二级协同靶向吲哚菁绿纳米探针用于脑胶质瘤光学诊疗一体化研究

A precise and accurate diagnosis and treatment of glioma is a great strategic demand. The blood brain barrier (BBB) is main bottleneck for glioma, which prevents the intracerebral delivery of almost all exogenous macromolecules. Moreover, the growth nature of glioma is heterogeneous and infiltrative, which leads to being difficult for the precise resection of tumor from the surrounding healthy brain tissue during surgery. Here, we design an indocyanine green (ICG)-based theranostic nanoprobe for near-infrared (NIR) fluorescence/photoacoustic dual-modal imaging and synergistic phototherapy of glioma. The nanoprobe is prepared by a programmed assembly strategy using ICG and human serum albumin (HSA), which have been approved by the U.S. Food and Drug Administration (FDA). The tumor vasculature targeted cyclic [RGDyK] peptides, and BBB-permeable Angiopep-2 peptides are labeled on the ICG nanoprobe by click chemistry. The two-order targeted strategy accelerates BBB transverse of the nanoprobe. The glioma tissue and brain normal tissue can be clearly identified via ICG-based in vivo NIR fluorescence/photoacoustic dual-modal imaging and spectrum-resolved technology. Meanwhile, ICG nanoprobe can efficiently induce ROS and local hyperthermia simultaneously for synergetic PDT/PTT treatments under a single NIR laser irradiation. This project focuses on the theranostic nanoprobe effectively across the BBB, the combined the dual-modality imaging, margin detection, and imaging-guided phototherapy. Briefly, it provides a promising strategy for promoting the application of theranostic nanoprobe in glioma.

本项目面向脑胶质瘤精准诊疗的重大需求，针对脑胶质瘤血脑屏障和浸润性生长的生物学结构和特性，采用美国FDA批准的吲哚菁绿近红外荧光染料和人血清白蛋白，通过程序化自组装的方法，制备吲哚菁绿纳米颗粒。通过“点击化学”偶联肿瘤新生血管靶向RGD环肽和血脑屏障穿透肽Angiopep-2，构建二级协同靶向纳米探针，高效跨越血脑屏障，特异性结合脑胶质瘤细胞，实现人脑胶质瘤原位移植小鼠模型的近红外荧光/光声双模态成像，脑胶质瘤组织和脑正常组织影像学边界检测。在此基础上，通过成像引导激光精确聚焦在肿瘤组织，引发脑胶质瘤细胞中的吲哚菁绿纳米探针同时产生高温和活性氧，协同杀伤临近的癌细胞，实现脑胶质瘤的精准光学诊疗一体化。本项目重点解决吲哚菁绿诊疗一体化纳米探针高效跨越血脑屏障、双模态成像及肿瘤影像学边界检测、成像引导光学治疗等关键科学问题，对于推动诊疗一体化纳米探针在脑胶质瘤诊疗中的应用具有重要意义。

本项目面向脑胶质瘤精准诊疗的重大需求，针对脑胶质瘤血脑屏障和浸润性生长的生物学结构和特性，采用美国FDA批准的吲哚菁绿近红外荧光染料和人血清白蛋白，通过程序化自组装的方法，制备吲哚菁绿纳米颗粒。通过“点击化学”偶联肿瘤新生血管靶向RGD环肽和血脑屏障穿透肽Angiopep-2，构建二级协同靶向纳米探针，高效跨越血脑屏障，特异性结合脑胶质瘤细胞，实现人脑胶质瘤原位移植小鼠模型的近红外荧光/光声双模态成像，脑胶质瘤组织和脑正常组织影像学边界检测。在此基础上，通过成像引导激光精确聚焦在肿瘤组织，引发脑胶质瘤细胞中的吲哚菁绿纳米探针同时产生高温和活性氧，协同杀伤临近的癌细胞，实现脑胶质瘤的精准光学诊疗一体化。本项目重点解决吲哚菁绿诊疗一体化纳米探针高效跨越血脑屏障、双模态成像及肿瘤影像学边界检测、成像引导光学治疗等关键科学问题，对于推动诊疗一体化纳米探针在脑胶质瘤诊疗中的应用具有重要意义。