CAS Key Laboratory of Molecular Imaging, Beijing Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, China.
Eur J Nucl Med Mol Imaging. 2022 Nov;49(13):4325-4337. doi: 10.1007/s00259-022-05890-x. Epub 2022 Jul 15.
The surgery of glioblastoma (GBM) requires a maximal resection of the tumor when it is safe and feasible. The infiltrating growth property of the GBM makes it a challenge for neurosurgeons to identify the tumor tissue even with the assistance of the surgical microscope. This highlights the urgent requirement for imaging techniques that can differentiate tumor tissues during surgery in real time. Fluorescence image-guided surgery of GBM has been investigated using several non-specific fluorescent probes that emit light in the visible and the first near-infrared window (NIR-I, 700-900 nm), which limit the detection accuracy because of the non-specific targeting mechanism and spectral characteristics. Targeted NIR-II (1000-1700 nm) fluorescent probes for GBM are thus highly desired. The folate receptor (FR) has been reported to be upregulated in GBM, which renders it to be a promising target for specific tumor imaging.
In this study, the folic acid (FA) that can target the FR was conjugated with the clinically approved indocyanine green (ICG) dye and DOTA chelator for radiolabeling with Cu to achieve targeted positron emission tomography (PET) and fluorescence imaging of GBM.
Surprisingly it was found that the resulted bioconjugate, DOTA-FA-ICG and non-radioactive Cu-DOTA-FA-ICG, were both self-assembled into nanoparticles with NIR-II emission signal. The radiolabeled DOTA-FA-ICG, Cu-DOTA-FA-ICG, was found to specifically accumulate in the orthotopic GBM models using in vivo PET, NIR-II, and NIR-I fluorescence imaging. The best time window of fluorescence imaging was demonstrated to be 24 h after DOTA-FA-ICG injection. NIR-II fluorescence image-guided surgery was successfully conducted in the orthotopic GBM models using DOTA-FA-ICG. All the fluorescent tissue was removed and proved to be GBM by the H&E examination.
Overall, our study demonstrates that the probes, Cu-DOTA-FA-ICG and DOTA-FA-ICG, hold promise for preoperative PET examination and intraoperative NIR-II fluorescence image-guided surgery of GBM, respectively.
在安全可行的情况下，胶质母细胞瘤（GBM）的手术需要最大限度地切除肿瘤。GBM 的浸润性生长特性使得神经外科医生即使在手术显微镜的帮助下，也难以识别肿瘤组织。这就迫切需要能够在手术过程中实时区分肿瘤组织的成像技术。已经使用几种在可见和近红外第一窗口（NIR-I，700-900nm）中发射光的非特异性荧光探针研究了 GBM 的荧光图像引导手术，这限制了检测精度，因为非特异性靶向机制和光谱特征。因此，非常需要针对 NIR-II（1000-1700nm）的 GBM 荧光探针。已经报道叶酸受体（FR）在 GBM 中上调，使其成为特定肿瘤成像的有前途的靶标。
在这项研究中，叶酸（FA）可靶向 FR，与临床批准的吲哚菁绿（ICG）染料和 DOTA 螯合剂缀合，并用 Cu 进行放射性标记，以实现 GBM 的靶向正电子发射断层扫描（PET）和荧光成像。
令人惊讶的是，发现所得的生物缀合物 DOTA-FA-ICG 和非放射性 Cu-DOTA-FA-ICG 都自组装成具有 NIR-II 发射信号的纳米颗粒。放射性标记的 DOTA-FA-ICG、Cu-DOTA-FA-ICG 被发现能够通过体内 PET、NIR-II 和 NIR-I 荧光成像在原位 GBM 模型中特异性积累。荧光成像的最佳时间窗口被证明是 DOTA-FA-ICG 注射后 24 小时。使用 DOTA-FA-ICG 成功地在原位 GBM 模型中进行了 NIR-II 荧光图像引导手术。所有荧光组织均被切除，并通过 H&E 检查证明为 GBM。
总的来说，我们的研究表明，探针 Cu-DOTA-FA-ICG 和 DOTA-FA-ICG 分别有望用于 GBM 的术前 PET 检查和术中 NIR-II 荧光图像引导手术。
