新型靶向探针GMT8-Ag@Au的构建及其在脑胶质瘤CT成像和辐射增敏一体化中的实验研究

Glioma is the most common intracranial malignant tumor and its prognosis is very poor due to high postoperative recurrent rate, insensitivity to chemotherapy and radiotherapy. In the clinic, effective enhancement of radiosensitivity in glioma cells and of target killing is still an unsolved problem. On the other hand, theranostics provides a new strategy for diagnosis and therapy of glioma. In this study, we will construct GMT8-Ag@Au molecular nanoprobe by coupling PEGylated silver-gold (core-shell) composite nanoparticles with aptamer GMT8, which is capable of targeting gliomas. The in vivo biocompatibility, distribution and metabolism, the cellular uptake and its mechanisms, the ability of in vitro/in vivo CT imaging, radiosensitizing effects on glioma, and the molecular mechanisms of radiosensitization of the probe will be investigated. For the in vivo theranostic study, the blood-brain barrier will be opened by ultrasound plus microbubbles. Our study will provide an experimental basis for the development of glioma-targeted theranostic multi-functional nanoprobes.

脑胶质瘤是颅内最常见的恶性肿瘤，由于术后复发率高，对化疗和辐射不敏感，故患者的预后极差。如何增强胶质瘤细胞的辐射敏感性，有效提高射线对肿瘤细胞的特异性杀伤是当今临床面临的难题之一。另一方面，诊疗一体化的理念为突破脑胶质瘤传统的诊断与治疗模式提供了新的思路。.本项目拟开展：①靶向胶质瘤细胞的适配体GMT8与PEG化银核金壳纳米颗粒偶联的分子探针（GMT8-Ag@Au）的制备；②生物相容性、体内分布及代谢规律；③细胞摄取及其机制，体外CT造影及辐射增敏杀伤胶质瘤细胞的能力；④拟以超声联合微泡开放血脑屏障，体内CT成像及辐射增敏抑瘤效果；⑤辐射增敏的分子机制。本研究为探索脑胶质瘤诊疗一体化的多功能纳米制剂提供实验以及理论依据。

胶质瘤恶性程度高，呈浸润性生长，手术难以完全切除。辐射治疗是胶质瘤重要治疗手段之一，但大部分胶质瘤对射线不敏感，辐射治疗效果亦不佳。如何增强胶质瘤细胞的辐射敏感性，有效提高射线对肿瘤细胞的特异性杀伤，一直是临床上亟待解决的热点问题。另一方面，目前临床上相对分离的诊断与治疗模式可能贻误最佳治疗时机，增加患者不必要的痛苦和风险，且在治疗过程中不能同步、动态跟踪治疗效果。.本研究旨在构建一种多功能纳米探针（GMT8-Ag@Au），探讨其对胶质瘤体内和体外CT成像与辐射增敏治疗的可行性，并研究GMT8-Ag@Au辐射增敏的可能机制。.本研究结果发现：.1. 制备的GMT8-Ag@Au具有良好的生物相容性和胶质瘤细胞靶向性，其内吞途径是由网格蛋白、陷窝蛋白及巨胞饮介导；.2. GMT8-Ag@Au提高了射线对胶质瘤细胞的特异性杀伤，进而延长了荷瘤鼠生存期，同时对肿瘤CT扫描影像有增强效应，显示了GMT8-Ag@Au的胶质瘤体内外辐射增敏抑瘤及CT成像潜能；.3. GMT8-Ag@Au通过活性氧介导的JNK信号通路诱导细胞凋亡发挥其辐射增敏作用。.本研究将为兼具肿瘤诊断和治疗功能的新型纳米探针的研发提供借鉴意义。