靶向调控血脑屏障通透性实现影像指导下脑肿瘤递药

The high mortality and recurrence rate of brain tumor are mainly resulted from the blood-brain barrier (BBB) that prevents the efficient drug delivery into the brain. Conventional strategies of the intracerebral drug delivery demonstrate the drawbacks including non-targeting specificity, compromised delivery efficacy and potential systemic toxicity. Brain tumor targeted drug delivery is crucial to achieve the satisfactory therapeutic efficacy. In this work, we plan to develop a nanoprobe to realize the image-guided brain tumor targeted drug delivery by spatially and temporally tuning the BBB permeability. The latest research work demonstrated that activation of the adenosine A2A receptor on the brain capillary endothelial cells leads to the cytoskeleton re-organization followed the BBB permeability increasing. Therefore, the aiming nanoprobe labeled the tumor neovasculature targeted c[RGDyK] peptide, the agonist of adenosine A2A receptor and imaging reporters not only can visualize the brain tumor with high targeting specificity, but also locally up-regulate the BBB permeability on the tumor periphery. After the nanoprobe injection, single-photon emission computed tomography (SPECT)/CT helps to determine the BBB opening time-window of a specific nanoprobe and clarify the relationship between labeling degree of the agnoist and length of BBB opening time by quantitatively monitoring the intracerebral delivery of the radioactive model drug. Based on the circulation lifetime of a therapeutic drug, it is possible to achieve its brain tumor targeted delivery with safety and high efficacy by choosing a nanoprobe with a suitable BBB opening time-window. Overall, this project holds promise to visualize the brain tumor with high signal to background ratio, enhance the therapeutic efficacy and accelerate the clinical translation of the individualized treatment of the brain tumor.

血脑屏障（BBB）阻止药物入脑是脑肿瘤高复发率、高死亡率的主要原因。传统跨BBB递药存在无靶向性、低效和安全性差等缺点。实现药物跨BBB靶向递送是提高脑肿瘤疗效的关键。本项目拟构建一类可区域性和时间性调控BBB通透性的纳米探针实现影像指导下脑肿瘤靶向递药。最新研究发现激活脑血管内皮细胞上腺苷A2A受体可引发细胞骨架收缩以提高BBB通透性，因此标记有靶向肿瘤新生血管RGD环肽、腺苷受体激动剂和影像基团的目标探针可实现脑肿瘤靶向示踪并开启肿瘤外周BBB，从而实现治疗药物高效递送。探针注射后，通过单光子发射计算机断层（SPECT）/CT成像监测模型药物入脑量可确定探针开启BBB时间窗口，并揭示探针激动剂标记数目与BBB开启时间的相关性。根据治疗药物血液滞留时间选择BBB开启窗口适合的探针可实现不同类型药物的高效、安全递送。本项目对实现脑肿瘤高信噪比示踪，促进个性化治疗方案临床转化均具有重要意义。

胶质瘤是最常见的脑原位恶性肿瘤,具有疗效不佳、复发率高、死亡率高等特点。胶质瘤浸润边缘血脑屏障往往相对完整，阻碍药物的高效入瘤并发挥疗效。我们紧扣任务书中研究目标，在血脑屏障通透性调控新方法，跨血脑屏障胶质瘤递药新策略和胶质瘤精确切除导航探针等方面获得系列进展。（1）对14例胶质瘤病人肿瘤浸润区域组织免疫组化发现不同级别胶质瘤边缘均存在完整的血脑屏障结构，证实调控血脑屏障通透性达到提高药物递送效率的必要性。（2）发展调控血脑屏障通透性的新方法。制备特异性激活腺苷2A受体的纳米激动剂，其不但能够高效、可逆、安全开启脑毛细血管内皮细胞间的紧密连接，提高血脑屏障通透性，还能够根据药物药代性质调控血脑屏障开启时间窗口，避免过量给药造成毒副作用；（3）构建靶向调控胶质瘤边缘血脑屏障通透性并提高药物递送效率新策略。利用多种无创影像学技术监测血脑屏障通透性、药物靶向递送效率和治疗疗效；（4）构建了pH响应双模态探针。利用表面增强共振拉曼成像的超高灵敏度和磁共振成像高空间分辨率同时进行手术前的胶质瘤定位和手术中切除导航。与目前临床使用的手术导航策略相比，有效避免开颅手术中病人头部移动导致导航信号失真。本课题共发表标注有本基金号SCI收录论文13篇，其中，IF＞10的文章2篇，IF＞5的9篇。申请中国专利5篇，获授权1项。本项目还获得国家科技进步二等奖一项（项目负责人排名第2），获得3次国际会议口头报告邀请。培养博士研究生1名，硕士研究生3名。培养研究生获得3项国家奖学金。本项目研究围绕脑胶质瘤血脑屏障通透性调控科学问题，在胶质瘤的早期诊断、手术导航、精准递药和疗效评估等方面开展研究，所获成果对实现胶质瘤的早期干预、提高手术和化疗预后均有重要的研究和临床意义。