Department of Medical Biophysics, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada.
Department of Chemical and Biological Engineering, Princeton University, 50-70 Olden St, Princeton, NJ, 08540, USA.
Mol Imaging Biol. 2020 Apr;22(2):324-334. doi: 10.1007/s11307-019-01397-4.
Blood-brain barrier disruption (BBBD) is of interest for treating neurodegenerative diseases and tumors by enhancing drug delivery. Focused ultrasound (FUS) is a powerful method to alleviate BBB challenges; however, the detection of BBB opening by non-invasive methods remains limited. The purpose of this work is to demonstrate that 3D transcranial color Doppler (3DCD) and photoacoustic imaging (PAI) combined with custom-made nanoparticle (NP)-mediated FUS delivery can detect BBBD in mice.
We use MRI and stereotactic ultrasound-mediated BBBD to create and confirm four openings in the left hemisphere and inject intravenously indocyanine green (ICG) and three sizes (40 nm, 100 nm, and 240 nm in diameter) of fluorophore-labeled NPs. We use PAI and fluorescent imaging (FI) to assess the spatial distribution of ICG/NPs in tissues.
A reversible 41 ± 12 % (n = 8) decrease in diameter of the left posterior cerebral artery (PCA) relative to the right after FUS treatment is found using CD images. The spectral unmixing of photoacoustic images of the in vivo (2 h post FUS), perfused, and ex vivo brain reveals a consistent distribution pattern of ICG and NPs at *FUS locations. Ex vivo spectrally unmixed photoacoustic images show that the opening width is, on average, 1.18 ± 0.12 mm and spread laterally 0.49 ± 0.05 mm which correlated well with the BBB opening locations on MR images. In vivo PAI confirms a deposit of NPs in tissues for hours and potentially days, is less sensitive to NPs of lower absorbance at a depth greater than 3 mm and too noisy with NPs above an absorbance of 85.4. FI correlates well with ex vivo PAI to a depth of 3 mm in tissues for small NPs and 4.74 mm for large NPs.
3DCD can monitor BBBD over time by detecting reversible anatomical changes in the PCA. In vivo 3DPAI at 15 MHz combined with circulating ICG and/or NPs with suitable properties can assess BBB opening 2 h post FUS.
通过增强药物输送，血脑屏障破坏（BBBD）在治疗神经退行性疾病和肿瘤方面引起了人们的兴趣。聚焦超声（FUS）是一种缓解 BBB 挑战的强大方法；然而，通过非侵入性方法检测 BBB 开放仍然有限。本工作旨在证明 3D 经颅彩色多普勒（3DCD）和光声成像（PAI）结合定制的纳米颗粒（NP）介导的 FUS 传递可以检测小鼠的 BBBD。
我们使用 MRI 和立体定向超声介导的 BBBD 在左半球创建并确认四个开口，并静脉注射吲哚菁绿（ICG）和三种尺寸（直径为 40nm、100nm 和 240nm）的荧光标记 NP。我们使用 PAI 和荧光成像（FI）评估 ICG/NP 在组织中的空间分布。
在 FUS 治疗后，通过 CD 图像发现左侧大脑后动脉（PCA）相对于右侧的直径可逆性减少 41±12%（n=8）。体内（FUS 后 2 小时）、灌注和离体脑的光声图像的光谱解混揭示了 ICG 和 NP 的一致分布模式在*FUS 位置。离体光谱解混的光声图像显示，开口宽度平均为 1.18±0.12mm，向侧面扩展 0.49±0.05mm，与 MR 图像上的 BBB 开口位置很好地相关。体内 PAI 可在数小时甚至数天内确认 NP 在组织中的沉积，对深度大于 3mm 处吸收较低的 NP 不太敏感，而对吸收高于 85.4 的 NP 则噪声较大。FI 与离体 PAI 在组织中 3mm 深处的小 NP 和 4.74mm 深处的大 NP 深度相关性良好。
3DCD 可以通过检测 PCA 中可逆的解剖结构变化来随时间监测 BBBD。在 15MHz 时，体内 3DPAI 结合循环 ICG 和/或具有合适特性的 NP 可以在 FUS 后 2 小时评估 BBB 开口。
