will employ patient-derived tumor xenografts to assess the efficacy of NIR II PTT in removing the main body of residual and recurrent tumor cells in the peritumoral brain area. We characterize whether synergic photothermal and radiotherapy leads to the inhibition of the PI3K/Akt oncogenic signalling pathway, deceleration of DNA DSB repair and enhancement of GBM radiosensitivity or not. Findings are expected to advance our understanding of the molecular mechanisms of PTT radiosensitization and provide a promising strategy for radiosensitization of glioblastoma.