Real-time near-infrared fluorescence imaging using cRGD-ZW800-1 for intraoperative visualization of multiple cancer types.
Real-time near-infrared fluorescence imaging using cRGD-ZW800-1 for intraoperative visualization of multiple cancer types.
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DOI：
10.18632/oncotarget.15486
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发表时间：
2017-03-28
期刊：
影响因子：
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通讯作者：
Vahrmeijer AL
中科院分区：
文献类型：
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作者：
Handgraaf HJM;Boonstra MC;Prevoo HAJM;Kuil J;Bordo MW;Boogerd LSF;Sibinga Mulder BG;Sier CFM;Vinkenburg-van Slooten ML;Valentijn ARPM;Burggraaf J;van de Velde CJH;Frangioni JV;Vahrmeijer AL
不完全切除和关键结构损伤会增加癌症患者的发病率和死亡率。有针对性的术中荧光成像通过提供肿瘤和重要结构的实时可视化来帮助外科医生。本研究评估了肿瘤靶向两性离子近红外荧光肽 cRGD-ZW800-1 作为多种癌症类型术中成像的示踪剂。 cRGD-ZW800-1 在胶质母细胞瘤 (U-87 MG) 和结直肠 (HT-29) 细胞系上进行了体外验证。随后，在患有 HT-29、乳腺癌 (MCF-7)、胰腺 (BxPC-3) 和口腔 (OSC-19) 肿瘤的原位小鼠模型中测试了示踪剂。异种移植肿瘤模型中的剂量范围研究，包括 0.25、1.0、10 和 30 nmol 的剂量，表明最佳剂量为 10 nmol，相当于人体等效剂量 63 μg/kg，以及注射后 2 至 24 小时之间的最佳成像窗口。 cRGD-ZW800-1在血液中的平均半衰期为25分钟。 4 小时时的生物分布显示肿瘤和肾脏中的荧光信号最高。体外和体内竞争实验显示，当 U-87 MG 细胞（负 36%，p = 0.02）或 HT-29 荷瘤小鼠（TBR 4 小时 3.2 ± 0.5 vs 1.8 ± 0.4，p = 0.03）同时用未标记的 cRGD 处理时，荧光信号显着降低。 cRGD-ZW800-1 可在小鼠体内显示所有结直肠癌、乳腺癌、胰腺癌和口腔肿瘤异种移植物。筛选脱靶相互作用后，cRGD-ZW800-1 仅显示出对 COX-2 的抑制作用，这可能是由于 cRGD-ZW800-1 与整合素 αVβ3 的结合所致。由于cRGD-ZW800-1能够识别在恶性细胞和新生血管生成细胞上表达的各种整合素，因此预计cRGD-ZW800-1将提供一种敏感且通用的工具来在手术期间可视化癌症。
Incomplete resections and damage to critical structures increase morbidity and mortality of patients with cancer. Targeted intraoperative fluorescence imaging aids surgeons by providing real-time visualization of tumors and vital structures. This study evaluated the tumor-targeted zwitterionic near-infrared fluorescent peptide cRGD-ZW800-1 as tracer for intraoperative imaging of multiple cancer types. cRGD-ZW800-1 was validated in vitro on glioblastoma (U-87 MG) and colorectal (HT-29) cell lines. Subsequently, the tracer was tested in orthotopic mouse models with HT-29, breast (MCF-7), pancreatic (BxPC-3), and oral (OSC-19) tumors. Dose-ranging studies, including doses of 0.25, 1.0, 10, and 30 nmol, in xenograft tumor models suggest an optimal dose of 10 nmol, corresponding to a human equivalent dose of 63 μg/kg, and an optimal imaging window between 2 and 24 h post-injection. The mean half-life of cRGD-ZW800-1 in blood was 25 min. Biodistribution at 4 h showed the highest fluorescence signals in tumors and kidneys. In vitro and in vivo competition experiments showed significantly lower fluorescence signals when U-87 MG cells (minus 36%, p = 0.02) or HT-29 tumor bearing mice (TBR at 4 h 3.2 ± 0.5 vs 1.8 ± 0.4, p = 0.03) were simultaneously treated with unlabeled cRGD. cRGD-ZW800-1 visualized in vivo all colorectal, breast, pancreatic, and oral tumor xenografts in mice. Screening for off-target interactions, cRGD-ZW800-1 showed only inhibition of COX-2, likely due to binding of cRGD-ZW800-1 to integrin αVβ3. Due to its recognition of various integrins, which are expressed on malignant and neoangiogenic cells, it is expected that cRGD-ZW800-1 will provide a sensitive and generic tool to visualize cancer during surgery.