脑胶质瘤术后易复发，药物治疗因血脑屏障（BBB）也疗效不佳。开启BBB是提高脑胶质瘤诊疗效果的关键，低强度聚焦超声（LIFU）及局部NO释放可开放BBB。项目组前期基于“连续空化”制备了一种射频增效纳米微囊；设计了肿瘤微环境刺激响应的US/MRI双模态分子探针。基于此，拟通过新型酶催化聚合工艺，设计和构建以Fe3O4纳米颗粒为内核、外壳为纳米凝胶、同时包裹治疗基因和NO供体分子的杂化纳米凝胶诊疗剂。后者在LIFU作用下可释放NO，开启BBB。拟通过共聚焦、紫外-可见光谱等研究该诊疗剂在LIFU作用下NO的释放特性；利用生物电镜、荧光成像、共聚焦等研究NO辅助LIFU开放BBB机制。同时研究NO气体和Fe3O4内核实现US/MRI双模态成像的机制； 并利用免疫组化、蛋白印记、肿瘤生长曲线等探讨NO与治疗基因协同治疗作用的机制。以上研究将为实现脑胶质瘤诊疗一体化提供新的思路。

Brain glioma often recurs after surgery and is not sensitive to radiation therapy. Drug therapy also shows unsatisfactory efficacy due to blood brain barrier (BBB). To open the BBB is the key to improve the diagnostic and therapeutic efficacy to brain glioma. Low intensity focused ultrasound (LIFU) and local NO release is able to open the BBB. In previous work, basing on a continuous cavitation strategy, we obtained a type of “all in one” theranostic radiofrequency ablation enhancement nano-agent. Moreover, we successfully designed a tumor microenvironment-responsive US/MR dual-modal imaging probe and a structurally optimized US/CT/MRI tri-modal molecular probe, respectively. Basing on these experiences, in this project, we will design and construct a hybrid nanohydrogel-based theranostic agents consisting of Fe3O4 nanoparticles as the inner core and nanogel as the outer shell that encapsulates NO donor and therapeutic genes for brain glioma. Upon exposure to LIFU irradiation, NO release from the constructed theranostic agent will open the BBB. Confocal imaging and UV-Vis absorption spectrometer will be employed to investigate the NO release. Marriage of NO and LIFU for opening BBB and related mechanism will be evaluated and explored in detail via various methods, such as biological election microscopy, inductively coupled plasma-atomic emission spectrometry (ICP-AES), in vivo animal fluorescence imaging, confocal imaging, flow cytometroy, etc. Moreover, we will employ some approaches, e.g., signal variation of ultrasound and MR, immunohistochemistry, Western blot, tumor growth profile, etc., to implement investigations of ultrasound/MR dual-modal imaging and synergistic treatment of NO and therapeutic genes for brain glioma, and we expect related investigations in this project can provide a new method for ‘all in one’ theranostic investigation of brain glioma.