NIR-Ⅱ fluorescence visualization of ultrasound-induced blood–brain barrier opening for enhanced photothermal therapy against glioblastoma using indocyanine green microbubbles  

近红外二区荧光可视化超声联合吲哚菁绿微泡开放血脑屏障增强脑胶质瘤光热治疗

作　　者：Simin Liang Dehong Hu Guofeng Li Duyang Gao Fei Li Hairong Zheng Min Pan Zonghai Sheng 梁思敏;胡德红;黎国锋;高笃阳;李飞;郑海荣;潘敏;盛宗海(Department of Ultrasonography,Shenzhen Hospital(Futian)of Guangzhou University of Chinese Medicine,Shenzhen 518034,China;Paul C.Lauterbur Research Center for Biomedical Imaging,CAS Key Laboratory of Health Informatics,Shenzhen Key Laboratory of Ultrasound Imaging and Therapy,Institute of Biomedical and Health Engineering,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen 518055,China;School of Biomedical Engineering,Guangdong Medical University,Dongguan 523808,China)

机构地区：[1]Department of Ultrasonography,Shenzhen Hospital(Futian)of Guangzhou University of Chinese Medicine,Shenzhen 518034,China [2]Paul C.Lauterbur Research Center for Biomedical Imaging,CAS Key Laboratory of Health Informatics,Shenzhen Key Laboratory of Ultrasound Imaging and Therapy,Institute of Biomedical and Health Engineering,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen 518055,China [3]School of Biomedical Engineering,Guangdong Medical University,Dongguan 523808,China

出　　处：《Science Bulletin》2022年第22期2316-2326,共11页科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China (92159304, 82171958, 81901812, 81971638, 91859117, 82027803, and 81927807);CAS Key Laboratory of Health Informatics (2011DP173015);the Science and Technology Key Project of Shenzhen(JCYJ20190812163614809, JCYJ20200109114612308, JCYJ2021032 4120011030, JCYJ20190809105207439, JCYJ20220531091408019, and JCYJ20200109114825064);Guangdong Basic and Applied Basic Research Fund (2020A1515110011, 2020A1515010395, and 2022A1515010384);Key Laboratory for Magnetic Resonance and Multimodality Imaging of Guangdong Province (2020B1212060051);the Key Technology and Equipment R&D Program of Major Science and Technology Infrastructure of Shenzhen (202100102, 202100104);Discipline Construction Project of Guangdong Medical University (4SG21017G)

摘　　要：Focused ultrasound(FUS)-induced blood–brain barrier(BBB) opening is crucial for enhancing glioblastoma(GBM) therapies. However, an in vivo imaging approach with a high spatial–temporal resolution to monitor the BBB opening process in situ and synchronously is still lacking. Herein, we report the use of indocyanine green(ICG)-dopped microbubbles(MBs-ICG) for visualizing the FUS-induced BBB opening and enhancing the photothermal therapy(PTT) against GBM. The MBs-ICG show bright fluorescence in the second near-infrared window(NIR-II), ultrasound contrast, and ultrasound-induced size transformation properties. By virtue of complementary contrast properties, MBs-ICG can be successfully applied for cerebral vascular imaging with NIR-II fluorescence resolution of ~168.9 lm and ultrasound penetration depth of ~7 mm. We further demonstrate that MBs-ICG can be combined with FUS for in situ and synchronous visualization of the BBB opening with a NIR-II fluorescence signal-tobackground ratio of 6.2 ± 1.2. Finally, our data show that the MBs-ICG transform into lipid-ICG nanoparticles under FUS irradiation, which then rapidly penetrate the tumor tissues within 10 min and enhance PTT in orthotopic GBM-bearing mice. The multifunctional MBs-ICG approach provides a novel paradigm for monitoring BBB opening and enhancing GBM therapy.聚焦超声开放血脑屏障是增强胶质母细胞瘤治疗的关键,然而,缺乏一种高时空分辨率的体内成像方法用于原位同步监测血脑屏障开放过程.本文报道了使用吲哚菁绿掺杂的微泡(MBs-ICG)可视化聚焦超声开放血脑屏障和增强对抗胶质母细胞瘤的光热治疗方法.结果显示, MBs-ICG具有明亮的近红外二区荧光,超声造影成像和超声响应特性.利用其互补的成像特性, MBs-ICG可实现脑血管的高分辨率(~168.9μm)近红外二区荧光成像、大穿透深度(~7 mm)超声造影成像.通过近红外二区荧光成像, MBs-ICG联合聚焦超声可原位同步可视化血脑屏障开放,信噪比为6.2±1.2.此外,在聚焦超声辐照下, MBs-ICG转化为脂质ICG纳米颗粒,并在10 min内迅速进入肿瘤组织,成功用于增强原位胶质母细胞瘤小鼠的光热治疗.多功能MBs-ICG为监测血脑屏障开放和增强胶质母细胞瘤治疗提供了一种新的范式.

关 键 词：NIR-II fluorescence imaging ULTRASOUND Blood-brain barrier Brain tumor Photothermal therapy 

分 类 号：O657.3[理学—分析化学] R739.41[理学—化学]